ORCID Profile
0000-0002-7773-4155
Current Organisations
Peter MacCallum Cancer Centre
,
University of Western Australia
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Publisher: Elsevier BV
Date: 11-1998
Publisher: Elsevier BV
Date: 08-2006
DOI: 10.1016/J.CANLET.2005.09.003
Abstract: A functional T to G germline polymorphism in the promoter region of MDM2 (SNP309) has been reported to profoundly accelerate tumor formation suggesting that it may also represent a powerful cancer predisposing allele. To investigate the role of SNP309 in cancer predisposition we undertook a case-control study of this polymorphism among 351 women diagnosed with breast cancer, 302 women diagnosed with ovarian and 258 female controls from a British population. The GG genotype was not associated with either breast cancer (OR 1.04, 95% CI 0.67-1.60) or ovarian cancer (OR 0.86, 95% CI 0.53-1.37). This study has found no evidence that the GG genotype of the MDM2 SNP309 polymorphism is associated with early onset or familial breast cancer or with ovarian cancer.
Publisher: Springer Science and Business Media LLC
Date: 12-05-2021
DOI: 10.1038/S41523-021-00255-3
Abstract: Bi-allelic loss-of-function (LoF) variants in the base excision repair (BER) gene NTHL1 cause a high-risk hereditary multi-tumor syndrome that includes breast cancer, but the contribution of heterozygous variants to hereditary breast cancer is unknown. An analysis of 4985 women with breast cancer, enriched for familial features, and 4786 cancer-free women revealed significant enrichment for NTHL1 LoF variants. Immunohistochemistry confirmed reduced NTHL1 expression in tumors from heterozygous carriers but the NTHL1 bi-allelic loss characteristic mutational signature (SBS 30) was not present. The analysis was extended to 27,421 breast cancer cases and 19,759 controls from 10 international studies revealing 138 cases and 93 controls with a heterozygous LoF variant (OR 1.06, 95% CI: 0.82–1.39) and 316 cases and 179 controls with a missense variant (OR 1.31, 95% CI: 1.09–1.57). Missense variants selected for deleterious features by a number of in silico bioinformatic prediction tools or located within the endonuclease III functional domain showed a stronger association with breast cancer. Somatic sequencing of breast cancers from carriers indicated that the risk associated with NTHL1 appears to operate through haploinsufficiency, consistent with other described low-penetrance breast cancer genes. Data from this very large international multicenter study suggests that heterozygous pathogenic germline coding variants in NTHL1 may be associated with low- to moderate- increased risk of breast cancer.
Publisher: Springer Science and Business Media LLC
Date: 26-11-2001
DOI: 10.1038/NG784
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-07-2017
Abstract: In May 2016, the Division of Cancer Prevention and the Division of Cancer Control and Population Sciences, National Cancer Institute, convened a workshop to discuss a conceptual framework for identifying and genetically testing previously diagnosed but unreferred patients with ovarian cancer and other unrecognized BRCA1 or BRCA2 mutation carriers to improve the detection of families at risk for breast or ovarian cancer. The concept, designated Traceback, was prompted by the recognition that although BRCA1 and BRCA2 mutations are frequent in women with ovarian cancer, many such women have not been tested, especially if their diagnosis predated changes in testing guidelines. The failure to identify mutation carriers among probands represents a lost opportunity to prevent cancer in unsuspecting relatives through risk-reduction intervention in mutation carriers and to provide appropriate reassurances to noncarriers. The Traceback program could provide an important opportunity to reach families from racial, ethnic, and socioeconomic groups who historically have not sought or been offered genetic counseling and testing and thereby contribute to a reduction in health disparities in women with germline BRCA mutations. To achieve an interdisciplinary perspective, the workshop assembled international experts in genetics, medical and gynecologic oncology, clinical psychology, epidemiology, genomics, cost-effectiveness modeling, pathology, bioethics, and patient advocacy to identify factors to consider when undertaking a Traceback program. This report highlights the workshop deliberations with the goal of stimulating research and providing a framework for pilot studies to assess the feasibility and ethical and logistical considerations related to the development of best practices for implementation of Traceback studies.
Publisher: Research Square Platform LLC
Date: 15-03-2021
DOI: 10.21203/RS.3.RS-294874/V1
Abstract: Background: While protein truncating variants in RAD51C have been shown to predispose to triple negative breast cancer (TNBC) and ovarian cancer, little is known about the pathogenicity of missense (MS) variants. Methods: The frequency of rare RAD51C MS variants were assessed in the BEACCON study of 5,734 familial breast cancer cases and 14,382 population controls, and integrated with tumour sequencing data from 21 cases carrying a candidate variant to assess bi-allelic inactivation. Results: Collectively, a significant enrichment of rare missense variants was detected in cases (MAF 0.001, OR 1.57, 95%CI 1.00 - 2.44, p = 0.05), particularly for variants with a REVEL score 0.5 (OR 3.95, 95%CI 1.40 - 12.01, p = 0.006). Despite the large s le size, the majority of variants detected were very rare, precluding definitive conclusions about pathogenicity based solely on the case-control data. Sequencing of 21 tumours from carriers of one of eight candidate MS variants, identified four cases with bi-allelic inactivation through loss of the wild-type allele, while six lost the variant allele and ten remained heterozygous. Loss of the wild-type alleles corresponded strongly with ER- and triple-negative breast tumours and a high homologous recombination deficiency score. Conclusions: Using this approach, the p.Gly264Ser variant, which was previously suspected to be pathogenic based on small case-control analyses and loss of activity in in vitro functional assays, was shown to be benign with similar prevalence in cases and controls, and eight out of nine tumours showing loss of the variant allele or retention of heterozygosity. Conversely, the combined case-control and tumour sequencing data identified p.Ile144Thr, p.Arg212His, p.Gln143Arg and p.Gly114Arg as variants warranting further investigation.
Publisher: Oxford University Press (OUP)
Date: 28-07-2021
DOI: 10.1093/JNCI/DJAB147
Abstract: Recent population-based female breast cancer and prostate cancer polygenic risk scores (PRS) have been developed. We assessed the associations of these PRS with breast and prostate cancer risks for male BRCA1 and BRCA2 pathogenic variant carriers. 483 BRCA1 and 1318 BRCA2 European ancestry male carriers were available from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A 147-single nucleotide polymorphism (SNP) prostate cancer PRS (PRSPC) and a 313-SNP breast cancer PRS were evaluated. There were 3 versions of the breast cancer PRS, optimized to predict overall (PRSBC), estrogen receptor (ER)–negative (PRSER-), or ER-positive (PRSER+) breast cancer risk. PRSER+ yielded the strongest association with breast cancer risk. The odds ratios (ORs) per PRSER+ standard deviation estimates were 1.40 (95% confidence interval [CI] =1.07 to 1.83) for BRCA1 and 1.33 (95% CI = 1.16 to 1.52) for BRCA2 carriers. PRSPC was associated with prostate cancer risk for BRCA1 (OR = 1.73, 95% CI = 1.28 to 2.33) and BRCA2 (OR = 1.60, 95% CI = 1.34 to 1.91) carriers. The estimated breast cancer odds ratios were larger after adjusting for female relative breast cancer family history. By age 85 years, for BRCA2 carriers, the breast cancer risk varied from 7.7% to 18.4% and prostate cancer risk from 34.1% to 87.6% between the 5th and 95th percentiles of the PRS distributions. Population-based prostate and female breast cancer PRS are associated with a wide range of absolute breast and prostate cancer risks for male BRCA1 and BRCA2 carriers. These findings warrant further investigation aimed at providing personalized cancer risks for male carriers and informing clinical management.
Publisher: Public Library of Science (PLoS)
Date: 10-09-2010
Publisher: Springer Science and Business Media LLC
Date: 07-1996
DOI: 10.1038/BJC.1996.324
Abstract: Forty-nine ovarian tumours were examined for loss of heterozygosity (LOH) on chromosome 5 using eight microsatellite markers spanning both arms, including one at the APC locus. LOH on 5q was a frequent event, detectable in 23 of 49 (47%) tumours, whereas 5p LOH was detected in only 1 of 22 tumours (5%). Six tumours showed partial LOH on 5q, enabling the candidate region to be localised to a 22 cM region proximal to APC, flanked by D5S424 and D5S644. An association was found between 5q LOH and TP53 mutation, with 18 of 23 (78%) tumours with LOH on 5q also harbouring a TP53 mutation. LOH on 5q was observed in 6 of 18 (33%) stage I tumours, suggesting that it may be an early event in the molecular pathogenesis of certain ovarian carcinomas.
Publisher: Springer Science and Business Media LLC
Date: 24-02-2007
DOI: 10.1007/S00198-007-0343-Y
Abstract: BMD and clinical risk factors predict hip and other osteoporotic fractures. The combination of clinical risk factors and BMD provide higher specificity and sensitivity than either alone. INTRODUCTION AND HYPOTHESES: To develop a risk assessment tool based on clinical risk factors (CRFs) with and without BMD. Nine population-based studies were studied in which BMD and CRFs were documented at baseline. Poisson regression models were developed for hip fracture and other osteoporotic fractures, with and without hip BMD. Fracture risk was expressed as gradient of risk (GR, risk ratio/SD change in risk score). CRFs alone predicted hip fracture with a GR of 2.1/SD at the age of 50 years and decreased with age. The use of BMD alone provided a higher GR (3.7/SD), and was improved further with the combined use of CRFs and BMD (4.2/SD). For other osteoporotic fractures, the GRs were lower than for hip fracture. The GR with CRFs alone was 1.4/SD at the age of 50 years, similar to that provided by BMD (GR = 1.4/SD) and was not markedly increased by the combination (GR = 1.4/SD). The performance characteristics of clinical risk factors with and without BMD were validated in eleven independent population-based cohorts. The models developed provide the basis for the integrated use of validated clinical risk factors in men and women to aid in fracture risk prediction.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952450
Abstract: Validation of KAP1-pS473 and CHK2-pS516 antibodies. b A, /b Parental RPE, RPE1–CHEK2-KO cells or RPE1–CHEK2-KO cells transfected with the wild-type or mutant pEGFP–CHEK2 were left untreated or were exposed to ionizing radiation (5 Gy, 3 hours). After fixation, cells were probed with KAP1-pS473 antibody. Representative images are shown. b B, /b Quantification of b A /b . The mean nuclear intensity of the KAP1-pS473 signal is plotted. Each dot represents one cell more than 300 cells were analyzed. Red line, error bars and numbers indicate mean ± SDs. Statistical significance was evaluated by the Mann–Whitney test (****, i P /i 0.0001). A representative experiment is shown from two independent replicates. b C, /b Cells were grown and treated as in b A /b and were probed with CHK2-pS516 antibody. Representative images are shown. b D, /b Quantification of b C /b . The mean nuclear intensity of the CHK2-pS516 signal is plotted. Each dot represents one cell more than 300 cells were analyzed. Red line, error bars and numbers indicate mean ± SDs. Statistical significance was evaluated by the Mann–Whitney test (****, i P /i 0.0001). A representative experiment is shown from two independent replicates. b E, /b Cells were grown and treated as in A. Whole-cell lysates were analyzed by immunoblotting with indicated antibodies.
Publisher: Springer Science and Business Media LLC
Date: 12-2004
DOI: 10.1007/S10585-004-4117-Z
Abstract: Current stocks of the LCC15-MB cell line, which we originally isolated from a human breast-bone metastasis, were found to be genetically matched to the MDA-MB-435 cell line from the Lombardi Cancer Center (MDA-MB-435-LCC) using comparative genomic hybridisation, DNA microsatellite analysis and chromosomal number. LCC15-MB stocks used for our previously published studies as well as the earliest available LCC15-MB cells also showed identity to MDA-MB-435-LCC cells. The original karyotype reported for LCC15-MB cells was considerably different to that of MDA-MB-435 cells, indicating that the original LCC15-MB cells were lost to contamination by MDA-MB-435-LCC cells. Chromosome number is the simplest test to distinguish original LCC15-MB cells (n approximately 75) from MDA-MB-435 (n approximately 52). Collectively, our results prove that LCC15-MB cells currently available are MDA-MB-435 cells and we suggest their re-designation as MDA-MB-435-LCC15 cells. We also review the known misclassification of breast and prostate cancer cell lines to date and have initiated a register maintained at www.svi.edu.au/cell_lines_registry.doc.
Publisher: Elsevier BV
Date: 2003
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952453
Abstract: Geographical origin of analyzed i CHEK2 /i missense variants.
Publisher: Springer Science and Business Media LLC
Date: 06-08-2003
Publisher: American Association for Cancer Research (AACR)
Date: 03-2017
DOI: 10.1158/1055-9965.EPI-16-0631
Abstract: Background: The precise mechanism by which the immune system is adversely affected in cancer patients remains poorly understood, but the accumulation of immunosuppressive rotumorigenic myeloid-derived suppressor cells (MDSCs) is thought to be a prominent mechanism contributing to immunologic tolerance of malignant cells in epithelial ovarian cancer (EOC). To this end, we hypothesized genetic variation in MDSC pathway genes would be associated with survival after EOC diagnoses. Methods: We measured the hazard of death due to EOC within 10 years of diagnosis, overall and by invasive subtype, attributable to SNPs in 24 genes relevant in the MDSC pathway in 10,751 women diagnosed with invasive EOC. Versatile Gene-based Association Study and the admixture likelihood method were used to test gene and pathway associations with survival. Results: We did not identify in idual SNPs that were significantly associated with survival after correction for multiple testing (P & 3.5 × 10−5), nor did we identify significant associations between the MDSC pathway overall, or the 24 in idual genes and EOC survival. Conclusions: In this well-powered analysis, we observed no evidence that inherited variations in MDSC-associated SNPs, in idual genes, or the collective genetic pathway contributed to EOC survival outcomes. Impact: Common inherited variation in genes relevant to MDSCs was not associated with survival in women diagnosed with invasive EOC. Cancer Epidemiol Biomarkers Prev 26(3) 420–4. ©2016 AACR.
Publisher: Springer Science and Business Media LLC
Date: 05-1997
DOI: 10.1038/BJC.1997.238
Publisher: American Association for Cancer Research (AACR)
Date: 30-11-2015
DOI: 10.1158/1078-0432.CCR-15-0632
Abstract: Purpose: Chemotherapy resistance remains a major challenge in the treatment of ovarian cancer. We hypothesize that germline polymorphisms might be associated with clinical outcome. Experimental Design: We analyzed approximately 2.8 million genotyped and imputed SNPs from the iCOGS experiment for progression-free survival (PFS) and overall survival (OS) in 2,901 European epithelial ovarian cancer (EOC) patients who underwent first-line treatment of cytoreductive surgery and chemotherapy regardless of regimen, and in a subset of 1,098 patients treated with ≥4 cycles of paclitaxel and carboplatin at standard doses. We evaluated the top SNPs in 4,434 EOC patients, including patients from The Cancer Genome Atlas. In addition, we conducted pathway analysis of all intragenic SNPs and tested their association with PFS and OS using gene set enrichment analysis. Results: Five SNPs were significantly associated (P ≤ 1.0 × 10−5) with poorer outcomes in at least one of the four analyses, three of which, rs4910232 (11p15.3), rs2549714 (16q23), and rs6674079 (1q22), were located in long noncoding RNAs (lncRNAs) RP11-179A10.1, RP11-314O13.1, and RP11-284F21.8, respectively (P ≤ 7.1 × 10−6). ENCODE ChIP-seq data at 1q22 for normal ovary show evidence of histone modification around RP11-284F21.8, and rs6674079 is perfectly correlated with another SNP within the super-enhancer MEF2D, expression levels of which were reportedly associated with prognosis in another solid tumor. YAP1- and WWTR1 (TAZ)-stimulated gene expression and high-density lipoprotein (HDL)-mediated lipid transport pathways were associated with PFS and OS, respectively, in the cohort who had standard chemotherapy (pGSEA ≤6 × 10−3). Conclusions: We have identified SNPs in three lncRNAs that might be important targets for novel EOC therapies. Clin Cancer Res 21(23) 5264–76. ©2015 AACR.
Publisher: BMJ
Date: 10-2012
DOI: 10.1136/JMEDGENET-2012-101191
Abstract: Recently, rare germline variants in XRCC2 were detected in non-BRCA1/2 familial breast cancer cases, and a significant association with breast cancer was reported. However, the breast cancer risk associated with these variants needs further evaluation. The coding regions and exon-intron boundaries of XRCC2 were scanned for mutations in an international cohort of 3548 non-BRCA1/2 familial breast cancer cases and 1435 healthy controls using various mutation scanning methods. Predictions on functional relevance of detected missense variants were obtained from three different prediction algorithms. The only protein-truncating variant detected was found in a control. Rare non-protein-truncating variants were detected in 20 familial cases (0.6%) and nine healthy controls (0.6%). Although the number of variants predicted to be damaging or neutral differed between prediction algorithms, in all instances these categories were evenly represented among cases and controls. Our data do not confirm an association between XRCC2 variants and breast cancer risk, although a relative risk smaller than two could not be excluded. Variants in XRCC2 are unlikely to explain a substantial proportion of familial breast cancer.
Publisher: Springer New York
Date: 2016
Publisher: Springer Science and Business Media LLC
Date: 12-2002
DOI: 10.1186/BCR457
Abstract: A growing body of evidence suggests that variations in the levels of folate may contribute to the development of cancer. A functional polymorphic variant (C-->T substitution at nucleotide 677) in the 5,10-methylenetetrahydrofolate reductase (MTHFR) gene results in the conversion of an alanine to a valine and may modify the risk of breast and other cancers. We have investigated the possible influence of this MTHFR variant on breast cancer risk in a case-control study of 233 healthy women and 335 women who had breast cancer that occurred under the age of 40 years, bilateral breast cancer or a family history of breast cancer. A significant excess of the valine genotypes was observed among the cases (odds ratio 1.43, 95% confidence interval 1.02-2.00). The effect was more pronounced among the cases with a breast cancer diagnosis under the age of 40 years, with an odds ratio of 1.66 (95% confidence interval 1.12-2.41). A nonsignificant excess of the valine genotypes was observed among the cases with a family history of breast cancer or bilateral breast cancer. The low activity C677T (valine) genotype of MTHFR may increase the risk of early onset breast cancer.
Publisher: American Association for Cancer Research (AACR)
Date: 02-2020
DOI: 10.1158/0008-5472.CAN-19-1840
Abstract: Aggressive prostate cancer risk in BRCA2 mutation carriers may vary according to the specific BRCA2 mutation inherited by the at-risk in idual.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.C.6532782.V1
Abstract: AbstractPurpose: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. Experimental Design: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC ( i n /i = 333), mucinous borderline ovarian tumors (MBOT, i n /i = 151), and upper GI ( i n /i = 65) and lower GI tumors ( i n /i = 55). Results: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77 95% confidence interval (CI), 1.04–7.41, i P /i = 0.042]. Increased expression of i THBS2 /i and i TAGLN /i was associated with shorter OS in MOC patients (HR, 1.25 95% CI, 1.04–1.51, i P /i = 0.016) and (HR, 1.21 95% CI, 1.01–1.45, i P /i = 0.043), respectively. i ERBB2 /i (HER2) lification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). Conclusions: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of i THBS2 /i and i TAGLN /i in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC s les clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies. /
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/1078-0432.23685621
Abstract: Detail description of the functional categorization of analyzed CHEK2 missense variants.
Publisher: Springer Science and Business Media LLC
Date: 27-03-2017
DOI: 10.1038/NG.3826
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952441
Abstract: Results of KAP1 and CHK2 kinase assays for 430 successfully analyzed missense i CHEK2 /i variants (shown as an average relative CHK2 kinase activity). Bars are colored as functionally WT-like (green), intermediate (IM yellow), and impaired (ID red), respectively, with thresholds for IM variants (0.428 and 0.479) and ID variants (0.705 and 0.710) for KAP1 and CHK2 assays, respectively (dashed lines). Error bars represent standard errors of mean. Color/gray letters for protein variants indicate concordant/discordant functional assays result, respectively. Blue boxes denote conserved CHK2 domains. DNL, variants that do not localize into the nucleus.
Publisher: Springer Science and Business Media LLC
Date: 03-02-2009
DOI: 10.1007/S10549-008-0269-X
Abstract: Heterozygous somatic mutations of the transcription factor, GATA-3, have recently been reported in approximately 5% breast of tumors unselected for family history. We sequenced the GATA-3 gene in 55 breast tumors from women with familial breast cancer, and found seven heterozygous somatic mutations, all in non-BRCA1/2 cases in which the frequency was 22%. In contrast, we found mutations of GATA-3 in only 4% of 81 sporadic tumors analysed. It is possible that GATA3 mutations occur earlier in the evolution of BRCAx tumors, compared to BRCA1, BRCA2 or sporadic tumors, and are therefore easier to detect by direct sequencing in the presence of some stromal contamination.
Publisher: Portland Press Ltd.
Date: 04-1990
DOI: 10.1042/BST0180178
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952444
Abstract: Kinase KAP1 and CHK2 assays ( b A /b ). The bar graphs show results of kinase assays for 430 i CHEK2 /i missense variants. In both assays, variants with normalized relative CHK2 activity (mean WT-activity = 1) exceeding that of the weakest signal of WT replicas (not shown) were categorized functionally WT-like, variants with normalized signal intensity lower than the strongest signal for any of kinase-dead/empty EGFP vector controls (in-frame exon 7 deletion–p.D265_H282del not shown) were categorized as functionally impaired. Variants with normalized CHK2 activities between these ranges were categorized functionally intermediate (0.428–0.705 and 0.479–0.710 for KAP1 and CHK2 assay, respectively indicated by red and yellow dashed lines). Scatterplot combines results from both assays showing 340 concordant (circles) and 90 discordant (crosses) variants. The nuclear-to-cytoplasmic ratio ( b B /b ) bar graph (left) displays all missense variants and a set of protein-truncating i CHEK2 /i variants (dark red bars at left, zoomed part of the graph). The missense variants, p.R521W and p.R521Q, with an aberrant localization are highlighted as bright-red bars the arrows denote WT (green bar) and catalytically-dead in-frame p.D265_H282del variant (white bar). The highest and lowest mean nuclear/cytoplasmic ratio values from all WT replicates are indicated by green dashed lines. Of all missense variants analyzed by ScanR microscopy, only codon 521 alterations revealed aberrant intracellular localization with intense cytoplasmic positivity (right), reminiscent of mislocalization of the c.1100delC (p.T367fsX size bar, 10 μm) variant. In comparison, the in-frame deletion p.D265_H282del revealed normal intranuclear accumulation, similar to WT. b C, /b Scatter plots depicting correlations between assays performed in this study and previous analyses of i CHEK2 /i VUS. Studies of Kleiblova i et al. /i ( a href="#bib17" target="_blank" /a ) and Boonen et al. ( a href="#bib18" target="_blank" /a ) used phosphorylation of KAP1 as a functional readout whereas the study of Delimitsou i et al. /i ( a href="#bib25" target="_blank" /a ) used a yeast growth retardation assay. The dots are colored according to the results of the KAP1 assay in this study (red, impaired yellow, intermediate green, wild-type–like). Blue line represents linear regression, R, correlation coefficient i P /i , i P /i value. The scatter plot does not show the p.Arg512Trp variant classified by Boonen et al. as intermediate with impaired nuclear localization in our localization assay.
Publisher: Elsevier BV
Date: 07-2017
DOI: 10.1038/MODPATHOL.2017.21
Abstract: The spectrum of genomic alterations in ductal carcinoma in situ (DCIS) is relatively unexplored, but is likely to provide useful insights into its biology, its progression to invasive carcinoma and the risk of recurrence. DCIS (n=20) with a range of phenotypes was assessed by massively parallel sequencing for mutations and copy number alterations and variants validated by Sanger sequencing. PIK3CA mutations were identified in 11/20 (55%), TP53 mutations in 6/20 (30%), and GATA3 mutations in 9/20 (45%). Screening an additional 91 cases for GATA3 mutations identified a final frequency of 27% (30/111), with a high proportion of missense variants (8/30). TP53 mutations were exclusive to high grade DCIS and more frequent in PR-negative tumors compared with PR-positive tumors (P=0.037). TP53 mutant tumors also had a significantly higher fraction of the genome altered by copy number than wild-type tumors (P=0.005), including a significant positive association with lification or gain of ERBB2 (P<0.05). The association between TP53 mutation and ERBB2 lification was confirmed in a wider DCIS cohort using p53 immunohistochemistry as a surrogate marker for TP53 mutations (P=0.03). RUNX1 mutations and MAP2K4 copy number loss were novel findings in DCIS. Frequent copy number alterations included gains on 1q, 8q, 17q, and 20q and losses on 8p, 11q, 16q, and 17p. Patterns of genomic alterations observed in DCIS were similar to those previously reported for invasive breast cancers, with all DCIS having at least one bona fide breast cancer driver event. However, an increase in GATA3 mutations and fewer copy number changes were noted in DCIS compared with invasive carcinomas. The role of such alterations as prognostic and predictive biomarkers in DCIS is an avenue for further investigation.
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/1078-0432.23685618
Abstract: List of all analyzed CHEK2 variants with results of KAP1/CHK2 kinase and localization assays and the results from recent previously published functional analyses of the CHEK2 VUS.
Publisher: Springer Science and Business Media LLC
Date: 22-01-2011
DOI: 10.1007/S10549-011-1346-0
Abstract: Mammographic density (MD) adjusted for age and body mass index (BMI) is a strong heritable breast cancer risk factor however, its biological basis remains elusive. Previous studies assessed MD-associated histology using random s ling approaches, despite evidence that high and low MD areas exist within a breast and are negatively correlated with respect to one another. We have used an image-guided approach to s le high and low MD tissues from within in idual breasts to examine the relationship between histology and degree of MD. Image-guided s ling was performed using two different methodologies on mastectomy tissues (n = 12): (1) s ling of high and low MD regions within a slice guided by bright (high MD) and dark (low MD) areas in a slice X-ray film (2) s ling of high and low MD regions within a whole breast using a stereotactically guided vacuum-assisted core biopsy technique. Pairwise analysis accounting for potential confounders (i.e. age, BMI, menopausal status, etc.) provides appropriate power for analysis despite the small s le size. High MD tissues had higher stromal (P = 0.002) and lower fat (P = 0.002) compositions, but no evidence of difference in glandular areas (P = 0.084) compared to low MD tissues from the same breast. High MD regions had higher relative gland counts (P = 0.023), and a preponderance of Type I lobules in high MD compared to low MD regions was observed in 58% of subjects (n = 7), but did not achieve significance. These findings clarify the histologic nature of high MD tissue and support hypotheses regarding the biophysical impact of dense connective tissue on mammary malignancy. They also provide important terms of reference for ongoing analyses of the underlying genetics of MD.
Publisher: Public Library of Science (PLoS)
Date: 19-06-2015
Publisher: Springer Science and Business Media LLC
Date: 19-01-2017
DOI: 10.1038/BJC.2016.426
Publisher: Oxford University Press (OUP)
Date: 1994
DOI: 10.1093/HMG/3.4.589
Abstract: A novel cDNA clone was isolated using a polyclonal serum directed against partially purified ovarian carcinoma antigen CA125. The deduced peptide sequence lacked membrane protein characteristics expected for CA125 but encompassed a B-box/coiled coil motif present in many genes with transformation potential. The gene was mapped by fluorescence in situ hybridization within the minimum region known to contain the familial breast/ovarian carcinoma gene, BRCA1. YAC and cosmid clones were isolated and used to refine the location of this gene adjacent and proximal to the RNU2 locus. The exon structure of the gene was determined. Extensive SSCP and sequence analysis of over 100 tumour and normal DNAs from familial and sporadic breast cancers and sporadic ovarian cancers failed to detect mutations in the coding region of this gene.
Publisher: S. Karger AG
Date: 2000
DOI: 10.1159/000052872
Abstract: It is well known that certain aspects of endometriosis are similar to those of malignant disease. For ex le, like cancer, endometriosis can be both locally and distantly metastatic it attaches to other tissues, invades, and damages them. Endometriosis is a common disease that does not create a cachectic or catabolic state, and is rarely fatal. There are, however, numerous reported cases of malignancy arising from endometriotic deposits and substantial histologic evidence that endometriosis is associated with endometrioid carcinoma and clear cell carcinoma of the ovary. A large review article by Mostoufizadeh and Scully investigated the association between endometriosis and endometrioid carcinoma, noting that women who had both diseases tended to be younger [1]. They found no association between endometriosis and serous or mucinous carcinoma of the ovary, and reported that malignant transformation of endometriosis was rare and associated with the use of exogenous estrogens. An epidemiological study of Swedish women reported a higher incidence of breast and ovarian cancer and non-Hodgkin’s lymphoma in women with endometriosis compared with controls [2]. Vercellini and colleagues also reported a higher incidence of endometrioid and clear cell carcinoma in women with endometriosis compared with controls [3]. Mutations in genes associated with galactose metabolism have been identified as one possible mechanism for this association. These mutations are more common in ovarian cancer and have been reported to be more common in women with endometriosis. We compared 78 women with endometriosis with 248 controls and were unable to demonstrate an increased frequency of these mutations in any of these groups.
Publisher: Springer Science and Business Media LLC
Date: 11-06-2021
DOI: 10.1038/S41523-021-00279-9
Abstract: Breast cancer (BC) has a significant heritable component but the genetic contribution remains unresolved in the majority of high-risk BC families. This study aims to investigate the monogenic causes underlying the familial aggregation of BC beyond BRCA1 and BRCA2 , including the identification of new predisposing genes. A total of 11,511 non-BRCA familial BC cases and population-matched cancer-free female controls in the BEACCON study were investigated in two sequencing phases: 1303 candidate genes in up to 3892 cases and controls, followed by validation of 145 shortlisted genes in an additional 7619 subjects. The coding regions and exon–intron boundaries of all candidate genes and 14 previously proposed BC genes were sequenced using custom designed sequencing panels. Pedigree and pathology data were analysed to identify genotype-specific associations. The contribution of ATM , PALB2 and CHEK2 to BC predisposition was confirmed, but not RAD50 and NBN . An overall excess of loss-of-function (LoF) (OR 1.27, p = 9.05 × 10 −9 ) and missense (OR 1.27, p = 3.96 × 10 −73 ) variants was observed in the cases for the 145 candidate genes. Leading candidates harbored LoF variants with observed ORs of 2–4 and in idually accounted for no more than 0.79% of the cases. New genes proposed by this study include NTHL1 , WRN , PARP2 , CTH and CDK9 . The new candidate BC predisposition genes identified in BEACCON indicate that much of the remaining genetic causes of high-risk BC families are due to genes in which pathogenic variants are both very rare and convey only low to moderate risk.
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/1078-0432.23685612
Abstract: Characteristics of 12 case-control datasets from the ENIGMA consortium partners.
Publisher: Bioscientifica
Date: 1996
Abstract: The human endometrium undergoes regular cyclical changes under the endocrine control of oestrogens and progesterone acting via specific nuclear receptors. The molecular and cellular events mediating these changes are not understood. The present study examined the changes in the endometrial progesterone receptor and its mRNA during the menstrual cycle. Forty-four endometrial s les obtained from women with normal menstrual cycles were ided into four categories: early proliferative (days 6-9), late proliferative (days 10-14), early secretory (days 15-21) and late secretory (days 22-28). The progesterone receptor protein was determined using a human progesterone receptor enzyme-linked immunoassay kit. Total RNA was extracted using RNAzol and the abundance of mRNA encoding the progesterone receptor was determined by reverse transcriptase-polymerase chain reaction and by northern blot analysis. The concentration of the progesterone receptor in the endometrium was highest during the late proliferative phase and was lowest in the late secretory phase. Significant differences were observed between the menstrual cycle phases (P < 0.003). No cyclical variation was observed in the concentration of mRNA encoding for the progesterone receptor in the endometrium when analysed by reverse transcriptase polymerase chain reaction or by northern analysis. There appears to be no association between the amounts of mRNA encoding the progesterone receptor and progesterone receptor protein during the menstrual cycle suggesting that the control of the expression of the progesterone receptor may not occur solely at the transcriptional level.
Publisher: Massachusetts Medical Society
Date: 10-04-2008
DOI: 10.1056/NEJMC086024
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488654.V1
Abstract: Supplementary Figures S1-S13
Publisher: BMJ
Date: 20-04-2012
DOI: 10.1136/JCLINPATH-2011-200629
Abstract: Spindle cell lesions of the breast represent an interesting diagnostic challenge as they comprise a wide range of tumours that are rare. Differentiating dermatofibrosarcoma protuberans (DFSP) from other dermatofibromas using CD34 immunohistochemistry alone is difficult therefore, fluorescence in situ hybridisation (FISH) analysis is often employed to identify typical COL1A1-PDGFB fusion or gene rearrangement. Although molecular confirmation of diagnosis is unnecessary in the majority of DFSP cases, the detection of chromosomal rearrangement is valuable in tumours that show unusual clinicopathological features as in this study the authors report a case of DFSP of breast that did not show any typical known molecular features. Morphological and immunohistochemical study was highly suggestive of the diagnosis of DFSP. To further investigate this case, DNA copy number alterations were investigated by the 250 K Affymetrix SNP Mapping array. DNA analysis did not show any of the known translocations reported in DFSP or any known solid tumour category. However, in addition to copy number changes on chromosome 1, lification of chromosome 7p which contains the epidermal growth factor receptor (EGFR) gene was observed. Results from EGFR FISH showed an increase in EGFR gene to chromosome 7 ratio (3:1) suggesting lification of the EGFR gene. This case of an unusual DFSP demonstrates that genomic interrogation provides additional potential targets such as a therapeutic avenue with anti-EGFR therapies and shows the power of molecular characterisation of unusual tumours for a personalised medicine approach.
Publisher: American Society for Microbiology
Date: 05-1986
DOI: 10.1128/AAC.29.5.807
Abstract: Twenty-one IncFIV-group plasmids conferring trimethoprim resistance in Escherichia coli isolates from humans and pigs were examined. Three evolutionary lines of plasmids were identified on the basis of restriction enzyme analysis. One was found exclusively in human isolates and another was found in pig isolates, while the third line consisted of plasmids from both sources. All R plasmids readily transferred to laboratory strains, and evidence was found for transfer to other biotypes of E. coli in the environment. The Tpr genes from representatives of the plasmid lines were cloned and compared by restriction analysis and by hybridization with two characterized Tpr dihydrofolate reductase genes. The sequences flanking the Tpr genes were different for each line, but all showed homology with the type 2 dihydrofolate reductase gene, irrespective of whether they were of human or animal origin. There was no hybridization to the type 1 gene. The remarkable degree of similarity among plasmids of the third line provided clear evidence of the exchange of plasmid-bearing E. coli between humans and pigs.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.C.6742698
Abstract: AbstractPurpose: Germline pathogenic variants in i CHEK2 /i confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense i CHEK2 /i variants of uncertain significance (VUS) have been identified, h ering the clinical utility of germline genetic testing (GGT). Experimental Design: We collected 460 i CHEK2 /i missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using i CHEK2 /i -complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1– i CHEK2 /i -knockout cells. Concordant results in both functional assays were used to categorize i CHEK2 /i VUS from 12 ENIGMA case–control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls. Results: A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired ( i N /i = 102), functionally intermediate ( i N /i = 12), or functionally wild-type (WT)–like ( i N /i = 226). We then examined their association with breast cancer risk in the case–control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35–3.41), 1.57 (95% CI, 1.41–1.75), and 1.19 (95% CI, 1.08–1.31), respectively. The meta-analysis of population-specific datasets showed similar results. Conclusions: We determined the functional consequences for the majority of i CHEK2 /i missense VUS found in patients with breast cancer (3,660/4,436 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating i CHEK2 /i variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers. /
Publisher: Public Library of Science (PLoS)
Date: 27-07-2016
Publisher: Hindawi Limited
Date: 2005
DOI: 10.1002/HUMU.20220
Abstract: Array-based genotyping platforms, such as the Affymetrix mapping array, have been validated as reliable methods for obtaining high-resolution copy number and allele status information when using DNA derived from fresh tissue sources. However, the suitability of such systems for the examination of DNA derived from formalin-fixed, paraffin-embedded (FFPE) tissues has not been tested. Therefore, we analyzed DNA derived from five matching fresh frozen and FFPE ovarian tumors for gene copy number changes and loss of heterozygosity using the Affymetrix GeneChip Human Mapping 10 K Array Xba 131. The data was analyzed using Affymetrix proprietary software, GeneChip DNA Analysis Software, and Chromosome Copy Number Tool. The average SNP call rate (rate of successful genotype identification) of the fresh s les was 89.44% (range 78.72-96.22%, median 92.72%) and was only slightly lower for the matching FFPE s les at 83.48% (range 76.93-93.17%, median 82.60%). The average concordance (rate of agreement between successful genotype calls) between the fresh and matching FFPE s les was 97.06% (range 92.70-99.41%, median 97.52%). Loss of heterozygosity (LOH) profiles of the fresh and FFPE s les were essentially identical across all chromosomes. Copy number data was also comparable, although the quantification of copy number changes appears overstated in the FFPE s les. In conclusion, we have shown that it is possible to achieve high-performance outcomes using FFPE-derived DNA in the Affymetrix 10 K mapping array. This advance will open up vast archival tissue resources to high-resolution genetic analysis and unlock a wealth of biological information.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952435
Abstract: Presence of analyzed i CHEK2 /i missense variants categorized according to the functional assays in patients with breast cancer (BC pts red numbers) and matched controls (dark green numbers). The association with breast cancer risk (odds ratio OR) were calculated for prevalent variants having ≥10 carriers among patients or controls, respectively. Colors of the numbers in the last column highlight significant association with moderate-or-higher risk (red OR 2), low risk (OR 2), protective variants (green) or variants without significant impact on breast cancer risk (black). Gray rows display variants that were discordant in the kinase assays. DNL, variants that do not localize into the nucleus.
Publisher: Wiley
Date: 04-07-1995
Abstract: Two morphologically distinct cell lines, GP2d and GP5d, derived from the same adenocarcinoma of the colon, have been established and characterised. Both clones have the same genetic changes, consistent with the usual pattern of tumour progression in colon cancer. The cells also have an inverted duplication of bands 10q11 to 10q21, but Southern blot analysis failed to identify any translocations involving the ret protooncogene, which maps to this region. GP2d grew by spreading from the edges of microcolonies to form a confluent layer of cells. GP5d grew in discrete islands of cells forming multi-layered colonies. These differing patterns of growth correlated with variation in expression or cellular distribution of alpha 2-integrin, desmoplakin and e-cadherin. Only GP2d responded to exogenously added epidermal growth factor (EGF), transforming growth factor-alpha (TGF alpha) or insulin with an increase in cell numbers, even though both cell lines possessed similar numbers of EGF receptors. Analysis of EGF receptor ligand expression showed that GP5d cells expressed relatively more TGF alpha mRNA than did GP2d in contrast, hiregulin mRNA, which was abundant in GP2d, was virtually undetectable in GP5d. Even though GP5d failed to exhibit a growth response to EGF, it underwent a marked epithelial-mesenchymal transition when treated with EGF, indicating separation of growth and morphological responses to EGF.
Publisher: BMJ
Date: 03-11-2015
Publisher: American Society for Microbiology
Date: 09-1987
Abstract: Trimethoprim resistance dihydrofolate reductase genes from plasmids known to be exchanging between human and animal populations were mapped. The dihydrofolate reductase gene has been highly conserved in all plasmids, but differences in the flanking regions provide evidence that the most recent exchange of plasmids between the two ecosystems has been from animals to humans.
Publisher: Springer Science and Business Media LLC
Date: 23-09-2019
DOI: 10.1038/S41467-019-12095-8
Abstract: An amendment to this paper has been published and can be accessed via a link at the top of the paper.
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/1078-0432.23685609
Abstract: Frequencies of all reported germline CHEK2 variant carriers and carriers of variants concordantly categorized by functional our kinase assays in breast cancer patients and controls in 12 analyzed population datasets.
Publisher: Informa UK Limited
Date: 04-2013
DOI: 10.4161/ONCI.24185
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952426.V1
Abstract: Funnel plot (left) and forest plots (right) for in idual datasets of breast cancer cases and controls from 12 datasets (10 countries) stratified according to the functional categorization.
Publisher: Springer Science and Business Media LLC
Date: 14-01-2022
DOI: 10.1038/S41431-021-00987-7
Abstract: Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to in idual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestries 7,669 women of East Asian ancestries 1,072 women of African ancestries, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestries. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38 (95% CI: 1.28–1.48, AUC: 0.588) per unit standard deviation, in women of European ancestries 1.14 (95% CI: 1.08–1.19, AUC: 0.538) in women of East Asian ancestries 1.38 (95% CI: 1.21–1.58, AUC: 0.593) in women of African ancestries hazard ratios of 1.36 (95% CI: 1.29–1.43, AUC: 0.592) in BRCA1 pathogenic variant carriers and 1.49 (95% CI: 1.35–1.64, AUC: 0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
Publisher: Springer Science and Business Media LLC
Date: 12-2004
DOI: 10.1007/S10585-004-3759-1
Abstract: Recently, the tissue origin of MDA-MB-435 cell line has been the subject of considerable debate. In this study, we set out to determine whether MDA-MB-435-DTP cells shown to express melanoma-specific genes were identical to various other MDA-MB-435 cell stocks worldwide. CGH-microarray, genetic polymorphism genotyping, microsatellite fingerprint analysis and/or chromosomal number confirmed that the MDA-MB-435 cells maintained at the Lombardi Comprehensive Cancer Center (MDA-MB-435-LCC) are almost identical to the MDA-MB-435-DTP cells, and showed a very similar profile to those obtained from the same original source (MD Anderson Cancer Center) but maintained independently (MDA-MB-435-PMCC). Gene expression profile analysis confirmed common expression of genes among different MDA-MB-435-LCC cell stocks, and identified some unique gene products in MDA-MB-435-PMCC cells. RT-PCR analysis confirmed the expression of the melanoma marker tyrosinase across multiple MDA-MB-435 cell stocks. Collectively, our results show that the MDA-MB-435 cells used widely have identical origins to those that exhibit a melanoma-like gene expression signature, but exhibit a small degree of genotypic and phenotypic drift.
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/1078-0432.23685609.V1
Abstract: Frequencies of all reported germline CHEK2 variant carriers and carriers of variants concordantly categorized by functional our kinase assays in breast cancer patients and controls in 12 analyzed population datasets.
Publisher: Impact Journals, LLC
Date: 12-07-2016
Publisher: Oxford University Press (OUP)
Date: 04-04-2001
Publisher: Wiley
Date: 24-12-2009
Publisher: Elsevier BV
Date: 02-1996
Publisher: Elsevier BV
Date: 03-2002
DOI: 10.1016/S0304-3835(01)00782-0
Abstract: Polymorphic variants of microsomal epoxide hydrolase (mEPHX) with altered enzyme activity have been associated with an increased risk for ovarian cancer. We assessed the frequency of exon 3 and exon 4 variants of mEPHX among 291 ovarian cancers and 257 controls from a UK-based population. The distribution of the exon 3 alleles among both the cancer and control groups was significantly different from that expected under Hardy-Weinberg equilibrium suggesting that the PCR restriction fragment length polymorphism (PCR-RFLP) genotyping assay might be flawed. The codon 113 polymorphism was reassessed using a two-color allele-specific PCR-based assay. We found that a codon 119 G>A polymorphism, present in 20% of the British population and linked to the wild-type exon 3 allele, resulted in some Tyr113/His113 heterozygotes being falsely classified as His113/His113 homozygotes when using the PCR-RFLP assay. Consequently, we reassessed all our codon 113 data using the new allele-specific assay. We found no evidence of an association of ovarian cancer risk with the exon 3 Tyr113>His113 variant. Similarly the frequencies of the exon 4 His139>Arg139 genotypes were not significantly different between cases and controls. Stratifying the genotyping data according to the predicted mEPHX activity revealed a highly significant decrease in high mEPHX activity among the serous ovarian cancers (P=0.01) suggesting that high mEPHX activity may be protective for this histological sub-type. Furthermore previous disease association studies of exon 3 alleles which utilized the PCR-RFLP assay may be compromised by the existence of a codon 119 G>A polymorphism which may be common in Caucasian populations.
Publisher: Wiley
Date: 15-01-2015
DOI: 10.1002/PATH.5262
Abstract: The current model for breast cancer progression proposes independent 'low grade (LG)-like' and 'high grade (HG)-like' pathways but lacks a known precursor to HG cancer. We applied low-coverage whole-genome sequencing to atypical ductal hyperplasia (ADH) with and without carcinoma to shed light on breast cancer progression. Fourteen out of twenty isolated ADH cases harboured at least one copy number alteration (CNA), but had fewer aberrations than LG or HG ductal carcinoma in situ (DCIS). ADH carried more HG-like CNA than LG DCIS (e.g. 8q gain). Correspondingly, 64% (7/11) of ADH cases with synchronous HG carcinoma were clonally related, similar to LG carcinoma (67%, 6/9). This study represents a significant shift in our understanding of breast cancer progression, with ADH as a common precursor lesion to the independent 'low grade-like' and 'high grade-like' pathways. These data suggest that ADH can be a precursor of HG breast cancer and that LG and HG carcinomas can evolve from a similar ancestor lesion. We propose that although LG DCIS may be committed to a LG molecular pathway, ADH may remain multipotent, progressing to either LG or HG carcinoma. This multipotent nature suggests that some ADH cases could be more clinically significant than LG DCIS, requiring biomarkers for personalising management. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Publisher: S. Karger AG
Date: 2000
DOI: 10.1159/000052878
Abstract: In a series of studies, we have hypothesised that endometriotic proliferation is, in part, precipitated by mutations in oncogenes or deletions in tumor suppressor genes that have been shown to be important steps in the transformation from a benign to a malignant epithelium. We reported previously that we could find no mutations in the i TP53 /i and i RASK /i genes in cases of endometriosis. However, having shown that endometriotic deposits were monoclonal, we showed loss of heterozygosity on chromosomes 9p (18%), 11q (18%), and 22q (15%) – in total 28% of endometriotic lesions showed loss of heterozygosity at one or more sites [1]. We could not demonstrate any loss of heterozygosity in normal endometrium. We examined adjacent endometriosis, atypical endometriosis, and endometrioid carcinoma of the ovary and showed common genetic alterations that are consistent with a common lineage. These common alterations were not seen in lesions that were distant from each other [2]. In endometrioid tumors, we reported an increased frequency of mutations in the i PTEN/MMAC /i tumor suppressor genes that was not seen in clear cell or serous carcinoma, suggesting distinct developmental pathways for these tumors [3].
Publisher: American Association for Cancer Research (AACR)
Date: 06-2011
DOI: 10.1158/1078-0432.CCR-10-3405
Abstract: Purpose: An assay for the single-nucleotide polymorphism (SNP), rs61764370, has recently been commercially marketed as a clinical test to aid ovarian cancer risk evaluation in women with family histories of the disease. rs67164370 is in a 3′-UTR miRNA binding site of the KRAS oncogene and is a candidate for epithelial ovarian cancer (EOC) susceptibility. However, only one published article, analyzing fewer than 1,000 subjects in total, has examined this association. Experimental Design: Risk association was evaluated in 8,669 cases of invasive EOC and 10,012 controls from 19 studies participating in the Ovarian Cancer Association Consortium, and in 683 cases and 2,044 controls carrying BRCA1 mutations from studies in the Consortium of Investigators of Modifiers of BRCA1/2. Prognosis association was also examined in a subset of five studies with progression-free survival (PFS) data and 18 studies with all-cause mortality data. Results: No evidence of association was observed between genotype and risk of unselected EOC (OR = 1.02, 95% CI: 0.95–1.10), serous EOC (OR = 1.08, 95% CI: 0.98–1.18), familial EOC (OR = 1.09, 95% CI: 0.78–1.54), or among women carrying deleterious mutations in BRCA1 (OR = 1.09, 95% CI: 0.88–1.36). There was little evidence for association with survival time among unselected cases (HR = 1.10, 95% CI: 0.99–1.22), among serous cases (HR = 1.12, 95% CI = 0.99–1.28), or with PFS in 540 cases treated with carboplatin and paclitaxel (HR = 1.18, 95% CI: 0.93–1.52). Conclusions: These data exclude the possibility of an association between rs61764370 and a clinically significant risk of ovarian cancer or of familial ovarian cancer. Use of this SNP for ovarian cancer clinical risk prediction, therefore, seems unwarranted. Clin Cancer Res 17(11) 3742–50. ©2011 AACR.
Publisher: Springer Science and Business Media LLC
Date: 09-01-2018
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/1078-0432.23685621.V1
Abstract: Detail description of the functional categorization of analyzed CHEK2 missense variants.
Publisher: Elsevier BV
Date: 05-2002
DOI: 10.1016/S0303-7207(02)00063-1
Abstract: Although DNA microarray analysis is presented as a revolution in gene expression studies, it is in fact based on the classic technique of Southern DNA hybridisation where a labelled DNA probe is hybridised to single stranded DNA that is bound to a solid support matrix. The truly revolutionary aspect of microarray analysis lies in the fact that, within a given cell population, the expression of tens of thousands of genes, and ultimately the entire genome, can be assayed simultaneously. This capability, when coupled with powerful data analysis software, allows researchers to rapidly compare gene expression between two cell populations. In the cancer field, this enables researchers to compare gene expression between normal and malignant cells and to identify genes that are differentially regulated during cancer development. Microarray data can also be used to categorize tumours on the basis of their molecular profile, which may provide important biological, diagnostic and prognostic information. As little as 5 years ago identifying even a few differentially expressed genes may have taken several years and cost tens of thousands of dollars. Today microarrays can identify ten times the number of candidate genes in just a few months and at a tenth of the cost. Even so, microarray analysis is still in its infancy and the technology is advancing rapidly. There is little doubt that microarrays will revolutionize our ability to quantify the complex changes that occur in gene expression during cancer development. The greatest challenge that lies ahead is how to translate this knowledge into clinically useful diagnostic and therapeutic tools. In this review, we describe the technical aspects of DNA microarray analysis and some of the current and future applications of this technology for analysing gene expression in ovarian cancer.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952414.V1
Abstract: List of all analyzed CHEK2 variants with results of KAP1/CHK2 kinase and localization assays and the results from recent previously published functional analyses of the CHEK2 VUS.
Publisher: Humana Press
Date: 2001
DOI: 10.1385/1-59259-071-3:365
Abstract: Although cancer is fundamentally a genetic disease, in the majority of cancers the mutations occur somatically (i.e., only in the tissue from which the cancer is derived). However, for many types of cancer, for ex le, breast, ovarian, and colorectal cancer there are a small number of cases that arise because of an inherited germline mutation. Genetic linkage analysis of such families enables the likely location of the TSG to be determined and has proven very successful in cloning some important TSGs. However, the genes responsible for inherited predisposition to cancer represent only a fraction of the total number of genetic defects that underlie the disease process.
Publisher: American Association for Cancer Research (AACR)
Date: 10-2005
Publisher: Springer Science and Business Media LLC
Date: 31-10-2007
DOI: 10.1007/S10549-007-9799-X
Abstract: Several studies in various populations have suggested that non-synonymous BARD1 variants are associated with increased breast cancer risk. Using DHPLC analysis we screened the coding region of BARD1 for variants in 210 probands of breast cancer families including 129 families with no mutations in BRCA1 or BRCA2. These families were ascertained in Australia through the Kathleen Cunningham Foundation Consortium for Research into Familial Breast Cancer (kConFab). Nine coding variants were detected among the kConFab families, including two novel variants (Thr598Ile and Ile692Thr). The frequency of five of these variants were evaluated in 258 non-cancer controls and 401 women with sporadic breast cancer. Three variants (1139del21, G1756C and A2285G) were detected in all three groups at a similar frequency suggesting that these do not represent BRCAX candidates. Two variants (Thr598Ile and Ile692Thr) were not detected in any of the 659 sporadic breast cancer cases and controls and were assessed for segregation with breast cancer in the families of the probands. However, neither variant was identified in any other breast cancer case in either family suggesting that these variants are non-pathogenic polymorphisms. We have found no evidence to support involvement of BARD1 in familial breast cancer risk in the Australian population. In addition, three variants previously reported to be pathogenic in other populations are likely to represent benign polymorphisms and therefore we conclude that BARD1 is unlikely to represent a high-penetrance breast cancer susceptibility gene.
Publisher: Oxford University Press (OUP)
Date: 10-10-2022
DOI: 10.1093/JNCI/DJAC160
Abstract: Known risk alleles for epithelial ovarian cancer (EOC) account for approximately 40% of the heritability for EOC. Copy number variants (CNVs) have not been investigated as EOC risk alleles in a large population cohort. Single nucleotide polymorphism array data from 13 071 EOC cases and 17 306 controls of White European ancestry were used to identify CNVs associated with EOC risk using a rare admixture maximum likelihood test for gene burden and a by-probe ratio test. We performed enrichment analysis of CNVs at known EOC risk loci and functional biofeatures in ovarian cancer–related cell types. We identified statistically significant risk associations with CNVs at known EOC risk genes BRCA1 (PEOC = 1.60E-21 OREOC = 8.24), RAD51C (Phigh-grade serous ovarian cancer [HGSOC] = 5.5E-4 odds ratio [OR]HGSOC = 5.74 del), and BRCA2 (PHGSOC = 7.0E-4 ORHGSOC = 3.31 deletion). Four suggestive associations (P & .001) were identified for rare CNVs. Risk-associated CNVs were enriched (P & .05) at known EOC risk loci identified by genome-wide association study. Noncoding CNVs were enriched in active promoters and insulators in EOC-related cell types. CNVs in BRCA1 have been previously reported in smaller studies, but their observed frequency in this large population-based cohort, along with the CNVs observed at BRCA2 and RAD51C gene loci in EOC cases, suggests that these CNVs are potentially pathogenic and may contribute to the spectrum of disease-causing mutations in these genes. CNVs are likely to occur in a wider set of susceptibility regions, with potential implications for clinical genetic testing and disease prevention.
Publisher: Elsevier BV
Date: 10-1992
DOI: 10.1016/S0888-7543(05)80236-8
Abstract: There has been interest in the high affinity folate receptor (FOLR) recently because of its high expression in the majority of ovarian tumors. The FOLR genes are part of a family that includes an adult gene, a fetal gene, and one or more pseudogenes, which have been localized to chromosome 11. As a step toward understanding why the adult FOLR gene product is expressed on tumors, we have determined the organization of all the human FOLR-related genes. YAC clones were isolated using the adult FOLR probe. The organization of the locus was determined by PFGE of YAC DNA and by YAC fragmentation. Four FOLR-related genes were found within 140 kb. The adult and fetal genes are not more than 23 kb apart, with the 3' end of the adult gene facing the 5' of the fetal gene. A physical map of over 900 kb of the surrounding region was also constructed. The chromosomal assignment of the FOLR locus was refined to 11q13.3-q13.5 telomeric of the FGF3 locus using fluorescence in situ hybridization.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952441.V1
Abstract: Results of KAP1 and CHK2 kinase assays for 430 successfully analyzed missense i CHEK2 /i variants (shown as an average relative CHK2 kinase activity). Bars are colored as functionally WT-like (green), intermediate (IM yellow), and impaired (ID red), respectively, with thresholds for IM variants (0.428 and 0.479) and ID variants (0.705 and 0.710) for KAP1 and CHK2 assays, respectively (dashed lines). Error bars represent standard errors of mean. Color/gray letters for protein variants indicate concordant/discordant functional assays result, respectively. Blue boxes denote conserved CHK2 domains. DNL, variants that do not localize into the nucleus.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952420.V1
Abstract: Detail description of the functional categorization of analyzed CHEK2 missense variants.
Publisher: Springer Science and Business Media LLC
Date: 20-12-2007
DOI: 10.1007/S10549-007-9862-7
Abstract: Mutations in BRCA1 predispose to breast cancer. CTIP interacts with BRCA1 and so could also be associated with increased risk. We screened CTIP for germline mutations in 210 probands of breast cancer families including 129 families with no mutations in BRCA1 or BRCA2. No coding variants were detected in CTIP, therefore, it is unlikely to be involved in breast cancer risk.
Publisher: Springer Science and Business Media LLC
Date: 08-08-2023
DOI: 10.1038/S41523-023-00569-4
Abstract: Internationally, population breast cancer screening is moving towards a risk-stratified approach and requires engagement and acceptance from current and future screening clients. A decision aid ( www.defineau.org ) was developed based on women’s views, values, and knowledge regarding risk-stratified breast cancer screening. This study aims to evaluate the impact of the decision aid on women’s knowledge, risk perception, acceptance of risk assessment and change of screening frequency, and decision-making. Here we report the results of a pre and post-survey in which women who are clients of BreastScreen Victoria were invited to complete an online questionnaire before and after viewing the decision aid. 3200 potential participants were invited, 242 responded with 127 participants completing both surveys. After reviewing the decision aid there was a significant change in knowledge, acceptance of risk-stratified breast cancer screening and of decreased frequency screening for lower risk. High levels of acceptance of risk stratification, genetic testing and broad support for tailored screening persisted pre and post review. The DEFINE decision aid has a positive impact on acceptance of lower frequency screening, a major barrier to the success of a risk-stratified program and may contribute to facilitating change to the population breast screening program in Australia.
Publisher: Elsevier BV
Date: 11-1985
DOI: 10.1016/0147-619X(85)90010-1
Abstract: A physical and genetic map of the 125.7-kb IncFIV plasmid R124 was constructed using the restriction enzymes Sal1 and EcoR1. Two discrete regions involved in plasmid replication were identified on the plasmid genome. One region was located on a 4.66-kb segment of an EcoR1 fragment at map coordinates 73.87 to 78.53 kb. Another was located within an 8.05-kb segment of an EcoR1 fragment at map coordinates 113.40 to 121.45. This region was very unstable but, when ligated to the 3.21-kb EcoR1 fragment E13 located at map coordinates 18.83 to 22.06 kb, replication was stable. Thus, at least three regions of R124 widely separated around the genome are associated with plasmid replication and stable maintenance. Each of these three regions expressed incompatibility with R124. The Tc resistance gene of R124 was located on the contiguous EcoR1 fragments E8 and E12 located at map coordinates 100.49 to 113.40.
Publisher: Springer Science and Business Media LLC
Date: 13-05-2012
DOI: 10.1007/S10549-012-2088-3
Abstract: KLLN is a p53 target gene with DNA binding function and represents a highly plausible candidate breast cancer predisposition gene. We screened for predisposing variants in 860 high-risk breast cancer families using high resolution melt analysis. A germline c.339_340delAG variant predicted to cause premature termination of the protein after 57 alternative amino acid residues was identified in 3/860 families who tested negative for BRCA1 and BRCA2 mutations and in 1/84 sporadic breast cancer cases. However, the variant was also detected in 2/182 families with known BRCA1 or BRCA2 mutations and in 2/464 non-cancer controls. Furthermore, loss of the mutant allele was detected in 2/2 breast tumors. Our data suggest that pathogenic mutations in KLLN are rare in breast cancer families and the c.339_340delAG variant does not represent a high-penetrance breast cancer risk allele.
Publisher: MDPI AG
Date: 07-07-2022
DOI: 10.3390/JPM12071112
Abstract: Background Research identifying and returning clinically actionable germline variants offer a new avenue of access to genetic information. The psychosocial and clinical outcomes for women who have received this ‘genome-first care’ delivering hereditary breast and ovarian cancer risk information outside of clinical genetics services are unknown. Methods: An exploratory sequential mixed-methods case-control study compared outcomes between women who did (cases group 1) and did not (controls group 2) receive clinically actionable genetic information from a research cohort in Victoria, Australia. Participants completed an online survey examining cancer risk perception and worry, and group 1 also completed distress and adaptation measures. Group 1 participants subsequently completed a semi structured interview. Results: Forty-five participants (group 1) and 96 (group 2) completed the online survey, and 31 group 1 participants were interviewed. There were no demographic differences between groups 1 and 2, although more of group 1 participants had children (p = 0.03). Group 1 reported significantly higher breast cancer risk perception (p 0.001) compared to group 2, and higher cancer worry than group 2 (p 0.001). Some group 1 participants described how receiving their genetic information heightened their cancer risk perception and exacerbated their cancer worry while waiting for risk-reducing surgery. Group 1 participants reported a MICRA mean score of 27.4 (SD 11.8, range 9–56 possible range 0–95), and an adaptation score of 2.9 (SD = 1.1). Conclusion: There were no adverse psychological outcomes amongst women who received clinically actionable germline information through a model of ‘genome-first’ care compared to those who did not. These findings support the return of clinically actionable research results to research participants.
Publisher: Oxford University Press (OUP)
Date: 2001
Abstract: Endometriosis is generally regarded as a benign disease but it does exhibit some characteristics reminiscent of malignancy. This raises the possibility that, like malignant diseases, the development of endometriosis may involve the acquisition of somatic genetic alterations in genes that regulate cell growth and differentiation. Studies over the past few years have substantiated this view with the identification of a variety of genetic abnormalities usually only associated with malignancies. Our own studies have shown that genetic alterations, as shown by loss of heterozygosity, are relatively common in endometriosis implying that tumour suppressor gene inactivation is likely to be involved in the proliferation and maintenance of all endometriotic implants. We have also shown by DNA fingerprinting that endometriotic lesions found adjacent to ovarian cancers have a common lineage, reinforcing the compelling histological and epidemiological data that endometriosis is a precursor of endometrioid and clear cell ovarian cancers. It is now well accepted that susceptibility to endometriosis may also involve an inherited genetic component. Studies aimed at identifying the predisposing genes are still in their infancy but should eventually provide invaluable insights into the pathology and aetiology of endometriosis.
Publisher: Elsevier BV
Date: 04-2010
DOI: 10.1016/J.YGYNO.2009.12.002
Abstract: Ovarian cancer is the leading cause of death from gynecologic malignancies in the Western world. Fibroblast growth factor receptor (FGFR) signaling has been implicated to play a role in ovarian tumorigenesis. Mutational activation of one member of this receptor family, FGFR2, is a frequent event in endometrioid endometrial cancer. Given the similarities in the histologic and molecular genetics of ovarian and endometrial cancers, we hypothesized that activating FGFR2 mutations may occur in a subset of endometrioid ovarian tumors, and possibly other histotypes. Six FGFR2 exons were sequenced in 120 primary ovarian tumors representing the major histologic subtypes. FGFR2 mutation was detected at low frequency in endometrioid (1/46, 2.2%) and serous (1/41, 2.4%) ovarian cancer. No mutations were detected in clear cell, mucinous, or mixed histology tumors or in the ovarian cancer cell lines tested. Functional characterization of the FGFR2 mutations confirmed that the mutations detected in ovarian cancer result in receptor activation. Despite the low incidence of FGFR2 mutations in ovarian cancer, the two FGFR2 mutations identified in ovarian tumors (S252W, Y376C) overlap with the oncogenic mutations previously identified in endometrial tumors, suggesting activated FGFR2 may contribute to ovarian cancer pathogenesis in a small subset of ovarian tumors.
Publisher: Cold Spring Harbor Laboratory
Date: 02-12-2020
DOI: 10.1101/2020.11.30.20219220
Abstract: Polygenic risk scores (PRS) for epithelial ovarian cancer (EOC) have the potential to improve risk stratification. Joint estimation of Single Nucleotide Polymorphism (SNP) effects in models could improve predictive performance over standard approaches of PRS construction. Here, we implemented computationally-efficient, penalized, logistic regression models (lasso, elastic net, stepwise) to in idual level genotype data and a Bayesian framework with continuous shrinkage, “select and shrink for summary statistics” (S4), to summary level data for epithelial non-mucinous ovarian cancer risk prediction. We developed the models in a dataset consisting of 23,564 non-mucinous EOC cases and 40,138 controls participating in the Ovarian Cancer Association Consortium (OCAC) and validated the best models in three populations of different ancestries: prospective data from 198,101 women of European ancestry 7,669 women of East Asian ancestry 1,072 women of African ancestry, and in 18,915 BRCA1 and 12,337 BRCA2 pathogenic variant carriers of European ancestry. In the external validation data, the model with the strongest association for non-mucinous EOC risk derived from the OCAC model development data was the S4 model (27,240 SNPs) with odds ratios (OR) of 1.38(95%CI:1.28–1.48,AUC:0.588) per unit standard deviation, in women of European ancestry 1.14(95%CI:1.08–1.19,AUC:0.538) in women of East Asian ancestry 1.38(95%CI:1.21-1.58,AUC:0.593) in women of African ancestry hazard ratios of 1.37(95%CI:1.30–1.44,AUC:0.592) in BRCA1 pathogenic variant carriers and 1.51(95%CI:1.36-1.67,AUC:0.624) in BRCA2 pathogenic variant carriers. Incorporation of the S4 PRS in risk prediction models for ovarian cancer may have clinical utility in ovarian cancer prevention programs.
Publisher: Research Square Platform LLC
Date: 10-2019
Abstract: Background Familial cases of appendiceal mucinous tumours (AMTs) are extremely rare and the underlying genetic aetiology uncertain. We identified potential predisposing germline genetic variants in a father and daughter with AMTs presenting with pseudomyxoma peritonei (PMP) and correlated these with regions of loss of heterozygosity (LOH) in the tumours. Materials and Methods Through germline whole exome sequencing, we identified novel heterozygous loss-of-function (LoF) (i.e. nonsense, frameshift and essential splice site mutations) and missense variants shared between father and daughter, and validated all LoF variants, and missense variants with a Combined Annotation Dependent Depletion (CADD) scaled score of ≥10. Genome-wide copy number analysis was performed on tumour tissue from both in iduals to identify regions of LOH. Results Seventeen novel variants in 17 genes were shared by the father and daughter: a nonsense mutation in REEP5 , an essential splice site mutation in THOP1 , and 15 missense variants. None of these germline variants were located in tumour regions of LOH shared by the father and daughter. Four genes ( EXOG , RANBP2, RANBP6 and TNFRSF1B ) harboured missense variants that fell in a region of LOH in the tumour from the father only, but none showed somatic loss of the wild type allele in the tumour. The REEP5 gene was sequenced in 23 in iduals with presumed sporadic PMP no LoF or rare missense germline variants were identified. Conclusion Germline exome sequencing of a father and daughter with AMTs identified novel candidate predisposing genes. Further studies are required to clarify the role of these genes in familial AMTs.
Publisher: Springer Science and Business Media LLC
Date: 17-05-2011
Abstract: MAP2K4 is a putative tumor and metastasis suppressor gene frequently found to be deleted in various cancer types. We aimed to conduct a comprehensive analysis of this gene to assess its involvement in ovarian cancer. We screened for mutations in MAP2K4 using High Resolution Melt analysis of 149 primary ovarian tumors and methylation at the promoter using Methylation-Specific Single-Stranded Conformation Polymorphism analysis of 39 tumors. We also considered the clinical impact of changes in MAP2K4 using publicly available expression and copy number array data. Finally, we used siRNA to measure the effect of reducing MAP2K4 expression in cell lines. In addition to 4 previously detected homozygous deletions, we identified a homozygous 16 bp truncating deletion and a heterozygous 4 bp deletion, each in one ovarian tumor. No promoter methylation was detected. The frequency of MAP2K4 homozygous inactivation was 5.6% overall, and 9.8% in high-grade serous cases. Hemizygous deletion of MAP2K4 was observed in 38% of s les. There were significant correlations of copy number and expression in three microarray data sets. There was a significant correlation between MAP2K4 expression and overall survival in one expression array data set, but this was not confirmed in an independent set. Treatment of JAM and HOSE6.3 cell lines with MAP2K4 siRNA showed some reduction in proliferation. MAP2K4 is targeted by genetic inactivation in ovarian cancer and restricted to high grade serous and endometrioid carcinomas in our cohort.
Publisher: Wiley
Date: 22-03-2023
DOI: 10.1002/CJP2.311
Abstract: Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high‐grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi‐institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36–3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11–2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.
Publisher: Springer Science and Business Media LLC
Date: 10-1995
DOI: 10.1038/BJC.1995.428
Abstract: Somatic mutations in TP53 are seen in many human cancers. In addition, the protein product of the wild-type TP53 can be sequestered by the protein MDM2 (murine double minute 2). This protein is commonly overexpressed in human sarcomas and gliomas, usually as a result of gene lification. In this study, 43 ovarian carcinomas (OCs) were analysed for aberrations in the TP53 gene by immunohistochemistry (IHC), loss of heterozygosity (LOH) or mutation analysis. The MDM2 gene and its product was studied by Southern blotting and IHC. Over 50% of the OCs studied showed mutations in TP53 by either direct sequencing (19/36, 53%), positive IHC (23,43, 53%) or both, whereas 0/32 had lification of MDM2 and only 1/37 tumours had positive IHC using the anti-MDM2 antibody IF-2. The solitary ex le of positive IHC in this series was seen in a mixed müllerian tumour with sarcomatous differentiation and was not accompanied by MDM2 DNA lification. These results support previous data showing that around 50% of OCs have mutations in TP53 and in addition, suggest that MDM2 is not lified in OC, but the presence of sarcomatous features in mixed müllerian tumours may result in positive immunohistochemistry with IF-2.
Publisher: American Association for Cancer Research (AACR)
Date: 15-06-2006
DOI: 10.1158/1078-0432.CCR-06-0800
Abstract: Purpose: A very high frequency of somatic mutations in the transforming growth factor-β signaling component km23 has been reported in a small series of ovarian cancers (8 of 19, 42%). Functional studies showed that some mutations disrupt km23 function, resulting in aberrant transforming growth factor-β signaling and presumably enhanced tumorigenicity. If verified, this would elevate mutation of km23 as the single most frequent somatic event in ovarian cancer. Experimental Design: We sought to verify the frequency of silencing of km23 among 104 primary ovarian cancers (49 serous, 18 mucinous, 29 endometrioid/clear cell, and 8 undifferentiated) as well as 72 breast and 61 colorectal cancers by undertaking both somatic mutation and promoter methylation analyses. All four exons of km23 were in idually lified from genomic DNA with primers complementary to surrounding intronic sequences and analyzed by single-stranded conformational polymorphism analysis. Results: Two germ line polymorphisms were identified, but none of the 237 tumors analyzed harbored somatic km23 mutations. In addition, promoter methylation analysis showed that in all cases, the 5′ CpG island was unmethylated. Conclusions: Our data suggest that silencing of km23, either through somatic genetic mutation or promoter hypermethylation, is rare in ovarian, breast, and colorectal cancers.
Publisher: Elsevier BV
Date: 06-2005
DOI: 10.1016/J.YGYNO.2005.03.007
Abstract: The object of this study was to test the hypothesis that BRAF is a low-risk susceptibility gene for low malignant potential (LMP) ovarian cancer. A recent study of the relationship between BRAF polymorphisms and malignant melanoma identified strong linkage disequilibrium across the BRAF gene with one of the three most common haplotypes (haplotype C) having a population attributable risk of approximately 1.6%. We therefore hypothesized that the same BRAF haplotype may confer an increased risk of serous ovarian tumors of low malignant potential. We genotyped 383 cases of LMP ovarian cancer, including 234 of serous histology, and 987 controls for seven SNPs, representative of the most common BRAF gene haplotypes, using MALDI-TOF mass spectrometry. Haplotype information was obtained for 369 LMP ovarian cancer cases and 983 healthy controls. None of the haplotypes were found to be associated with risk of LMP ovarian cancer (OR for haplotype C 0.81, 95% CI = 0.54-1.22), or with the risk of serous LMP ovarian cancer (OR for haplotype C 0.90, 95% CI = 0.56-1.45). We found no evidence to suggest that BRAF is a low-risk LMP ovarian cancer susceptibility gene.
Publisher: Springer Science and Business Media LLC
Date: 04-11-2011
DOI: 10.1007/S10549-011-1835-1
Abstract: Ductal carcinoma in situ (DCIS) is a non-obligate precursor to invasive ductal carcinoma (IDC). Annotation of the genetic differences between the two lesions may assist in the identification of genes that promote the invasive phenotype. Synchronous DCIS and IDC cells were microdissected from FFPE tissue and analysed by molecular inversion probe (MIP) copy number arrays. Matched IDC and DCIS showed highly similar copy number profiles (average of 83% of the genome shared) indicating a common clonal origin although there is evidence that the DCIS continues to evolve in parallel with the co-existing IDC. Four chromosomal regions of loss (3q, 6q, 8p and 11q) and four regions of gain (5q, 16p, 19q and 20) were recurrently affected in IDC but not in DCIS. CCND1 and MYC showed increased litude of gain in IDC. One region of loss (17p11.2) was specific to DCIS. IDC-specific regions include genes with previous links to breast cancer progression and potential therapeutic targets such as AXL, SPHK1 and PLAUR.
Publisher: BMJ
Date: 23-02-2015
DOI: 10.1136/JCLINPATH-2014-202824
Abstract: Low-grade fibromatosis-like spindle cell carcinomas are very rare breast carcinomas comprising <0.5% of all breast cancers. They demonstrate immunohistochemical (IHC) features of basal-like/metaplastic breast carcinomas, but the underlying molecular characteristics are unknown. We hypothesised that, as with IHC similarities, there may be common genomic alterations between spindle cell and basal-like/metaplastic carcinomas. Genomic mutational profile and genomic copy number aberration (CNA) analyses were performed on three cases of this unusual entity, and findings were compared with that reported for basal-like/metaplastic breast carcinomas. Copy number analyses by molecular inversion probe assays of the three spindle cell carcinoma s les revealed little overall genomic CNAs with only minor changes identified (fraction of the genome altered 1.3%-6.4%), but with a common 9p21.3 loss in 2 out of 3 s les, with CDKN2A (p16) being a likely candidate. No areas of commonality were identified in an in silico analysis compared with publically available basal-like/metaplastic carcinoma copy number data. These tumours are characterised by low genomic instability, and share no CNAs with other metaplastic carcinomas. These findings favour this entity being a unique group genotype and belie their apparent homogeneous morphology and phenotype.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952453.V1
Abstract: Geographical origin of analyzed i CHEK2 /i missense variants.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.C.6532782
Abstract: AbstractPurpose: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. Experimental Design: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC ( i n /i = 333), mucinous borderline ovarian tumors (MBOT, i n /i = 151), and upper GI ( i n /i = 65) and lower GI tumors ( i n /i = 55). Results: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77 95% confidence interval (CI), 1.04–7.41, i P /i = 0.042]. Increased expression of i THBS2 /i and i TAGLN /i was associated with shorter OS in MOC patients (HR, 1.25 95% CI, 1.04–1.51, i P /i = 0.016) and (HR, 1.21 95% CI, 1.01–1.45, i P /i = 0.043), respectively. i ERBB2 /i (HER2) lification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). Conclusions: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of i THBS2 /i and i TAGLN /i in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC s les clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies. /
Publisher: Elsevier BV
Date: 1990
DOI: 10.1016/0009-8981(90)90033-O
Abstract: Transforming growth factor beta-1 (TGF-beta 1) has been proposed as a mediator of tumour growth in a number of tumours and cell lines including prostate, and in a recent study was shown to be up-regulated in the stroma of breast cancer tissue following treatment with the anti-oestrogen tamoxifen. Immunolocalisation of the intracellular form of TGF-beta 1 confirmed that the source of the stromal TGF-beta 1 was the peritumoral fibroblasts. We present here the results of a study in which five patients with hormonally unresponsive prostatic carcinoma and seven patients responding to a luteinising hormone-releasing hormone analogue had prostate biopsies taken before and during treatment. These were stained for TGF-beta expression prior to treatment and at either relapse or 3 months later respectively. Six of seven clinically responding tumours and three of five relapsed tumours showed up-regulation of extracellular TGF-beta 1, again primarily in the stroma, with no apparent up-regulation of intracellular TGF-beta 1, TGF-beta 2 or TGF-beta 3. These data illustrate that the epithelial growth inhibitor TGF-beta 1 can be induced by hormonal manipulation in prostate cancer in vivo, and may continue to be up-regulated even after relapse. This suggests that relapse of hormonally treated prostate cancer may be associated with a failure of the epithelium to respond to stromal TGF-beta 1.
Publisher: Elsevier BV
Date: 11-2008
DOI: 10.1593/NEO.08718
Abstract: Chromodomain, helicase, DNA binding 5 (CHD5) is a member of a subclass of the chromatin remodeling Swi/Snf proteins and has recently been proposed as a tumor suppressor in a erse range of human cancers. We analyzed all 41 coding exons of CHD5 for somatic mutations in 123 primary ovarian cancers as well as 60 primary breast cancers using high-resolution melt analysis. We also examined methylation of the CHD5 promoter in 48 ovarian cancer s les by methylation-specific single-stranded conformation polymorphism and bisulfite sequencing. In contrast to previous studies, no mutations were identified in the breast cancers, but somatic heterozygous missense mutations were identified in 3 of 123 ovarian cancers. We identified promoter methylation in 3 of 45 s les with normal CHD5 and in 2 of 3 s les with CHD5 mutation, suggesting these tumors may have biallelic inactivation of CHD5. Hemizygous copy number loss at CHD5 occurred in 6 of 85 s les as assessed by single nucleotide polymorphism array. Tumors with CHD5 mutation or methylation were more likely to have mutation of KRAS or BRAF (P = .04). The aggregate frequency of CHD5 haploinsufficiency or inactivation is 16.2% in ovarian cancer. Thus, CHD5 may play a role as a tumor suppressor gene in ovarian cancer however, it is likely that there is another target of the frequent copy number neutral loss of heterozygosity observed at 1p36.
Publisher: Hindawi Limited
Date: 04-11-2011
DOI: 10.1002/HUMU.21625
Abstract: There is strong evidence that overtly inactivating mutations in RAD51C predispose to hereditary breast and ovarian cancer but the prevalence of such mutations, and whether they are associated with a particular clinical phenotype, remains unclear. Resolving these questions has important implications for the implementation of RAD51C into routine clinical genetic testing. Consequently, we have performed a large RAD51C mutation screen of hereditary breast and ovarian cancer families, and the first study of unselected patients diagnosed with ovarian cancer. Our data confirm a consistent but low frequency (2/335 families) of inactivating RAD51C mutations among families with a history of both breast and ovarian cancer and an absence of mutations among breast cancer only families (0/1,053 families). Our data also provide support for the designation of the missense variant p.Gly264Ser as a moderate penetrance allele.
Publisher: Springer Science and Business Media LLC
Date: 21-06-2016
Publisher: Wiley
Date: 08-03-2019
DOI: 10.1002/PATH.5251
Abstract: Breast cancer (BC) diagnosed after a negative mammogram but prior to the next screening episode is termed an 'interval BC' (IBC). Understanding the molecular differences between IBC and screen-detected BCs (SDBC) could improve mammographic screening and management options. Therefore, we assessed both germline and somatic genomic aberrations in a prospective cohort. Utilising the Lifepool cohort of >54 000 women attending mammographic screening programs, 930 BC cases with screening status were identified (726 SDBC and 204 IBC). Clinico-pathological and family history information were recorded. Germline and tumour DNA were collected where available and sequenced for BC predisposition and driver gene mutations. Compared to SDBC, IBCs were significantly associated with a younger age at diagnosis and tumour characteristics associated with worse prognosis. Germline DNA assessment of BC cases that developed post-enrolment (276 SDBCs and 77 IBCs) for pathogenic mutations in 12 hereditary BC predisposition genes identified 8 carriers (2.27%). The germline mutation frequency was higher in IBC versus SDBC, although not statistically significant (3.90% versus 1.81%, p = 0.174). Comparing somatic genetic features of IBC and SDBC matched for grade, histological subtype and hormone receptor revealed no significant differences, with the exception of higher homologous recombination deficiency scores in IBC, and copy number changes on chromosome Xq in triple negative SDBCs. Our data demonstrates that while IBCs are clinically more aggressive than SDBC, when matched for confounding clinico-pathological features they do not represent a unique molecular class of invasive BC, but could be a consequence of timing of tumour initiation and mammographic screening. Copyright © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2011
DOI: 10.1158/1078-0432.CCR-10-3314
Abstract: Purpose: Ovarian clear cell adenocarcinoma (OCCA) is an uncommon histotype that is generally refractory to platinum-based chemotherapy. We analyze here the most comprehensive gene expression and copy number data sets, to date, to identify potential therapeutic targets of OCCA. Experimental Design: Gene expression and DNA copy number were carried out using primary human OCCA tumor s les, and findings were confirmed by immunohistochemistry on tissue microarrays. Circulating interleukin (IL) 6 levels were measured in serum from patients with OCCA or high-grade serous cancers and related to progression-free and overall survival. Two patients were treated with sunitinib, and their therapeutic responses were measured clinically and by positron emission tomography. Results: We find specific overexpression of the IL6-STAT3-HIF (interleukin 6-signal transducer and activator of transcription 3-hypoxia induced factor) pathway in OCCA tumors compared with high-grade serous cancers. Expression of PTHLH and high levels of circulating IL6 in OCCA patients may explain the frequent occurrence of hypercalcemia of malignancy and thromboembolic events in OCCA. We describe lification of several receptor tyrosine kinases, most notably MET, suggesting other potential therapeutic targets. We report sustained clinical and functional imaging responses in two OCCA patients with chemotherapy-resistant disease who were treated with sunitinib, thus showing significant parallels with renal clear cell cancer. Conclusions: Our findings highlight important therapeutic targets in OCCA, suggest that more extensive clinical trials with sunitinib in OCCA are warranted, and provide significant impetus to the growing realization that OCCA is molecularly and clinically distinct to other forms of ovarian cancer. Clin Cancer Res 17(8) 2538–48. ©2011 AACR.
Publisher: Springer Science and Business Media LLC
Date: 13-04-2008
DOI: 10.1038/NG.117
Publisher: American Association for Cancer Research (AACR)
Date: 15-03-2007
DOI: 10.1158/0008-5472.CAN-06-3597
Abstract: Formalin-fixed, paraffin-embedded (FFPE) material tends to yield degraded DNA and is thus suboptimal for use in many downstream applications. We describe an integrated analysis of genotype, loss of heterozygosity (LOH), and copy number for DNA derived from FFPE tissues using oligonucleotide microarrays containing over 500K single nucleotide polymorphisms. A prequalifying PCR test predicted the performance of FFPE DNA on the microarrays better than age of FFPE s le. Although genotyping efficiency and reliability were reduced for FFPE DNA when compared with fresh s les, closer examination revealed methods to improve performance at the expense of variable reduction in resolution. Important steps were also identified that enable equivalent copy number and LOH profiles from paired FFPE and fresh frozen tumor s les. In conclusion, we have shown that the Mapping 500K arrays can be used with FFPE-derived s les to produce genotype, copy number, and LOH predictions, and we provide guidelines and suggestions for application of these s les to this integrated system. [Cancer Res 2007 (6):2544–51]
Publisher: Wiley
Date: 2000
DOI: 10.1002/1097-0215(20000915)87:6<798::AID-IJC6>3.0.CO;2-X
Abstract: Loss of heterozygosity on chromosome 22q was detected in 53% of 123 ovarian carcinomas, suggesting the presence of at least one tumour suppressor gene. We have refined the location of one possible tumour suppressor gene to the region between the microsatellite markers D22S299 and CYP2D. Located within this region are the genes SREBP2 (sterol regulatory element binding protein 2) and NAGA (N-acetyl-alpha-D-galactosaminidase). Investigation of the coding exons of these genes by single stranded conformational polymorphism/heteroduplex analysis failed to identify any somatic genetic alterations in 57 ovarian tumours which exhibited LOH on 22q13. The CYP2D gene locus straddles the distal boundary of the candidate region. Germline variants of the active CYP2D6 gene with differing abilities to metabolise specific substrates have been implicated in the development of various cancers. Comparison of the frequency of the two common germline mutations among 258 ovarian tumours and 231 non-cancer controls did not reveal any significant differences between the two groups. This suggests that the known polymorphic variants of CYP2D6 are not involved in ovarian cancer predisposition. We also conclude that neither NAGA nor SREBP2 are likely to be mutated in ovarian carcinomas.
Publisher: Public Library of Science (PLoS)
Date: 27-05-2011
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488651
Abstract: Supplementary Methods
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488654
Abstract: Supplementary Figures S1-S13
Publisher: Informa UK Limited
Date: 15-02-2009
DOI: 10.4161/CC.8.4.7669
Abstract: Recent evidence on the genomic integrity of non-malignant cells surrounding carcinoma cells has reinvigorated the discussion about the origin of the altered phenotype exhibited by carcinoma associated fibroblasts. Many hypotheses have been proposed for the origin of these altered cells, including standard connective tissue acute phase and stress response, fibroblast senescence, reciprocal interactions with the cancer cells, fibroblast specific somatic mutations, differentiation precursors and infiltrating mesenchymal stem cells. Here we review the definition of CAF phenotype and the evidence for each of those hypotheses, in the context of our current understanding of cancer etiology.
Publisher: American Association for Cancer Research (AACR)
Date: 15-12-2006
DOI: 10.1158/0008-5472.CAN-06-1968
Abstract: Ovarian cancer is the major cause of death from gynecological malignancy, and there is an urgent need for new therapeutic targets. The phosphatidylinositol 3-kinase (PI3K)/AKT pathway has been strongly implicated in the genesis of ovarian cancer. However, to identify and evaluate potential targets for therapeutic intervention, it is critical to understand the mechanism by which the PI3K/AKT pathway facilitates ovarian carcinogenesis. Here, we show that AKT3 is highly expressed in 19 of 92 primary ovarian tumors. Strikingly, purified AKT3 exhibited up to 10-fold higher specific activity than AKT1, potentially lifying the effects of AKT3 overexpression. Consistent with this finding, AKT3 levels in a range of ovarian cancer cell lines correlated with total AKT activity and proliferation rates, implicating AKT3 as a key mediator of ovarian oncogenesis. Specific silencing of AKT3 using short hairpin RNA markedly inhibited proliferation of the two cell lines with highest AKT3 expression and total AKT activity, OVCA429 and DOV13, by slowing G2-M phase transition. These findings are consistent with AKT3 playing a key role in the genesis of at least one subset of ovarian cancers. (Cancer Res 2006 66(24): 11718-25)
Publisher: Springer Science and Business Media LLC
Date: 15-06-2015
DOI: 10.1038/NG.3336
Publisher: Oxford University Press (OUP)
Date: 31-10-2022
DOI: 10.1093/JNCI/DJAC196
Abstract: Breast cancers (BCs) that arise in in iduals heterozygous for a germline pathogenic variant in a susceptibility gene, such as BRCA1 and BRCA2, PALB2, and RAD51C, have been shown to exhibit biallelic loss in the respective genes and be associated with triple-negative breast cancer (TNBC) and distinctive somatic mutational signatures. Tumor sequencing thus presents an orthogonal approach to assess the role of candidate genes in BC development. Exome sequencing was performed on paired normal-breast tumor DNA from 124 carriers of germline loss-of-function (LoF) or missense variant carriers in 15 known and candidate BC predisposition genes identified in the BEACCON case-control study. Biallelic inactivation and association with tumor genome features including mutational signatures and homologous recombination deficiency (HRD) score were investigated. BARD1-carrying TNBC (4 of 5) displayed biallelic loss and associated high HRD scores and mutational signature 3, as did a RAD51D-carrying TNBC and ovarian cancer. Biallelic loss was less frequent in BRIP1 BCs (4 of 13) and had low HRD scores. In contrast to other established BC genes, BCs from carriers of CHEK2 LoF (6 of 17) or missense (2 of 20) variant had low rates of biallelic loss. Exploratory analysis of BC from carriers of LoF variants in candidate genes such as BLM, FANCM, PARP2, and RAD50 found little evidence of biallelic inactivation. BARD1 and RAD51D behave as classic BRCA-like predisposition genes with biallelic inactivation, but this was not observed for any of the candidate genes. However, as demonstrated for CHEK2, the absence of biallelic inactivation does not provide definitive evidence against the gene’s involvement in BC predisposition.
Publisher: American Association for Cancer Research (AACR)
Date: 30-11-2011
DOI: 10.1158/1078-0432.CCR-11-2080
Abstract: Purpose: Serous ovarian carcinomas are the predominant epithelial ovarian cancer subtype and it has been widely believed that some or all of these may arise from precursors derived from the ovarian surface epithelium or fimbriae, although direct molecular evidence for this is limited. This study aimed to conduct copy number (CN) analysis using a series of benign and borderline serous ovarian tumors to identify underlying genomic changes that may be indicative of early events in tumorigenesis. Experimental Design: High resolution CN analysis was conducted on DNA from the epithelial and fibroblast components of a cohort of benign (N = 39) and borderline (N = 24) serous tumors using the Affymetrix OncoScan assay and SNP6.0 arrays. Results: CN aberrations were detected in the epithelium of only 2.9% (1 of 35) of serous cystadenomas and cystadenofibromas. In contrast, CN aberrations were detected in the epithelium of 67% (16 of 24) of the serous borderline tumors (SBT). Unexpectedly, CN aberrations were detected in the fibroblasts of 33% (13 of 39) of the benign serous tumors and in 15% (3 of 20) of the SBTs. Of the 16 cases with CN aberrations in the fibroblasts, 12 of these carried a gain of chromosome 12. Conclusions: Chromosome 12 trisomy has been previously identified in pure fibromas, supporting the concept that a significant proportion of benign serous tumors are in fact primary fibromas with an associated cystic mass. This is the first high resolution genomic analysis of benign serous ovarian tumors and has shown not only that the majority of benign serous tumors have no genetic evidence of epithelial neoplasia but that a significant proportion may be more accurately classified as primary fibromas. Clin Cancer Res 17(23) 7273–82. ©2011 AACR.
Publisher: Springer Science and Business Media LLC
Date: 10-08-2014
DOI: 10.1038/S41467-019-11862-X
Abstract: Mucinous ovarian carcinoma (MOC) is a unique subtype of ovarian cancer with an uncertain etiology, including whether it genuinely arises at the ovary or is metastatic disease from other organs. In addition, the molecular drivers of invasive progression, high-grade and metastatic disease are poorly defined. We perform genetic analysis of MOC across all histological grades, including benign and borderline mucinous ovarian tumors, and compare these to tumors from other potential extra-ovarian sites of origin. Here we show that MOC is distinct from tumors from other sites and supports a progressive model of evolution from borderline precursors to high-grade invasive MOC. Key drivers of progression identified are TP53 mutation and copy number aberrations, including a notable licon on 9p13. High copy number aberration burden is associated with worse prognosis in MOC. Our data conclusively demonstrate that MOC arise from benign and borderline precursors at the ovary and are not extra-ovarian metastases.
Publisher: Elsevier BV
Date: 1994
DOI: 10.1016/0959-8049(94)90432-4
Abstract: Frequent loss of heterozygosity has been described on several chromosomes in ovarian carcinoma (OC), but few tumour suppressor genes (TSGs) have been analysed. Mutations in the GTPase-related domain (GRD) of the TSG NF1 have been described in tumours not usually associated with neurofibromatosis type 1 (NF1). We analysed 36 OCs for mutations in this domain using single-strand conformation polymorphism. The NF1-GRD can downregulate the active form of p21RAS and, therefore, we analysed the same tumours for mutations in RASK. No cases of mutations in NF1-GRD were seen, and only two cases of RASK mutations were found. Thus, activation of the RAS signalling pathway by RASK or NF1 mutations does not appear to be common in OC.
Publisher: Wiley
Date: 02-2001
DOI: 10.1002/1097-0215(200002)9999:9999<::AID-IJC1050>3.0.CO;2-1
Abstract: Many tumor types including that of the ovary show loss of heterozygosity (LOH) on chromosome arm 7q, which suggests the existence of at least one tumor suppressor gene (TSG) on this chromosome arm. We have studied the region surrounding the putative tumor suppressor gene CUTL1 at 7q22 in 127 epithelial ovarian tumors. LOH was found across 7q22 in 31% of malignant and 14% of benign ovarian tumors. In 16% of the tumors the LOH appeared to be centered on the CUTL1 gene. This gene has been implicated previously as a TSG in both uterine leiomyomas and breast carcinoma. However, mutation analysis of the CUTL1 gene in 47 tumors with 7q22 LOH failed to identify any somatic alterations in the coding regions. This finding suggests that CUTL1 may not be the target of the 7q22 LOH in ovarian cancers.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488645
Abstract: Supplementary Tables S1-S11
Publisher: Springer Science and Business Media LLC
Date: 12-03-2020
DOI: 10.1038/S41523-020-0150-6
Abstract: Intraductal papillomas (IDP) are challenging breast findings because of their variable risk of progression to malignancy. The molecular events driving IDP development and genomic features of malignant progression are poorly understood. In this study, genome-wide CNA and/or targeted mutation analysis was performed on 44 cases of IDP, of which 20 cases had coexisting ductal carcinoma in situ (DCIS), papillary DCIS or invasive ductal carcinoma (IDC). CNA were rare in pure IDP, but 69% carried an activating PIK3CA mutation. Among the synchronous IDP cases, 55% (11/20) were clonally related to the synchronous DCIS and/or IDC, only one of which had papillary histology. In contrast to pure IDP, PIK3CA mutations were absent from clonal cases. CNAs in any of chromosomes 1, 16 or 11 were significantly enriched in clonal IDP lesions compared to pure and non-clonal IDP. The observation that 55% of IDP are clonal to DCIS/IDC indicates that IDP can be a direct precursor for breast carcinoma, not limited to the papillary type. The absence of PIK3CA mutations and presence of CNAs in IDP could be used clinically to identify patients at high risk of progression to carcinoma.
Publisher: Wiley
Date: 02-2005
DOI: 10.1002/IJC.20866
Abstract: A small number of enteroviruses possess the capacity to induce rapid and marked lytic infections in cells of various human malignancies. During screening of representative human enteroviruses for their oncolytic capacity, we observed that echovirus type 1 (EV1) displayed a high level of tropism for human ovarian cancer cells. EV1 is an enterovirus which largely causes asymptomatic infections in humans and whose tissue tropism is primarily regulated via interactions with the I domain of the alpha subunit of cell surface-expressed integrin alpha2beta1. We evaluated the capacity of wild-type EV1 to act as an oncolytic agent of ovarian cancers propagated as cell monolayers, multicellular spheroids or xenografts in SCID mice. EV1 infection of in vitro propagated ovarian cell lines expressing high levels of integrin alpha2beta1 was assessed for specific viral attachment, antibody blockade, induction of cytopathic effect and production of progeny virions. EV1 lytically infected all 8 human ovarian cancer cell lines tested (2008, DOV13, JAM, OVCA-429, OVCAR-3, OVHS-1, OAW-42 and IGROV-1) but not the immortalized normal ovarian surface epithelial cell line (HOSE) or human PBMCs. EV1 challenge was equally effective in the oncolysis of human ovarian cancer cells whether in monolayer or spheroidal environments. The therapeutic efficacy of EV1 was demonstrated by rapid reduction of tumor burden by a single viral intratumoral injection in SCID mice bearing multiple preformed s.c. xenografts. Using an in vivo i.p. human ovarian cancer xenograft model, administration of EV1 was further shown to significantly inhibit the formation and burden of ascites tumors. These findings demonstrate an important proof of principle for employing wild-type EV1 as a potential oncolytic agent in the control of human ovarian cancers.
Publisher: Elsevier BV
Date: 05-2016
Publisher: Springer Science and Business Media LLC
Date: 02-1998
DOI: 10.1038/BJC.1998.108
Abstract: To evaluate the efficacy on best corrected visual acuity (BCVA) and microvascular structure changes of conbercept intravitreal injection for the treatment of macular edema (ME) secondary to different types of retinal vein occlusion (RVO) and to explore the baseline OCTA parameters which were related to the change of BCVA and CRT after the intravitreal conbercept injection to RVO. A retrospective observational study was conducted involving 67 eyes from 67 patients who were diagnosed with ME secondary to RVO between April 2019 to December 2020. The subjects were ided into branch retinal vein occlusion (BRVO) and central retinal vein occlusion (CRVO) according to the involved vessel, subsequently the subjects received intravitreal conbercept treatment. The BCVA and fundus microstructure were measured to identify predictors of effective outcomes. BCVA, central retinal thickness (CRT), fovea avascular zone (FAZ), and foveal vascular density (FVD) in superficial capillary plexus (SCP) were significantly changed from baseline to 6-month follow-up in both CRVO and BRVO. In the BRVO group, age and baseline BCVA were correlated with changes of BCVA, while the baseline CRT, FVD in the DCP, and parafovea vascular density (PFVD) in DCP were associated with changes of CRT ( Intravitreal injections of conbercept can improve BCVA and CRT and change the FVD in SCP effectively both in BRVO and CRVO groups. In addition, the baseline FVD and PFVD in the DCP were related to the change of CRT after intravitreal conbercept treatment.
Publisher: Wiley
Date: 11-09-1998
DOI: 10.1002/(SICI)1097-0215(19980911)77:6<825::AID-IJC4>3.0.CO;2-W
Abstract: Impaired galactose metabolism has been proposed as a risk factor for ovarian cancer and endometriosis, which is a putative precursor of endometrioid and clear cell histological sub-types of ovarian cancer. The prevalence of the most common galactose-I-phosphate uridyl transferase gene mutations, Q188R and N314D, was assessed in 206 women with ovarian cancer, 78 women with endometriosis and 248 controls. No Q188R mutations were found in any of the groups. A statistically significant increase in the frequency of N314D mutations was observed in women with serous and undifferentiated histological sub-types of ovarian cancer, but not mucinous, endometrioid or clear cell sub-types. There were no significant differences observed in the N314D mutation frequency between women with endometriosis (18%) and controls (17%). Our results support previous reports of an association of impaired galactose metabolism with serous and undifferentiated ovarian cancers but contradict previous findings of increased N314D mutation frequencies among women with endometriosis and endometrioid and clear cell sub-types ovarian cancer.
Publisher: Springer Science and Business Media LLC
Date: 26-03-1999
Publisher: Wiley
Date: 20-03-2003
DOI: 10.1002/IJC.11107
Abstract: Ovarian cancer represents a major cause of cancer death among women and yet remarkably little is known about its etiology. The paradigm established by the colorectal carcinogenesis model would suggest that ovarian cancers are likely to arise through malignant transformation of benign ovarian tumors. However, molecular genetic data that could answer this important question is lacking. In our study, we analyzed 80 benign ovarian tumors for TP53 and K-ras mutations and for LOH on chromosomes 6, 7, 9, 11 and 17 using 56 microsatellite markers. Twenty-five percent (5/20) of non-epithelial tumors and 73% (44/60) of epithelial tumors exhibited LOH on at least 1 chromosome arm. A particularly high frequency of LOH was detected among the epithelial tumors on chromosome arms 6q (17%), 7p (17%), 7q (27%) and 11p (18%), which are also regions of frequent LOH among ovarian carcinomas. No K-ras mutations were detected in any tumor but somatic TP53 mutations were detected in 2/34 (6%) serous and 1/26 (4%) mucinous epithelial tumors. In contrast to most previous studies our data is derived from a relatively large number of microdissected tumors and is likely to represent a more accurate picture of the frequency of alterations in these tumors. We conclude that LOH is common in benign ovarian tumors, suggesting that inactivation of tumor suppressor genes are pivotal in their development. The high frequency of alterations is consistent with their being precursors to malignant disease but does not unequivocally prove this continuum. It does however provide a framework for future analysis of the molecular genetic etiology of ovarian tumorigenesis.
Publisher: Wiley
Date: 28-02-2006
DOI: 10.1002/IJC.21706
Abstract: Mutation of PIK3CA, the gene coding for the p110alpha catalytic subunit of phosphoinositide 3-kinase (PI3K), has been reported in a limited range of human tumors. We now report that PIK3CA is also mutated in esophageal tumors. Single-strand conformational polymorphism (SSCP) and denaturing high-performance liquid chromatography (DHPLC) were used to screen all 20 exons of PIK3CA in 101 s les from 95 in iduals with esophageal cancer and/or Barrett's esophagus. Somatic mutation of PIK3CA was detected in 4 of 35 (11.8%) of esophageal squamous cell carcinomas (SCC) and 3 of 50 (6%) adenocarcinomas. No mutations were detected in any of 17 s les of Barrett's esophagus. For PIK3CB, we screened exons 11 and 22, which code for the regions corresponding to the exon 9 and 20 mutational 'hotspots' of PIK3CA. No somatic changes were detected in PIK3CB This study extends previous observations in other tumor types by demonstrating the presence of somatic PIK3CA mutations in both SCC and adenocarcinoma of the esophagus, thus implicating the PI3K pathway in the initiation and/or progression of esophageal cancers.
Publisher: Springer Science and Business Media LLC
Date: 16-06-2015
Publisher: MDPI AG
Date: 20-01-2023
Abstract: FANCI was recently identified as a new candidate ovarian cancer (OC)-predisposing gene from the genetic analysis of carriers of FANCI c.1813C T p.L605F in OC families. Here, we aimed to investigate the molecular genetic characteristics of FANCI, as they have not been described in the context of cancer. We first investigated the germline genetic landscape of two sisters with OC from the discovery FANCI c.1813C T p.L605F family (F1528) to re-affirm the plausibility of this candidate. As we did not find other conclusive candidates, we then performed a candidate gene approach to identify other candidate variants in genes involved in the FANCI protein interactome in OC families negative for pathogenic variants in BRCA1, BRCA2, BRIP1, RAD51C, RAD51D, and FANCI, which identified four candidate variants. We then investigated FANCI in high-grade serous ovarian carcinoma (HGSC) from FANCI c.1813C T carriers and found evidence of loss of the wild-type allele in tumour DNA from some of these cases. The somatic genetic landscape of OC tumours from FANCI c.1813C T carriers was investigated for mutations in selected genes, copy number alterations, and mutational signatures, which determined that the profiles of tumours from carriers were characteristic of features exhibited by HGSC cases. As other OC-predisposing genes such as BRCA1 and BRCA2 are known to increase the risk of other cancers including breast cancer, we investigated the carrier frequency of germline FANCI c.1813C T in various cancer types and found overall more carriers among cancer cases compared to cancer-free controls (p = 0.007). In these different tumour types, we also identified a spectrum of somatic variants in FANCI that were not restricted to any specific region within the gene. Collectively, these findings expand on the characteristics described for OC cases carrying FANCI c.1813C T p.L605F and suggest the possible involvement of FANCI in other cancer types at the germline and/or somatic level.
Publisher: Springer Science and Business Media LLC
Date: 23-10-1997
Abstract: It is presently unclear if ovarian cancers arise through malignant transformation of pre-existing benign tumours. The apparent rarity of loss of heterozygosity (LOH) reported for benign tumours has led to speculation that they lack malignant potential and represent a biological entity distinct from ovarian carcinoma. We reasoned that the absence of detectable LOH may be due to the masking of such losses by contamination with normal tissue present in excess in the majority of benign tumour biopsies. Therefore we utilized a microdissection technique to examine for LOH using 14 microsatellite markers on chromosome arms 6q, 7p, 7q, 9p, 11q and 17p in 31 solitary benign epithelial ovarian tumours. LOH was detected on all chromosome arms with the most frequent LOH occurring on 7p (27%) and 9p (26%). In addition, a point mutation in codon 157 of TP53 was detected in one tumour which is the first report of a TP53 mutation in a solitary benign ovarian tumour. In total 48% of tumours harboured genetic alterations which supports the idea that all benign ovarian tumours may carry a genetic predisposition to malignancy and are therefore not inherently different from their malignant counterparts.
Publisher: Springer Science and Business Media LLC
Date: 13-02-2006
Abstract: Multiple lines of evidence have provided compelling evidence for the existence of a tumor suppressor gene (TSG) on chromosome 7q31.1. ST7 may be the target of this genetic instability but its designation as a TSG is controversial. In this study, we show that, functionally, ST7 behaves as a tumor suppressor in human cancer. ST7 suppressed growth of PC-3 prostate cancer cells inoculated subcutaneously into severe combined immunodeficient mice, and increased the latency of tumor detection from 13 days in control tumors to 23 days. Re-expression of ST7 was also associated with suppression of colony formation under anchorage-independent conditions in MDA-MB-231 breast cancer cells and ST7 mRNA expression was downregulated in 44% of primary breast cancers. Expression profiling of PC-3 cells revealed that ST7 predominantly induces changes in genes involved in re-modeling the extracellular matrix such as SPARC, IGFBP5 and several matrix metalloproteinases. These data indicate that ST7 may mediate tumor suppression through modification of the tumor microenvironment.
Publisher: Wiley
Date: 13-08-2003
DOI: 10.1002/IJC.11343
Abstract: The LIM domain-only genes LMO1 and LMO2 are translocated in acute T cell leukemia (T-ALL) and have been shown to be oncogenes in T lymphoid cells. LMO4, the fourth member of this family, is overexpressed in more than 50% of sporadic breast cancers, suggesting a role in breast oncogenesis. We recently found that LMO4 interacts with the breast/ovarian tumor suppressor BRCA1 and that LMO4 can repress its transcriptional activity. Since proto-oncogene deregulation can result from activating mutations in their coding or regulatory sequences, we explored whether the LMO4 gene undergoes somatic mutagenesis in breast cancer. Mutation analysis of the coding and 3' untranslated regions of the LMO4 gene was performed on 82 primary breast and 22 tumor cell lines. A somatic mutation was detected in one primary breast cancer, at the 3' end of exon 2, but was not present in normal DNA derived from the same patient. This mutation causes a frame-shift and potentially results in a truncated LMO4 polypeptide, LIM1(mut), lacking the second LIM domain. This mutant protein could still bind Ldb1 but no longer associated with CtIP or BRCA1. Our results show that somatic mutations within the LMO4 gene do occur in breast cancer but at a very low frequency. Thus, the primary mechanism by which LMO4 is deregulated in breast cancers appears to reflect overexpression of the gene rather than the acquisition of activating genetic mutations.
Publisher: Wiley
Date: 07-02-2022
DOI: 10.1002/PATH.5849
Abstract: ARID1A (BAF250a) is a component of the SWI/SNF chromatin modifying complex, plays an important tumour suppressor role, and is considered prognostic in several malignancies. However, in ovarian carcinomas there are contradictory reports on its relationship to outcome, immune response, and correlation with clinicopathological features. We assembled a series of 1623 endometriosis‐associated ovarian carcinomas, including 1078 endometrioid (ENOC) and 545 clear cell (CCOC) ovarian carcinomas, through combining resources of the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Canadian Ovarian Unified Experimental Resource (COEUR), local, and collaborative networks. Validated immunohistochemical surrogate assays for ARID1A mutations were applied to all s les. We investigated associations between ARID1A loss/mutation, clinical features, outcome, CD8 + tumour‐infiltrating lymphocytes (CD8 + TILs), and DNA mismatch repair deficiency (MMRd). ARID1A loss was observed in 42% of CCOCs and 25% of ENOCs. We found no associations between ARID1A loss and outcomes, stage, age, or CD8 + TIL status in CCOC. Similarly, we found no association with outcome or stage in endometrioid cases. In ENOC, ARID1A loss was more prevalent in younger patients ( p = 0.012) and was associated with MMRd ( p 0.001) and the presence of CD8 + TILs ( p = 0.008). Consistent with MMRd being causative of ARID1A mutations, in a subset of ENOCs we also observed an association with ARID1A loss‐of‐function mutation as a result of small indels ( p = 0.035, versus single nucleotide variants). In ENOC, the association with ARID1A loss, CD8 + TILs, and age appears confounded by MMRd status. Although this observation does not explicitly rule out a role for ARID1A influence on CD8 + TIL infiltration in ENOC, given current knowledge regarding MMRd, it seems more likely that effects are dominated by the hypermutation phenotype. This large dataset with consistently applied biomarker assessment now provides a benchmark for the prevalence of ARID1A loss‐of‐function mutations in endometriosis‐associated ovarian cancers and brings clarity to the prognostic significance. © 2021 The Pathological Society of Great Britain and Ireland.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952435.V1
Abstract: Presence of analyzed i CHEK2 /i missense variants categorized according to the functional assays in patients with breast cancer (BC pts red numbers) and matched controls (dark green numbers). The association with breast cancer risk (odds ratio OR) were calculated for prevalent variants having ≥10 carriers among patients or controls, respectively. Colors of the numbers in the last column highlight significant association with moderate-or-higher risk (red OR 2), low risk (OR 2), protective variants (green) or variants without significant impact on breast cancer risk (black). Gray rows display variants that were discordant in the kinase assays. DNL, variants that do not localize into the nucleus.
Publisher: American Association for Cancer Research (AACR)
Date: 14-03-2013
DOI: 10.1158/1078-0432.CCR-12-3433
Abstract: Purpose: Ovarian cancer has the highest mortality rate of all the gynecologic malignancies and is responsible for approximately 140,000 deaths annually worldwide. Copy number lification is frequently associated with the activation of oncogenic drivers in this tumor type, but their cytogenetic complexity and heterogeneity has made it difficult to determine which gene(s) within an licon represent(s) the genuine oncogenic driver. We sought to identify licon targets by conducting a comprehensive functional analysis of genes located in the regions of lification in high-grade serous and endometrioid ovarian tumors. Experimental Design: High-throughput siRNA screening technology was used to systematically assess all genes within regions commonly lified in high-grade serous and endometrioid cancer. We describe the results from a boutique siRNA screen of 272 genes in a panel of 18 ovarian cell lines. Hits identified by the functional viability screen were further interrogated in primary tumor cohorts to determine the clinical outcomes associated with lification and gene overexpression. Results: We identified a number of genes as critical for cellular viability when lified, including URI1, PAK4, GAB2, and DYRK1B. Integration of primary tumor gene expression and outcome data provided further evidence for the therapeutic use of such genes, particularly URI1 and GAB2, which were significantly associated with survival in 2 independent tumor cohorts. Conclusion: By taking this integrative approach to target discovery, we have streamlined the translation of high-resolution genomic data into preclinical in vitro studies, resulting in the identification of a number of genes that may be specifically targeted for the treatment of advanced ovarian tumors. Clin Cancer Res 19(6) 1411–21. ©2013 AACR.
Publisher: Springer Science and Business Media LLC
Date: 11-1994
DOI: 10.1038/BJC.1994.418
Abstract: Frequent loss of heterozygosity (LOH) has been reported on 22q in ovarian carcinoma, implying the presence of a tumour-suppressor gene. The neurofibromatosis type 2 gene (NF2) at 22q12 is a plausible candidate. Analysis of 9 of the 17 exons of NF2 by single-strand conformational polymorphism (SSCP) in 67 ovarian carcinomas did not detect any somatic mutations, suggesting that NF2 is not involved in the pathogenesis of ovarian carcinoma. LOH data support this conclusion and that the putative tumour-suppressor gene lies distal to NF2, beyond D22S283.
Publisher: Springer Science and Business Media LLC
Date: 2008
Publisher: Wiley
Date: 05-2015
DOI: 10.1111/IMJ.12736
Abstract: Identifying in iduals with a genetic predisposition to developing familial colorectal cancer (CRC) is crucial to the management of the affected in idual and their family. In order to do so, the physician requires an understanding of the different gene mutations and clinical manifestations of familial CRC. This review summarises the genetics, clinical manifestations and management of the known familial CRC syndromes, specifically Lynch syndrome, familial adenomatous polyposis, MUTYH-associated neoplasia, juvenile polyposis syndrome and Peutz-Jeghers syndrome. An in idual suspected of having a familial CRC with an underlying genetic predisposition should be referred to a familial cancer centre to enable pre-test counselling and appropriate follow up.
Publisher: Springer Science and Business Media LLC
Date: 02-04-2020
DOI: 10.1038/S41467-020-15461-Z
Abstract: High-grade serous ovarian carcinoma (HGSOC) has a significant hereditary component, approximately half of which cannot be explained by known genes. To discover genes, we analyse germline exome sequencing data from 516 BRCA1/2 -negative women with HGSOC, focusing on genes enriched with rare, protein-coding loss-of-function (LoF) variants. Overall, there is a significant enrichment of rare protein-coding LoF variants in the cases ( p 0.0001, chi-squared test). Only thirty-four (6.6%) have a pathogenic variant in a known or proposed predisposition gene. Few genes have LoF mutations in more than four in iduals and the majority are detected in one in idual only. Forty-three highly-ranked genes are identified with three or more LoF variants that are enriched by three-fold or more compared to GnomAD. These genes represent erse functional pathways with relatively few involved in DNA repair, suggesting that much of the remaining heritability is explained by previously under-explored genes and pathways.
Publisher: American Association for Cancer Research (AACR)
Date: 12-2006
DOI: 10.1158/1078-0432.CCR-06-1770
Abstract: Purpose: Germ-line variants in CHEK2 have been associated with increased breast, thyroid, prostate, kidney, and colorectal cancer risk however, the prevalence of somatic inactivation of CHEK2 in common cancer types is less clear. The aim of this study was to determine if somatic mutation and/or epigenetic modification play a role in development of sporadic breast, colon, or ovarian cancers. Experimental Design: We undertook combined genetic and epigenetic analysis of CHEK2 in sporadic primary breast, ovarian, and colon tumors [all exhibiting chromosome 22q loss of heterozygosity (LOH)] and cancer cell lines. Expression of Chk2 was assessed by immunohistochemistry in 119 ovarian tumors. Results: Two novel germ-line variants were identified however, none of the primary tumors harbored somatic mutations. Two CpG clusters previously implicated in CHEK2 silencing were investigated for evidence of hypermethylation. No methylation was detected at the distal CpG island. The proximal CpG cluster was methylated in all tumor and normal DNA, suggesting that this might not represent a true CpG island and is not relevant in the control of CHEK2 expression. Twenty-three percent of ovarian tumors were negative for Chk2 protein by immunohistochemistry, but there was no significant correlation between LOH across the CHEK2 locus and intensity of Chk2 staining (P = 0.12). Conclusions: LOH across the CHEK2 locus is common in sporadic breast, ovarian, and colorectal cancers, but point mutation or epigenetic inactivation of the retained allele is uncommon. Loss of Chk2 protein in ovarian cancer was not associated with allelic status, suggesting that inactivation does not occur as a consequence of haploinsufficiency.
Publisher: Oxford University Press (OUP)
Date: 25-11-2017
DOI: 10.1093/IJE/DYX236
Publisher: American Association for Cancer Research (AACR)
Date: 14-12-2014
DOI: 10.1158/1078-0432.CCR-14-1292
Abstract: Purpose: Low-grade serous ovarian carcinomas (LGSC) are Ras pathway-mutated, TP53 wild-type, and frequently associated with borderline tumors. Patients with LGSCs respond poorly to platinum-based chemotherapy and may benefit from pathway-targeted agents. High-grade serous carcinomas (HGSC) are TP53-mutated and are thought to be rarely associated with borderline tumors. We sought to determine whether borderline histology associated with grade 2 or 3 carcinoma was an indicator of Ras mutation, and we explored the molecular relationship between coexisting invasive and borderline histologies. Experimental Design: We reviewed & ,200 patients and identified 102 serous carcinomas with adjacent borderline regions for analyses, including candidate mutation screening, copy number, and gene expression profiling. Results: We found a similar frequency of low, moderate, and high-grade carcinomas with coexisting borderline histology. BRAF/KRAS alterations were common in LGSC however, we also found recurrent NRAS mutations. Whereas borderline tumors harbored BRAF/KRAS mutations, NRAS mutations were restricted to carcinomas, representing the first ex le of a Ras oncogene with an obligatory association with invasive serous cancer. Coexisting borderline and invasive components showed nearly identical genomic profiles. Grade 2 cases with coexisting borderline included tumors with molecular features of LGSC, whereas others were typical of HGSC. However, all grade 3 carcinomas with coexisting borderline histology were molecularly indistinguishable from typical HGSC. Conclusion: Our findings suggest that NRAS is an oncogenic driver in serous ovarian tumors. We demonstrate that borderline histology is an unreliable predictor of Ras pathway aberration and underscore an important role for molecular classification in identifying patients that may benefit from targeted agents. Clin Cancer Res 20(24) 6618–30. ©2014 AACR.
Publisher: Springer Science and Business Media LLC
Date: 28-08-2014
Publisher: Springer Science and Business Media LLC
Date: 17-01-2022
DOI: 10.1038/S41523-021-00373-Y
Abstract: While protein-truncating variants in RAD51C have been shown to predispose to triple-negative (TN) breast cancer (BC) and ovarian cancer, little is known about the pathogenicity of missense (MS) variants. The frequency of rare RAD51C MS variants was assessed in the BEACCON study of 5734 familial BC cases and 14,382 population controls, and findings were integrated with tumour sequencing data from 21 cases carrying a candidate variant. Collectively, a significant enrichment of rare MS variants was detected in cases (MAF 0.001, OR 1.57, 95% CI 1.00–2.44, p = 0.05), particularly for variants with a REVEL score .5 (OR 3.95, 95% CI 1.40–12.01, p = 0.006). Sequencing of 21 tumours from 20 heterozygous and 1 homozygous carriers of nine candidate MS variants identified four cases with biallelic inactivation through loss of the wild-type allele, while six lost the variant allele and ten that remained heterozygous. Biallelic loss of the wild-type alleles corresponded strongly with ER- and TN breast tumours, high homologous recombination deficiency scores and mutational signature 3. Using this approach, the p.Gly264Ser variant, which was previously suspected to be pathogenic based on small case–control analyses and loss of activity in in vitro functional assays, was shown to be benign with similar prevalence in cases and controls and seven out of eight tumours showing no biallelic inactivation or characteristic mutational signature. Conversely, evaluation of case–control findings and tumour sequencing data identified p.Ile144Thr, p.Arg212His, p.Gln143Arg and p.Gly114Arg as variants warranting further investigation.
Publisher: Elsevier BV
Date: 02-2006
DOI: 10.1016/J.CANLET.2005.03.008
Abstract: LZTS1 has been shown to have tumour suppressor activities against prostate and breast cancer and is located within a region of frequent loss of heterozygosity (LOH) at 8p22 in ovarian cancer. We have analysed the expression of LZTS1 in ovarian cancer and found no evidence of loss of expression relative to normal ovarian surface epithelial cells. We have also analysed the coding region of the LZTS1 gene in 87 primary ovarian adenocarcinomas by DHPLC and detected a single silent somatic mutation. These data indicate that LZTS1 is not the target of LOH at 8p22 in ovarian cancer.
Publisher: Oxford University Press (OUP)
Date: 2001
Abstract: It is likely that heritable genetic factors contribute to the development of endometriosis, which is a putative precursor of the endometrioid and clear cell histological subtypes of ovarian cancer. The phase II glutathione S-transferases (GSTs) are a family of enzymes responsible for metabolism of a broad range of xenobiotics and carcinogens. Allelic variants of GSTs that have impaired detoxification function may increase the rate of genetic damage and thereby increase the susceptibility to cancer. The null genetic polymorphism in the gene encoding the GST class mu (GSTM1) enzyme has been reported to be significantly elevated in endometriosis patients and may represent an endometriosis susceptibility allele. In this study the frequency of the GSTM1 null genotype was investigated in 84 cases of endometriosis, 293 cases of ovarian cancer and 219 controls. All cases and controls were derived from women resident in the south east of England. The frequency of the GSTM1 null allele was not over-represented in the endometriosis patients (47.6%) compared with the controls (48.9%) (P = 0.898). In the ovarian cancer group the GSTM1 null genotype was significantly elevated compared with controls (59.0 versus 48.9%, P = 0.025). When stratified according to histological subtype a significantly increased GSTM1 null genotype was only observed for the endometrioid (65.4%, P = 0.013) and the combined endometrioid/clear cell ovarian cancers (67.0%, P = 0.004). We conclude that the GSTM1 null allele is not an endometriosis susceptibility allele, however, it may predispose endometriotic lesions to malignant transformation to endometrioid and clear cell ovarian cancer.
Publisher: Elsevier BV
Date: 06-1997
Abstract: The alpha-inhibin gene has been shown in knockout mouse models to be a suppressor of granulosa tumorigenesis in the mouse. To determine if alpha-inhibin has the same function in humans, we have assessed the frequency of loss of heterozygosity (LOH) of the alpha-inhibin gene locus on chromosome 2q in 17 human granulosa cell tumors and 36 epithelial ovarian cancers. LOH was detected in 12 of 36 (33.3%) epithelial tumors but in only 1 of 17 (6%) granulosa cell tumors. These data suggest that in contrast to the suggestions from the mouse model alpha-inhibin does not function as a granulosa cell tumor suppressor gene in the human. Furthermore, analysis of the TP53 gene in the granulosa cell tumors failed to detect either LOH or point mutations, indicating that they have a developmental pathway distinct from that of epithelial ovarian tumors.
Publisher: Springer Science and Business Media LLC
Date: 2020
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/1078-0432.C.6742698.V1
Abstract: AbstractPurpose: Germline pathogenic variants in i CHEK2 /i confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense i CHEK2 /i variants of uncertain significance (VUS) have been identified, h ering the clinical utility of germline genetic testing (GGT). Experimental Design: We collected 460 i CHEK2 /i missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using i CHEK2 /i -complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1– i CHEK2 /i -knockout cells. Concordant results in both functional assays were used to categorize i CHEK2 /i VUS from 12 ENIGMA case–control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls. Results: A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired ( i N /i = 102), functionally intermediate ( i N /i = 12), or functionally wild-type (WT)–like ( i N /i = 226). We then examined their association with breast cancer risk in the case–control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35–3.41), 1.57 (95% CI, 1.41–1.75), and 1.19 (95% CI, 1.08–1.31), respectively. The meta-analysis of population-specific datasets showed similar results. Conclusions: We determined the functional consequences for the majority of i CHEK2 /i missense VUS found in patients with breast cancer (3,660/4,436 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating i CHEK2 /i variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers. /
Publisher: Springer Science and Business Media LLC
Date: 16-07-1998
Abstract: Forty early stage malignant and seven borderline ovarian tumours were analysed for loss of heterozygosity (LOH) on chromosomes 6, 7, 9, 11 and 17. LOH involving at least one locus was observed in 32 (80%) early stage and six (86%) borderline tumours. Frequent LOH in the early stage tumours was detected on chromosome arms 7p (31%), 7q (50%), 9p (42%) and 11q (34%) suggesting that these chromosomes harbour tumour suppressor genes which are inactivated early in tumorigenesis. Borderline tumours exhibited a similar pattern of LOH to that observed in the early stage malignant tumours, indicating that the development of both malignant and borderline forms may involve inactivation of the same set of tumour suppressor genes. Together with our previous investigation of benign ovarian tumours this data supports the theory that malignant ovarian tumours may arise from benign and borderline precursors.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.C.6742698.V2
Abstract: AbstractPurpose: Germline pathogenic variants in i CHEK2 /i confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense i CHEK2 /i variants of uncertain significance (VUS) have been identified, h ering the clinical utility of germline genetic testing (GGT). Experimental Design: We collected 460 i CHEK2 /i missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using i CHEK2 /i -complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1– i CHEK2 /i -knockout cells. Concordant results in both functional assays were used to categorize i CHEK2 /i VUS from 12 ENIGMA case–control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls. Results: A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired ( i N /i = 102), functionally intermediate ( i N /i = 12), or functionally wild-type (WT)–like ( i N /i = 226). We then examined their association with breast cancer risk in the case–control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35–3.41), 1.57 (95% CI, 1.41–1.75), and 1.19 (95% CI, 1.08–1.31), respectively. The meta-analysis of population-specific datasets showed similar results. Conclusions: We determined the functional consequences for the majority of i CHEK2 /i missense VUS found in patients with breast cancer (3,660/4,436 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating i CHEK2 /i variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers. /
Publisher: American Association for Cancer Research (AACR)
Date: 11-2004
DOI: 10.1158/0008-5472.CAN-04-2933
Abstract: Phosphatidylinositol 3′-kinases are lipid kinases with important roles in neoplasia. Recently, a very high frequency of somatic mutations in PIK3CA has been reported among a large series of colorectal cancers. However, the relevance of PIK3CA mutation in other cancer types remains unclear because of the limited number of tumors investigated. We have screened a total of 284 primary human tumors for mutations in all coding exons of PIK3CA using a combination of single stranded conformational polymorphism and denaturing high-performance liquid chromatography analysis. Among 70 primary breast cancers, 40% (28 of 70) harbored mutations in PIK3CA, making it the most common mutation described to date in this cancer type. Mutations were not associated with histologic subtype, estrogen receptor status, grade or presence of tumor in lymph nodes. Among the primary epithelial ovarian cancers only 11 of 167 (6.6%) contain somatic mutations, but there was a clear histologic subtype bias in their distribution. Only 2 of 88 (2.3%) of serous carcinomas had PIK3CA mutations compared with 8 of 40 (20.0%) endometrioid and clear cell cancers, which was highly significant (P = 0.001). In contrast, PIK3CA gene lification (& -fold) was common among all histologic subtypes (24.5%) and was inversely associated with the presence of mutations. Overall, PIK3CA mutation or gene lification was detected in 30.5% of all ovarian cancers and 45% of the endometrioid and clear cell subtypes. Our study is the first direct evidence that PIK3CA is an oncogene in ovarian cancer and greatly extends recent findings in breast cancer.
Publisher: Springer Science and Business Media LLC
Date: 29-04-2005
Publisher: Public Library of Science (PLoS)
Date: 08-04-2010
Publisher: Wiley
Date: 30-03-2018
DOI: 10.1002/PATH.5055
Abstract: PALB2 is established as the most clinically important moderate to high penetrance breast cancer predisposition gene after BRCA1 and BRCA2. Mutations in classical familial cancer predisposition genes are presumed to be recessive at the cellular level and therefore a second inactivating somatic mutation is required in the tumour tissue. However, from the limited data that exist, PALB2 may be an ex le of a cancer predisposition gene that does not conform to Knudson's 'two hit' paradigm. We conducted genome-wide copy number analysis and targeted sequencing of PALB2 and other breast cancer driver genes in 15 invasive breast cancers from in iduals carrying pathogenic germline mutations in PALB2. The majority of cancers showed clear evidence of bi-allelic inactivation of PALB2 (10/15) either as loss of heterozygosity involving the wild-type allele (six tumours) or as somatic point mutations (four tumours). All PALB2-null cancers had high homologous recombination deficiency (HRD) scores consistent with a homologous recombination repair deficiency. Interestingly, all but one of the PALB2 heterozygous cancers also had high HRD scores, suggesting that alternative mechanisms of PALB2 functional loss might be operating in these cancers. Our findings demonstrate that PALB2 does undergo bi-allelic inactivation in the majority of breast cancers from PALB2 germline mutation carriers. This feature has implications for the discovery of new moderate to high penetrance breast cancer predisposition genes as it supports using the existence of a 'second hit' and mutation signatures as important search criteria. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Publisher: Springer Science and Business Media LLC
Date: 06-1998
DOI: 10.1038/BJC.1998.366
Abstract: If genetic testing for breast and ovarian cancer predisposition is to become available within a public health care system there needs to be a rational and cost-effective approach to mutation analysis. We have screened for BRCA1 mutations in 230 women with breast cancer, all from the Wessex region of southern England, in order to establish the parameters on which to base a cost-effective regional mutation analysis strategy. Truncating mutations were detected in 10/155 (6.5%) consecutive cases selected only for diagnosis under the age of 40 (nine of these ten women had a strong family history of breast or ovarian cancer), 3/61 (4.9%) bilateral-breast cancer cases (all three mutations occurring among women for whom the first cancer was diagnosed under 40 years) and 8/30 (26.6%) breast cancer cases presenting to the genetics clinic (for whom a strong family history of breast and/or ovarian cancer was present). Ten different mutations were detected in 17 families, but three of these accounted for 10/17 (59%) of the families. The cost of screening the population for mutations in the entire BRCA1 gene is unacceptably high. However, the cost of screening a carefully selected patient cohort is low, the risk of misinterpretation much less and the potential clinical benefits clearer.
Publisher: Springer Science and Business Media LLC
Date: 23-10-2017
DOI: 10.1038/NG.3785
Publisher: American Association for Cancer Research (AACR)
Date: 06-2019
DOI: 10.1158/1940-6207.CAPR-18-0443
Abstract: In idualized screening is our logical next step to improve population breast cancer screening in Australia. To explore breast screening participants' views of the current program in Victoria, Australia, examine their openness to change, and attitudes toward an in idualized screening model, this qualitative work was performed from a population-based breast screening cohort. This work was designed to inform the development of a decision aid to facilitate women's decisions about participating in in idualized screening, and to elicit Australian consumer perspectives on the international movement toward in idualized breast screening. A total of 52 women participated in one of four focus groups, and were experienced with screening with 90% of participants having had more than three mammograms. Focus group discussion was facilitated following three main themes: (i) experience of breast screening (ii) breast cancer risk perception, and (iii) views on in idualized screening. Participants had strong, positive, emotional ties to breast screening in its current structure but were supportive, with some reservations, of the idea of in idualized screening. There was good understanding about the factors contributing to personalized risk and a wide range of opinions about the inclusion of genetic testing with genetic testing being considered a foreign and evolving domain. In idualized breast screening that takes account of risk factors such as mammographic density, lifestyle, and genetic factors would be acceptable to a population of women who are invested in the current system. The communication and implementation of a new program would be critical to its acceptance and potential success. Reservations may be had in regards to uptake of genetic testing, motivations behind the change, and management of the women allocated to a lower risk category.
Publisher: American Association for Cancer Research (AACR)
Date: 31-08-2009
Publisher: Wiley
Date: 28-07-2008
DOI: 10.1002/GCC.20595
Abstract: High-resolution techniques for analysis of genome copy number (CN) enable the analysis of complex cancer somatic genetics. However, the analysis of these data is difficult, and failure to consider a number of issues in depth may result in false leads or unnecessary rejection of true positives. First, segmental duplications may falsely generate CN breakpoints in aneuploid s les. Second, even when tumor data were each normalized to matching lymphocyte DNA, we still observed copy number polymorphisms masquerading as somatic alterations due to allelic imbalance. We investigated a number of different solutions and determined that evaluating matching normal DNA, or at least using locally derived normal baseline data, were preferable to relying on current online databases because of poor cross-platform compatibility and the likelihood of excluding genuine small somatic alterations.
Publisher: Springer Science and Business Media LLC
Date: 06-10-2022
DOI: 10.1038/S42003-022-03978-6
Abstract: The contribution of germline copy number variants (CNVs) to risk of developing cancer in in iduals with pathogenic BRCA1 or BRCA2 variants remains relatively unknown. We conducted the largest genome-wide analysis of CNVs in 15,342 BRCA1 and 10,740 BRCA2 pathogenic variant carriers. We used these results to prioritise a candidate breast cancer risk-modifier gene for laboratory analysis and biological validation. Notably, the HR for deletions in BRCA1 suggested an elevated breast cancer risk estimate (hazard ratio (HR) = 1.21), 95% confidence interval (95% CI = 1.09–1.35) compared with non-CNV pathogenic variants. In contrast, deletions overlapping SULT1A1 suggested a decreased breast cancer risk (HR = 0.73, 95% CI 0.59-0.91) in BRCA1 pathogenic variant carriers. Functional analyses of SULT1A1 showed that reduced mRNA expression in pathogenic BRCA1 variant cells was associated with reduced cellular proliferation and reduced DNA damage after treatment with DNA damaging agents. These data provide evidence that deleterious variants in BRCA1 plus SULT1A1 deletions contribute to variable breast cancer risk in BRCA1 carriers.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952420
Abstract: Detail description of the functional categorization of analyzed CHEK2 missense variants.
Publisher: Elsevier BV
Date: 03-2007
DOI: 10.1016/J.CANLET.2006.03.024
Abstract: Chromosome 22q shows a high frequency of loss of heterozygosity (LOH) in ovarian cancers suggesting the existence of one or more important tumor suppressor genes (TSGs). The tissue inhibitor of metalloproteinase-3 (TIMP-3) is a plausible TSG candidate since it is often encompassed within these regions of LOH. TIMP-3 has not previously been investigated for somatic mutations or promoter hypermethylation in ovarian cancer. We analyzed 65 ovarian cancers for both somatic genetic mutations and TIMP-3 promoter hypermethylation. Screening of all coding exons of TIMP-3 did not reveal any somatic genetic mutations and only 1/65 showed TIMP-3 methylation. Our data indicate that inactivation of TIMP-3 by somatic mutation or promoter hypermethylation is rare in ovarian cancer.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952426
Abstract: Funnel plot (left) and forest plots (right) for in idual datasets of breast cancer cases and controls from 12 datasets (10 countries) stratified according to the functional categorization.
Publisher: T.M.C. Asser Press
Date: 24-12-2013
Publisher: Wiley
Date: 2006
DOI: 10.1002/MC.20187
Abstract: The incidence of hormone-related diseases such as prostatic, breast, ovarian, and endometrial cancer is lower in Asian populations compared to Western countries. High consumption of soybean products that are rich in phytoestrogens, predominantly genistein, is postulated to be responsible for the lower incidence of hormone-related disease, although the mechanism through which this effect might be mediated is unclear. In this study, microarray analysis was used to identify the changes in gene expression elicited by treatment of the human endometrial cancer cell line, Ishikawa, with genistein at both physiologically achievable and supraphysiological concentrations. Genistein treatment at 5 microM concentration induced multiple changes in gene expression including some implicated in oncogenesis. In contrast, treatment with a supraphysiological concentration of genistein predominantly activated stress response genes and showed very limited overlap with the genes regulated at lower concentrations. Of the genes regulated by genistein, 9.3% were also regulated by 17beta-estradiol suggesting that genistein exerts its response via the estrogen pathway. These results indicate that at physiological concentrations, genistein is able to elicit pleiotropic effects on a variety of pathways believed to be involved in tumorigenesis. Supraphysiological concentrations of genistein, such as those used in many previous studies, elicit changes in gene expression that are unlikely to occur in vivo.
Publisher: Springer Science and Business Media LLC
Date: 06-1997
DOI: 10.1038/BJC.1997.318
Publisher: American Association for Cancer Research (AACR)
Date: 07-10-2022
DOI: 10.1158/1078-0432.CCR-22-1206
Abstract: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC (n = 333), mucinous borderline ovarian tumors (MBOT, n = 151), and upper GI (n = 65) and lower GI tumors (n = 55). Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77 95% confidence interval (CI), 1.04–7.41, P = 0.042]. Increased expression of THBS2 and TAGLN was associated with shorter OS in MOC patients (HR, 1.25 95% CI, 1.04–1.51, P = 0.016) and (HR, 1.21 95% CI, 1.01–1.45, P = 0.043), respectively. ERBB2 (HER2) lification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of THBS2 and TAGLN in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC s les clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies.
Publisher: Oxford University Press (OUP)
Date: 02-2001
Abstract: The production of estrogen from androgen via the estrogen biosynthesis pathway is catalyzed by aromatase P450 (cyp19). We have assessed the frequency of allelic variants of the CYP19 intron 4 [TTTA]n repeat in 327 breast cancer cases and 253 controls from southern England. Previous studies have suggested that the [TTTA](10) repeat and [TTTA](12) repeat variants represent low penetrance breast cancer susceptibility alleles. Compared with controls our breast cancer cases had a statistically significant positive association with the [TTTA](10) allele (1.5 versus 0.2%, P = 0.028) and the [TTTA](8) allele (13.5 versus 8.7%, P = 0.012). The frequency of the [TTTA](12) allele was not significantly elevated in our study group compared with controls (2.3 versus 2.2%, P = 1.00). The CYP19 intron 4 [TTTA]n repeat is unlikely to have a functional effect on aromatase activity and it is more likely that the [TTTA](8) and [TTTA](10) variants are in linkage disequilibrium with other functional CYP19 variants.
Publisher: Wiley
Date: 28-10-2020
DOI: 10.1002/PATH.5545
Publisher: Elsevier BV
Date: 2009
DOI: 10.1016/J.TIG.2008.10.012
Abstract: Increasing evidence indicates that tumor-stromal cell interactions have a crucial role in tumor initiation and progression. These interactions modify cellular compartments, leading to the co-evolution of tumor cells and their microenvironment. Although the importance of microenvironmental alterations in tumor development is recognized, the molecular mechanisms underlying these changes are only now beginning to be understood. Epigenetic and gene expression changes have consistently been reported in cancer-associated stromal cells and the influence of the host genotype on tumorigenesis is also well documented. However, the presence of clonally selected somatic genetic alterations within the tumor microenvironment has been controversial. A thorough understanding of the co-evolution of these two cellular compartments will require carefully executed molecular studies combined with mathematical modeling.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488651.V1
Abstract: Supplementary Methods
Publisher: Wiley
Date: 27-08-1999
DOI: 10.1002/(SICI)1097-0215(19990827)82:5<625::AID-IJC1>3.0.CO;2-2
Abstract: The molecular mechanisms involved in the generation of epithelial ovarian cancers are poorly understood, but evidence suggests that the different histological subtypes may arise from independent tumorigenic events. beta-Catenin is emerging as an important oncogene in the transformation of a number of epithelial cancers, and mutations have been reported in a small study of endometrioid ovarian adenocarcinomas. Mutations in the NH(2)-regulatory domain of beta-catenin stabilise the cytoplasmic levels of this protein, which promotes up-regulation of the beta-catenin-T-cell factor-lymphoid enhancer factor transcriptional complex. We report here beta-catenin (CTNNB1) exon 3 mutation analysis in 149 epithelial ovarian carcinomas. This revealed 10/63 (16%) endometrioid ovarian tumours with activating mutations of the beta-catenin gene. All mutations were missense changes within the GSK3beta consensus site, affecting serine residues at codons 33 and 37 and glycine at codon 34. Immuno-histochemical analysis identified cytoplasmic stabilisation and nuclear translocation in those endometrioid tumours with mutations. This phenotypic change was also identified in 3 other endometrioid tumours that did not have somatic mutations within exon 3 of CTNNB1. Stabilisation of the free, monomeric pool of beta-catenin and the probable resulting constitutive activation of its Tcf-associated transcriptional complex appears to be a specific oncogenic event in endometrioid ovarian adenocarcinoma.
Publisher: Springer Science and Business Media LLC
Date: 04-03-2005
DOI: 10.1186/BCR1009
Publisher: Springer Science and Business Media LLC
Date: 19-09-2010
DOI: 10.1038/NG.666
Publisher: Springer Science and Business Media LLC
Date: 19-09-2010
DOI: 10.1038/NG.668
Publisher: Springer Science and Business Media LLC
Date: 07-08-2020
DOI: 10.1038/S41523-020-00176-7
Abstract: Mammographic density (MD) influences breast cancer risk, but how this is mediated is unknown. Molecular differences between breast cancers arising in the context of the lowest and highest quintiles of mammographic density may identify the mechanism through which MD drives breast cancer development. Women diagnosed with invasive or in situ breast cancer where MD measurement was also available ( n = 842) were identified from the Lifepool cohort of ,000 women participating in population-based mammographic screening. This group included 142 carcinomas in the lowest quintile of MD and 119 carcinomas in the highest quintile. Clinico-pathological and family history information were recorded. Tumor DNA was collected where available ( n = 56) and sequenced for breast cancer predisposition and driver gene mutations, including copy number alterations. Compared to carcinomas from low-MD breasts, those from high-MD breasts were significantly associated with a younger age at diagnosis and features associated with poor prognosis. Low- and high-MD carcinomas matched for grade, histological subtype, and hormone receptor status were compared for somatic genetic features. Low-MD carcinomas had a significantly increased frequency of TP53 mutations, higher homologous recombination deficiency, higher fraction of the genome altered, and more copy number gains on chromosome 1q and losses on 17p. While high-MD carcinomas showed enrichment of tumor-infiltrating lymphocytes in the stroma. The data demonstrate that when tumors were matched for confounding clinico-pathological features, a proportion in the lowest quintile of MD appear biologically distinct, reflective of microenvironment differences between the lowest and highest quintiles of MD.
Publisher: Springer Science and Business Media LLC
Date: 13-09-2004
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952411
Abstract: Characteristics of 12 case-control datasets from the ENIGMA consortium partners.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952414
Abstract: List of all analyzed CHEK2 variants with results of KAP1/CHK2 kinase and localization assays and the results from recent previously published functional analyses of the CHEK2 VUS.
Publisher: American Association for Cancer Research (AACR)
Date: 14-11-2008
DOI: 10.1158/1078-0432.CCR-08-1348
Abstract: Purpose: There is accumulating evidence that microRNAs may function like classic tumor suppressor genes but little is known about their mechanism of inactivation in cancer cells. We investigated whether somatic mutations are a common mechanism of inactivation of microRNA genes in ovarian cancer. Experimental Design: Ten cancer-implicated microRNA genes were analyzed for somatic mutations in 90 ovarian epithelial cancers and matching normal DNA. High-resolution melt analysis and bidirectional sequencing was used to detect sequence variations. Results: High-resolution melt analysis and direct sequencing did not identify any somatic mutations but did reveal numerous novel and previously reported germ line base substitutions, deletions, and insertions surrounding the mature microRNA sequences. The majority of variants were detected in the same proportion of non–cancer control in iduals suggesting that they do not represent ovarian cancer–predisposing alleles. Conclusion: The absence of somatic mutations in any of the 10 cancer-implicated microRNAs in our large cohort of ovarian tumors suggests that this may be an uncommon mechanism of inactivation of microRNAs in ovarian cancer.
Publisher: Springer Science and Business Media LLC
Date: 22-03-2022
Publisher: Wiley
Date: 17-01-2011
DOI: 10.1002/PATH.2842
Abstract: Numerous in vitro and in vivo studies have established that carcinoma-associated fibroblasts differ phenotypically from fibroblasts associated with normal tissue but the mechanisms underlying these differences are unclear. Since carcinoma-associated fibroblasts can be propagated in vitro for extended periods and still maintain their cancer-promoting phenotype, some investigators have proposed that they might have acquired somatic genetic alterations analogous to those observed in malignant epithelium. Early molecular genetic studies appeared to validate this hypothesis by demonstrating remarkably high frequencies of clonal somatic genetic alterations in carcinoma-associated fibroblasts, including loss of heterozygosity, gene lification, and point mutations in tumour suppressor genes such as TP53 and PTEN. The initial excitement of these paradigm-changing studies overshadowed concerns that there may have been a more mundane explanation for these observations. In addition to the fact that the data would necessarily invoke an unlikely scenario of the simultaneous generation of two symbiotic malignancies, subsequent molecular genetic studies found no evidence of frequent genomic aberrations. One striking common trait of those studies reporting frequent clonal somatic alterations in carcinoma-associated fibroblasts is the use of tissues and techniques which are well known to be highly prone to generating artefacts such as limiting and poor quality DNA followed by highly multiplexed PCR-based analyses. It is now clear that clonal somatic mutations are not the biological basis of the cancer-promoting attributes of carcinoma-associated fibroblasts.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488645.V1
Abstract: Supplementary Tables S1-S11
Publisher: Springer Science and Business Media LLC
Date: 23-06-2012
DOI: 10.1007/S10549-012-2128-Z
Abstract: Mammographic density (MD) is the area of breast tissue that appears radiologically white on mammography. Although high MD is a strong risk factor for breast cancer, independent of BRCA1/2 mutation status, the molecular basis of high MD and its associated breast cancer risk is poorly understood. MD studies will benefit from an animal model, where hormonal, gene and drug perturbations on MD can be measured in a preclinical context. High and low MD tissues were selectively s led by stereotactic biopsy from operative specimens of high-risk women undergoing prophylactic mastectomy. The high and low MD tissues were transferred into separate vascularised biochambers in the groins of SCID mice. Chamber material was harvested after 6 weeks for histological analyses and immunohistochemistry for cytokeratins, vimentin and a human-specific mitochondrial antigen. Within-in idual analysis was performed in replicate mice, eliminating confounding by age, body mass index and process-related factors, and comparisons were made to the parental human tissue. Maintenance of differential MD post-propagation was assessed radiographically. Immunohistochemical staining confirmed the preservation of human glandular and stromal components in the murine biochambers, with maintenance of radiographic MD differential. Propagated high MD regions had higher stromal (p = 0.0002) and lower adipose (p = 0.0006) composition, reflecting the findings in the original human breast tissue, although glands appeared small and non-complex in both high and low MD groups. No significant differences were observed in glandular area (p = 0.4) or count (p = 0.4) between high and low MD biochamber tissues. Human mammary glandular and stromal tissues were viably maintained in murine biochambers, with preservation of differential radiographic density and histological features. Our study provides a murine model for future studies into the biomolecular basis of MD as a risk factor for breast cancer.
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/1078-0432.23685618.V1
Abstract: List of all analyzed CHEK2 variants with results of KAP1/CHK2 kinase and localization assays and the results from recent previously published functional analyses of the CHEK2 VUS.
Publisher: American Association for Cancer Research (AACR)
Date: 06-2015
DOI: 10.1158/1535-7163.MCT-15-0039
Abstract: Identification of genomic alterations defining ovarian carcinoma subtypes may aid the stratification of patients to receive targeted therapies. We characterized high-grade serous ovarian carcinoma (HGSC) for the association of lified and overexpressed genes with clinical outcome using gene expression data from 499 HGSC patients in the Ovarian Tumor Tissue Analysis cohort for 11 copy number lified genes: ATP13A4, BMP8B, CACNA1C, CCNE1, DYRK1B, GAB2, PAK4, RAD21, TPX2, ZFP36, and URI. The Australian Ovarian Cancer Study and The Cancer Genome Atlas datasets were also used to assess the correlation between gene expression, patient survival, and tumor classification. In a multivariate analysis, high GAB2 expression was associated with improved overall and progression-free survival (P = 0.03 and 0.02), whereas high BMP8B and ATP13A4 were associated with improved progression-free survival (P = 0.004 and P = 0.02). GAB2 overexpression and copy number gain were enriched in the AOCS C4 subgroup. High GAB2 expression correlated with enhanced sensitivity in vitro to the dual PI3K/mTOR inhibitor PF-04691502 and could be used as a genomic marker for identifying patients who will respond to treatments inhibiting PI3K signaling. Mol Cancer Ther 14(6) 1495–503. ©2015 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 07-2006
DOI: 10.1158/1055-9965.EPI-05-0986
Abstract: Background: Loss of heterozygosity (LOH) in breast ductal lavage (DL) fluid has been reported to be a potential biomarker of malignant change. Interpretation of LOH is reliant on sufficient quality and quantity of DNA. We investigated LOH of the BRCA1/2 loci in DL s les from BRCA1/2 mutation carriers, while also assessing the effect of DNA quantity. Methods: DNA yield was estimated using quantitative real-time PCR. Allelic status of DL DNA was determined using fluorescently tagged microsatellite markers with the subject's lymphocytic DNA serving as a control. S les were scored as consistently heterozygous or as demonstrating LOH if the same result was observed in replicate experiments. Additionally, s les were scored as “discordant LOH” if they initially showed LOH, but in replicate experiments either showed heterozygosity or LOH of the opposite allele. Results: In 11 BRCA1 carriers, 46 ducts were assessable, and 39 ducts from 14 BRCA2 carriers were assessable. LOH was observed in 17% and 18% of ducts from BRCA1 and BRCA2, respectively. Discordant results were seen in 23 BRCA1 (50%) and 15 BRCA2 (38%) s les. DNA yield was significantly greater in s les that were consistently heterozygous than those that were either discordant or showed LOH in replicate experiments for both BRCA1 (P = 0.003) and BRCA2 (P = 0.003). Conclusions: DNA quantity is highly variable between DL s les, with low yields likely to detrimentally affect the interpretation of LOH. In conclusion, LOH may not be an adequate method to detect the early stages of malignant change in s les obtained via DL. (Cancer Epidemiol Biomarkers Prev 2006 (7):1396–8)
Publisher: American Association for Cancer Research (AACR)
Date: 31-08-2017
DOI: 10.1158/1078-0432.CCR-17-0743
Abstract: Purpose: The immune microenvironment of breast ductal carcinoma in situ (DCIS) has yet to be fully explored, and the relationship of immune cells to genetic features of DCIS is unknown. Experimental Design: We quantified tumor associated lymphocytes (TIL) and evaluated PD-L1 protein levels by immunohistochemistry in a cohort of pure DCIS (138 and 79 cases, respectively), some of which had copy number (n = 55) and mutation data (n = 20). Results: TILs were identified in the stroma surrounding DCIS (119/138, 86%) and present at a median TIL score of 5% (range, 0%–90%). Most DCIS were negative for tumor cell PD-L1 staining (89%), but 25% of cases were positive for immune cell staining. We observed that, as in invasive breast cancer, TILs and PD-L1 positivity were significantly greater in high-grade (P = 0.002/0.035), ER-negative (P = 0.02/0.02), and ERBB2- lified tumors (P & 0.001/0.048). Comedo necrosis was significantly positively associated with TILs (P & 0.0001) but not with PD-L1. The TILs score was significantly higher in cases with TP53 mutation (P = 0.03) but not with PIK3CA or GATA3 mutation. In the cases with copy number data, both the fraction of the genome altered and the number of telomeric imbalances were significantly positively correlated with TILs (both P & 0.001). This result strongly contrasted with invasive breast cancer data, where aneuploidy was not correlated to TIL levels. Conclusions: Although a small cohort, our data suggest a preliminary model by which the progression of DCIS to invasive carcinoma may involve an altered relationship of tumor copy number with the immune microenvironment, possibly by the immunoediting of the tumor. Clin Cancer Res 23(17) 5210–7. ©2017 AACR.
Publisher: Springer Science and Business Media LLC
Date: 25-01-2019
DOI: 10.1038/S41467-018-08054-4
Abstract: Quantifying the genetic correlation between cancers can provide important insights into the mechanisms driving cancer etiology. Using genome-wide association study summary statistics across six cancer types based on a total of 296,215 cases and 301,319 controls of European ancestry, here we estimate the pair-wise genetic correlations between breast, colorectal, head/neck, lung, ovary and prostate cancer, and between cancers and 38 other diseases. We observed statistically significant genetic correlations between lung and head/neck cancer ( r g = 0.57, p = 4.6 × 10 −8 ), breast and ovarian cancer ( r g = 0.24, p = 7 × 10 −5 ), breast and lung cancer ( r g = 0.18, p =1.5 × 10 −6 ) and breast and colorectal cancer ( r g = 0.15, p = 1.1 × 10 −4 ). We also found that multiple cancers are genetically correlated with non-cancer traits including smoking, psychiatric diseases and metabolic characteristics. Functional enrichment analysis revealed a significant excess contribution of conserved and regulatory regions to cancer heritability. Our comprehensive analysis of cross-cancer heritability suggests that solid tumors arising across tissues share in part a common germline genetic basis.
Publisher: Oxford University Press (OUP)
Date: 23-11-2010
DOI: 10.1093/BIOINFORMATICS/BTP654
Abstract: Motivation: Cancer evolves through microevolution where random lesions that provide the biggest advantage to cancer stand out in their frequent occurrence in multiple s les. At the same time, a gene function can be changed by aberration of the corresponding gene or modification of microRNA (miRNA) expression, which attenuates the gene. In a large number of cancer s les, these two mechanisms might be distributed in a coordinated and almost mutually exclusive manner. Understanding this coordination may assist in identifying changes which significantly produce the same functional impact on cancer phenotype, and further identify genes that are universally required for cancer. Present methodologies for finding aberrations usually analyze single datasets, which cannot identify such pairs of coordinating genes and miRNAs. Results: We have developed MIRAGAA, a statistical approach, to assess the coordinated changes of genome copy numbers and miRNA expression. We have evaluated MIRAGAA on The Cancer Genome Atlas (TCGA) Glioblastoma Multiforme datasets. In these datasets, a number of genome regions coordinating with different miRNAs are identified. Although well known for their biological significance, these genes and miRNAs would be left undetected for being less significant if the two datasets were analyzed in idually. Availability and Implementation: The source code, implemented in R and java, is available from our project web site at www.csse.unimelb.edu.au/∼rgaire/MIRAGAA/index.html Contact: rgaire@csse.unimelb.edu.au Supplementary information: Supplementary data are available at Bioinformatics online.
Publisher: Elsevier BV
Date: 03-1987
DOI: 10.1016/0147-619X(87)90018-7
Abstract: The genetic arrangement of the regions involved in R124 replication and incompatibility have been located and their homology to the IncFI basic replicons has been assessed. We show that R124 has homology with all three basic replicons, RepFIA, RepFIB, and RepFIC, and that these regions, FIVA, RepFIVB, and RepFIVC, are widely separated on the R124 genome. Cloning of autonomously replicating fragments has shown that RepFIVB and RepFIVC are functional in R124 and express incompatibility. The FIVA region was unable to form a functional replicon and when cloned into pUC8 lacked incompatibility activity. A fourth region of R124 was identified, which although not essential for replication stabilized mini-R124 plasmid replication and exhibited incompatibility with R124. This region, designated IncIV, showed no homology to RepFIA, RepFIB, or RepFIC. Incompatibility expression of IncIV required only the EcoRI fragment E13 but the strength of the reaction was modified in the presence of other fragments. The replication and incompatibility properties of an R124 deletion derivative indicated that R124 can switch its replication to either RepFIVB or RepFIVC when in the presence of an incompatible plasmid. The ambiguous incompatibility reactions reported for R124 is a result of the expression of the two functional replicons, RepFIVB and RepFIVC, and that expressed by IncIV.
Publisher: Springer Science and Business Media LLC
Date: 04-11-1999
Abstract: The PPP2R1B gene has recently been implicated as a tumor suppressor based on the finding of somatic alterations in lung and colon cancers. PPP2R1B is located on chromosome 11q22-24 which coincides with the site of frequent loss of heterozygosity (LOH) in ovarian cancer. We investigated if the PPP2R1B gene was inactivated in ovarian cancer by single strand conformational polymorphism (SSCP) and heteroduplex (HD) analysis of 99% of the coding region. LOH at the PPP2R1B locus was detected in 32% of the malignant tumors but no somatic alterations were detected in any of 65 malignant, five borderline or six benign tumors. A germline G > A transition (GGC > GAC) in codon 90 was detected in 4/76 tumors. This alteration has previously been described as a mutation but on further investigation we found that the frequency of this variant among 167 ovarian cancers (4.2%) was not statistically significantly different from that observed in 247 non-cancer random controls (2.4%). We conclude that the PPP2R1B gene is not involved in the pathogenesis of ovarian cancer. The codon 90 Gly > Asp alteration may represent a non-pathological polymorphism and consequently the mutation frequency reported in lung cancers may have been overstated and the designation of PPP2R1B as a tumor suppressor gene should be regarded with caution.
Publisher: Springer Science and Business Media LLC
Date: 17-09-2018
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952450.V1
Abstract: Validation of KAP1-pS473 and CHK2-pS516 antibodies. b A, /b Parental RPE, RPE1–CHEK2-KO cells or RPE1–CHEK2-KO cells transfected with the wild-type or mutant pEGFP–CHEK2 were left untreated or were exposed to ionizing radiation (5 Gy, 3 hours). After fixation, cells were probed with KAP1-pS473 antibody. Representative images are shown. b B, /b Quantification of b A /b . The mean nuclear intensity of the KAP1-pS473 signal is plotted. Each dot represents one cell more than 300 cells were analyzed. Red line, error bars and numbers indicate mean ± SDs. Statistical significance was evaluated by the Mann–Whitney test (****, i P /i 0.0001). A representative experiment is shown from two independent replicates. b C, /b Cells were grown and treated as in b A /b and were probed with CHK2-pS516 antibody. Representative images are shown. b D, /b Quantification of b C /b . The mean nuclear intensity of the CHK2-pS516 signal is plotted. Each dot represents one cell more than 300 cells were analyzed. Red line, error bars and numbers indicate mean ± SDs. Statistical significance was evaluated by the Mann–Whitney test (****, i P /i 0.0001). A representative experiment is shown from two independent replicates. b E, /b Cells were grown and treated as in A. Whole-cell lysates were analyzed by immunoblotting with indicated antibodies.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952444.V1
Abstract: Kinase KAP1 and CHK2 assays ( b A /b ). The bar graphs show results of kinase assays for 430 i CHEK2 /i missense variants. In both assays, variants with normalized relative CHK2 activity (mean WT-activity = 1) exceeding that of the weakest signal of WT replicas (not shown) were categorized functionally WT-like, variants with normalized signal intensity lower than the strongest signal for any of kinase-dead/empty EGFP vector controls (in-frame exon 7 deletion–p.D265_H282del not shown) were categorized as functionally impaired. Variants with normalized CHK2 activities between these ranges were categorized functionally intermediate (0.428–0.705 and 0.479–0.710 for KAP1 and CHK2 assay, respectively indicated by red and yellow dashed lines). Scatterplot combines results from both assays showing 340 concordant (circles) and 90 discordant (crosses) variants. The nuclear-to-cytoplasmic ratio ( b B /b ) bar graph (left) displays all missense variants and a set of protein-truncating i CHEK2 /i variants (dark red bars at left, zoomed part of the graph). The missense variants, p.R521W and p.R521Q, with an aberrant localization are highlighted as bright-red bars the arrows denote WT (green bar) and catalytically-dead in-frame p.D265_H282del variant (white bar). The highest and lowest mean nuclear/cytoplasmic ratio values from all WT replicates are indicated by green dashed lines. Of all missense variants analyzed by ScanR microscopy, only codon 521 alterations revealed aberrant intracellular localization with intense cytoplasmic positivity (right), reminiscent of mislocalization of the c.1100delC (p.T367fsX size bar, 10 μm) variant. In comparison, the in-frame deletion p.D265_H282del revealed normal intranuclear accumulation, similar to WT. b C, /b Scatter plots depicting correlations between assays performed in this study and previous analyses of i CHEK2 /i VUS. Studies of Kleiblova i et al. /i ( a href="#bib17" target="_blank" /a ) and Boonen et al. ( a href="#bib18" target="_blank" /a ) used phosphorylation of KAP1 as a functional readout whereas the study of Delimitsou i et al. /i ( a href="#bib25" target="_blank" /a ) used a yeast growth retardation assay. The dots are colored according to the results of the KAP1 assay in this study (red, impaired yellow, intermediate green, wild-type–like). Blue line represents linear regression, R, correlation coefficient i P /i , i P /i value. The scatter plot does not show the p.Arg512Trp variant classified by Boonen et al. as intermediate with impaired nuclear localization in our localization assay.
Publisher: American Association for Cancer Research (AACR)
Date: 13-07-2023
DOI: 10.1158/1078-0432.CCR-23-0212
Abstract: Germline pathogenic variants in CHEK2 confer moderately elevated breast cancer risk (odds ratio, OR ∼ 2.5), qualifying carriers for enhanced breast cancer screening. Besides pathogenic variants, dozens of missense CHEK2 variants of uncertain significance (VUS) have been identified, h ering the clinical utility of germline genetic testing (GGT). We collected 460 CHEK2 missense VUS identified by the ENIGMA consortium in 15 countries. Their functional characterization was performed using CHEK2-complementation assays quantifying KAP1 phosphorylation and CHK2 autophosphorylation in human RPE1–CHEK2-knockout cells. Concordant results in both functional assays were used to categorize CHEK2 VUS from 12 ENIGMA case–control datasets, including 73,048 female patients with breast cancer and 88,658 ethnicity-matched controls. A total of 430/460 VUS were successfully analyzed, of which 340 (79.1%) were concordant in both functional assays and categorized as functionally impaired (N = 102), functionally intermediate (N = 12), or functionally wild-type (WT)–like (N = 226). We then examined their association with breast cancer risk in the case–control analysis. The OR and 95% CI (confidence intervals) for carriers of functionally impaired, intermediate, and WT-like variants were 2.83 (95% CI, 2.35–3.41), 1.57 (95% CI, 1.41–1.75), and 1.19 (95% CI, 1.08–1.31), respectively. The meta-analysis of population-specific datasets showed similar results. We determined the functional consequences for the majority of CHEK2 missense VUS found in patients with breast cancer (3,660/4,436 82.5%). Carriers of functionally impaired missense variants accounted for 0.5% of patients with breast cancer and were associated with a moderate risk similar to that of truncating CHEK2 variants. In contrast, 2.2% of all patients with breast cancer carried functionally wild-type/intermediate missense variants with no clinically relevant breast cancer risk in heterozygous carriers.
Publisher: Springer Science and Business Media LLC
Date: 19-05-2004
DOI: 10.1186/BCR807
Publisher: Wiley
Date: 14-07-2009
DOI: 10.1002/GCC.20694
Abstract: Ovarian cancer is characterized by complex genetic alterations, including copy number loss and copy number-neutral loss of heterozygosity (LOH). These alterations are assumed to represent the "second hit" of the underlying tumor suppressor gene (TSG), however, relative to the number of LOH hotspots reported, few ovarian TSGs have been identified. We conducted a high-resolution LOH analysis using SNP arrays (500K and SNP6.0) of 106 primary ovarian tumors of various histological subtypes together with matching normal DNA. LOH was detected in at least 35% of s les on chromosomes 17, 19p, 22q, Xp, 13q, 8p, 6q, 4q, 5q, 1p, 16q, and 9q with a median minimal region of overlap of only 300 kb. Subtype-specific differences in LOH frequency were noted, particularly for mucinous cases. We also identified 192 somatic homozygous deletions (HDs). Recurrent HDs targeted known TSGs such as CDKN2A (eight s les), RB1 (five s les), and PTEN (three s les). Additional recurrent HDs targeted 16 candidate TSGs near minimal regions of LOH on chromosomes 17, 13, 8p, 5q, and X. Given the importance of HDs in inactivating known genes, these candidates are highly likely to be ovarian TSGs. Our data suggest that the poor success of previous LOH studies was due to the inability of previous technology to resolve complex genomic alterations and distinguish true LOH from allelic imbalance. This study shows that recurrent regions of LOH and HD frequently align with known TSGs suggesting that LOH analysis remains a valid approach to discovering new candidates.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952405
Abstract: Frequencies of all reported germline CHEK2 variant carriers and carriers of variants concordantly categorized by functional our kinase assays in breast cancer patients and controls in 12 analyzed population datasets.
Publisher: Springer Science and Business Media LLC
Date: 05-2020
DOI: 10.1186/S12885-020-6705-Y
Abstract: Familial cases of appendiceal mucinous tumours (AMTs) are extremely rare and the underlying genetic aetiology uncertain. We identified potential predisposing germline genetic variants in a father and daughter with AMTs presenting with pseudomyxoma peritonei (PMP) and correlated these with regions of loss of heterozygosity (LOH) in the tumours. Through germline whole exome sequencing, we identified novel heterozygous loss-of-function (LoF) (i.e. nonsense, frameshift and essential splice site mutations) and missense variants shared between father and daughter, and validated all LoF variants, and missense variants with a Combined Annotation Dependent Depletion (CADD) scaled score of ≥10. Genome-wide copy number analysis was performed on tumour tissue from both in iduals to identify regions of LOH. Fifteen novel variants in 15 genes were shared by the father and daughter, including a nonsense mutation in REEP5 . None of these germline variants were located in tumour regions of LOH shared by the father and daughter. Four genes ( EXOG , RANBP2, RANBP6 and TNFRSF1B ) harboured missense variants that fell in a region of LOH in the tumour from the father only, but none showed somatic loss of the wild type allele in the tumour. The REEP5 gene was sequenced in 23 in iduals with presumed sporadic AMTs or PMP no LoF or rare missense germline variants were identified. Germline exome sequencing of a father and daughter with AMTs identified novel candidate predisposing genes. Further studies are required to clarify the role of these genes in familial AMTs.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2007
DOI: 10.1158/1078-0432.CCR-07-0502
Abstract: Purpose: Genetic changes in sporadic ovarian cancer are relatively poorly characterized compared with other tumor types. We have evaluated the use of high-resolution whole genome arrays for the genetic profiling of epithelial ovarian cancer. Experimental Design: We have evaluated 31 primary ovarian cancers and matched normal DNA for loss of heterozygosity and copy number alterations using 500K single nucleotide polymorphism arrays. Results: In addition to identifying the expected large-scale genomic copy number changes, & small regions of copy number gain or loss (& kb) were identified among the 31 tumors, including 33 regions of high-level gain (& copies) and 27 homozygous deletions. The existence of such a high frequency of small regions exhibiting copy number alterations had not been previously suspected because earlier genomic array platforms lacked comparable resolution. Interestingly, many of these regions harbor known cancer genes. For ex le, one tumor harbored a 350-kb high-level lification centered on FGFR1 and three tumors showed regions of homozygous loss 109 to 216 kb in size involving the RB1 tumor suppressor gene only. Conclusions: These data suggest that novel cancer genes may be located within the other identified small regions of copy number alteration. Analysis of the number of copy number breakpoints and the distribution of the small regions of copy number change indicate high levels of structural chromosomal genetic instability in ovarian cancer.
Publisher: American Association for Cancer Research (AACR)
Date: 2010
DOI: 10.1158/1055-9965.EPI-09-0359
Abstract: Purpose: Genomic alterations (including gene hypermethylation) are likely to precede the phenotypic changes associated with breast tumorigenesis. From a prospective collection of ductal lavage (DL) s les from women with a known mutation in BRCA1 or BRCA2, we have assessed promoter methylation with a comparison of results with several variables, including breast cancer (BC) outcome. Experimental Design: Hypermethylation of p16, RASSF1A, twist, and RARβ was assessed using a qualitative, real-time, nested PCR assay. Associations between methylation status and variables were tested using Fisher's exact test or logistic regression. Analyses were done at three levels: a single breast, a single duct (both over time), and each DL s le in isolation. Results: A total of 168 s les from 93 ducts in 54 breasts have been analyzed in 34 women (16 BRCA1 and 18 BRCA2 mutation carriers). A median of 2 DL was done (range, 1–5), with 7 women developing BC on study, 1 bilateral. Methylation of p16 was associated with a known BRCA1 mutation (P = 0.001, P & 0.001, and P & 0.001 for breast, duct, and s le levels, respectively) and women with a history of contralateral BC (P = 0.001 and P & 0.001 for duct and s le levels, respectively). An association was seen for women who developed BC on study and RASSF1A methylation (P = 0.001 for s le level). Conclusions: Genetic methylation patterns could potentially be used to predict future BC risk. In addition, p16 methylation may be a predictor of BRCA1 mutation status. Further research is required to corroborate these findings. Cancer Epidemiol Biomarkers Prev 19(1) 265–74
Publisher: Springer Science and Business Media LLC
Date: 14-05-2004
DOI: 10.1186/BCR803
Publisher: American Society for Clinical Investigation
Date: 02-2012
DOI: 10.1172/JCI59309
Publisher: Wiley
Date: 09-10-1995
Abstract: The CDKN2 gene encodes a cell cycle regulatory protein and is located on chromosome 9p21, a region deleted in a wide variety of primary tumours. While mutations in the CDKN2 gene itself are frequently observed in tumour cell lines, they are less common in primary tumours. We have investigated the role of the CDKN2 gene in ovarian cancer by analysis for allelic loss of 9p21 and single-strand conformational polymorphism analysis of exons 1 and 2 of CDKN2 in 67 primary ovarian tumours. Loss of heterozygosity on 9p21 was frequently observed (24/50 informative tumours) and was common in early-stage tumours, suggesting that it is an early event in ovarian tumorigenesis. Homozygous deletion of the CDKN2 gene was detected in only 1 tumour. No somatic or germline mutations were observed in CDKN2, though a codon 140 polymorphism was detected in 2 cases. This suggests that CDKN2 is not involved in ovarian tumorigenesis and that another gene(s) may be the target of the frequent 9p allelic losses observed.
Publisher: Springer Science and Business Media LLC
Date: 02-1993
DOI: 10.1038/BJC.1993.51
Abstract: The 11q13 chromosomal region encodes oncogenes relevant to a variety of human cancers as well as a tumour suppressor gene implicated in multiple endocrine neoplasia type 1. In addition, high affinity folate receptor (FOLR1), which maps to 11q13.3-13.5, is expressed at an elevated level on the surface of over 80% of nonmucinous epithelial ovarian cancers. Further telomeric, 11q breakpoints are found in many cancers. We studied the involvement of 11q markers in ovarian cancer by looking for tumour-specific loss of heterozygosity (LOH), as well as lification or rearrangements that might explain the overexpression of FOLR1. Twenty eight epithelial ovarian cancers, along with lymphocyte DNA from the same in idual were used for Southern blotting with polymorphic probes from 11q. PCR primers from 11q23.3 were also used. The 11q13 band was lified in four out of 28 cancers. The licon included the probe D11S146 as well as FGF3 (formerly INT2) and FOLR1 in one out of these four cases, thus crossing the bcl1 translocation breakpoint. LOH was seen in three out of 16 cases with FGF3 (11q13). A much higher frequency of LOH (8/12) was found at 11q23.3-qter, implying the presence of a tumour suppressor gene in this region.
Publisher: Elsevier BV
Date: 09-2016
Publisher: Wiley
Date: 19-05-2003
DOI: 10.1002/MC.10127
Abstract: Leiomyomas are the most common gynecologic tumors in women, but very little is known about their molecular pathology. We used single-stranded conformational polymorphism/heteroduplex analysis to analyze 42 unselected uterine leiomyomas for somatic mutations in all coding exons of the gene encoding CCAAT displacement protein (CDP), as well as exons 5-8 of TP53 and codons 1-36 and 38-80 of KRAS. No somatic mutations were identified in either TP53 or KRAS, indicating that disregulation of these genes is not required for leiomyomas development. Aberrant band shifts were identified in CDP, but these were all germline nonpathogenic variants that have been reported previously. There is good functional and genetic evidence indicating that CDP is a leiomyoma suppressor, but our data suggested that somatic mutations in this gene were rare in unselected uterine leiomyomas. It is possible that CDP belongs to a class of tumor suppressor in which loss of only one copy of the gene, either by genetic or epigenetic mechanisms, is sufficient to allow tumor growth.
Publisher: Cambridge University Press (CUP)
Date: 30-11-2005
DOI: 10.1017/S1470903105004748
Abstract: Citation of original article: B. Frank, K. Hemminki, M. Wirtenberger, J. L. Bermejo, P. Bugert, R. Klaes, R. K. Schmutzler, B. Wappenschmidt, C. R. Bartram, B. Burwinkel. The rare ERBB2 variant lle654Val is associated with an increased familial breast cancer risk. Carcinogenesis 2005 26 : 643–7. Abstract of the original article Overexpression of the proto-oncogene ERBB2 (HER2/NEU) has been observed in 20–30% of breast cancers involving poor prognosis. Genetic alterations within ERBB2 have been shown to induce carcinogenesis and metastasis. We investigated eight annotated single nucleotide polymorphisms for occurrence in familial breast cancer s les. The confirmed variants Ile654Val, Ile655Val and Ala1170Pro were analysed in subsequent epidemiological studies on familial breast cancer risk. While Ala1170Pro resides within a C-terminally located regulatory domain, the two adjacent polymorphisms Ile654Val and Ile655Val are part of the transmembrane domain. A case–control study analysing a cohort of 348 German familial breast cancer cases and 960 corresponding controls showed no significant association of either Ile655Val (OR = 1.05, 95% CI = 0.82–1.34, P = 0.728) or Ala1170Pro (OR = 0.94, 95% CI = 0.74–1.20, P = 0.632) with familial breast cancer risk. Differences in haplotype frequencies between cases and controls could also not be detected. The ERBB2 variant Ile654Val, however, revealed an increased risk for carriers of the heterozygous Val654 allele (OR = 2.56, 95% CI = 1.08–6.08, P = 0.028). The rare Val654 variant is linked with the more frequent Val655, resulting in two consecutive valine instead of two isoleucine residues within the transmembrane domain. Computational analyses suggest that the Val654–Val655 allele provokes receptor dimerisation and activation, thus stimulating kinase activity and cell transformation. We hypothesise that ERBB2 Val654 represents an oncogenic variant which might, in addition, influence clinical outcome and predict a worse prognosis.
Publisher: Elsevier BV
Date: 06-2014
DOI: 10.1016/J.AJPATH.2014.02.013
Abstract: Intraepithelial carcinomas of the fallopian tube are putative precursors to high-grade serous carcinomas of the ovary and peritoneum. Molecular characterization of these early precursors is limited but could be the key to identifying tumor biomarkers for early detection. This study presents a genome-wide copy number analysis of occult fallopian tube carcinomas identified through risk-reducing prophylactic oophorectomy from three women with germline BRCA1 mutations, demonstrating that extensive genomic aberrations are already established at this early stage. We found no indication of a difference in the level of genomic aberration observed in fallopian tube carcinomas compared with high-grade serous ovarian carcinomas. These findings suggest that spread to the peritoneal cavity may require no or very little further tumor evolution, which raises the question of what is the real window of opportunity to detect high-grade serous peritoneal carcinoma arising from the fallopian tube before it spreads. Nonetheless, the similarity of the genomic aberrations to those observed in high-grade serous ovarian carcinomas suggests that genetic biomarkers identified in late-stage disease may be relevant for early detection.
Publisher: Elsevier BV
Date: 12-2016
Publisher: Wiley
Date: 13-09-2002
DOI: 10.1002/IJC.10682
Abstract: The putative tumour suppressor gene EP300 is located on chromosome 22q13 which is a region showing frequent loss of heterozygosity (LOH) in colon, breast and ovarian cancers. We analysed 203 human breast, colon and ovarian primary tumours and cell lines for somatic mutations in EP300. LOH across the EP300 locus was detected in 38% of colon, 36% of breast, and 49% of ovarian primary tumours but no somatic mutations in EP300 were identified in any primary tumour. Analysis of 17 colon, 11 breast, and 11 ovarian cancer cell lines identified truncating mutations in 4 colon cancer cell lines (HCT116, HT29, LIM2405 and LIM2412). We confirmed the presence of a previously reported frameshift mutation in HCT116 at codon 1699 and identified a second frameshift mutation at codon 1468. Bi-allelic inactivation of EP300 was also detected in LIM2405 that harbours an insC mutation at codon 927 as well an insA mutation at codon 1468. An insA mutation at codon 1468 was identified in HT29 and a CGA>TGA mutation at codon 86 was identified in LIM2412. Both these lines were heterozygous across the EP300 locus and western blot analysis confirmed the presence of an apparently wild-type protein. Our study has established that genetic inactivation of EP300 is rare in primary colorectal, breast and ovarian cancers. In contrast, mutations are common among colorectal cancer cell lines with 4/17 harbouring homozygous or heterozygous mutations. The rarity of EP300 mutations among these tumour types that show a high frequency of LOH across 22q13 may indicate that another gene is the target of the loss. It is possible that bi-allelic inactivation of EP300 is not necessary and that haploinsufficiency is sufficient to promote tumorigenesis. Alternatively, silencing of EP300 may be achieved by epigenetic mechanisms such as promoter methylation.
Publisher: American Medical Association (AMA)
Date: 14-12-2017
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952411.V1
Abstract: Characteristics of 12 case-control datasets from the ENIGMA consortium partners.
Publisher: Springer Science and Business Media LLC
Date: 12-01-2015
DOI: 10.1038/NG.3185
Publisher: Research Square Platform LLC
Date: 30-11-2022
DOI: 10.21203/RS.3.RS-2258886/V1
Abstract: Background: Internationally, population breast cancer screening is moving towards a risk-stratified approach and requires engagement and acceptance from current and future screening clients. A decision aid (www.defineau.org) was developed based on women’s views, values, and knowledge regarding risk-stratified breast cancer screening. This study aims to evaluate the impact of the decision aid on women’s knowledge, risk perception, acceptance of risk assessment and change of screening frequency, and decision-making. Methods: Women who are clients of BreastScreen Victoria were invited to complete an online questionnaire before and after viewing the decision aid. Results: 3200 potential participants were invited, 242 responded with 127 participants completing both surveys. After reviewing the decision aid there was a significant change in knowledge, acceptance of risk stratified breast cancer screening and of decreased frequency screening for lower risk. High levels of acceptance of risk stratification, genetic testing and broad support for tailored screening persisted pre and post review. Conclusions: The DEFINE decision aid had a positive impact on accepting lower frequency screening, a major barrier to the success of a risk-stratified program and may contribute to facilitating change to the population breast screening program in Australia.
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2023
DOI: 10.1158/1078-0432.23952405.V1
Abstract: Frequencies of all reported germline CHEK2 variant carriers and carriers of variants concordantly categorized by functional our kinase assays in breast cancer patients and controls in 12 analyzed population datasets.
Publisher: Cold Spring Harbor Laboratory
Date: 04-2011
DOI: 10.1261/RNA.2528811
Abstract: Long noncoding RNAs (lncRNAs) are increasingly recognized to play major regulatory roles in development and disease. To identify novel regulators in breast biology, we identified differentially regulated lncRNAs during mouse mammary development. Among the highest and most differentially expressed was a transcript ( Zfas1 ) antisense to the 5′ end of the protein-coding gene Znfx1 . In vivo, Zfas1 RNA is localized within the ducts and alveoli of the mammary gland. Zfas1 intronically hosts three previously undescribed C/D box snoRNAs (SNORDs): Snord12 , Snord12b , and Snord12c . In contrast to the general assumption that noncoding SNORD-host transcripts function only as vehicles to generate snoRNAs, knockdown of Zfas1 in a mammary epithelial cell line resulted in increased cellular proliferation and differentiation, while not substantially altering the levels of the SNORDs. In support of an independent function, we also found that Zfas1 is extremely stable, with a half-life h. Expression analysis of the SNORDs revealed these were expressed at different levels, likely a result of distinct structures conferring differential stability. While there is relatively low primary sequence conservation between Zfas1 and its syntenic human ortholog ZFAS1 , their predicted secondary structures have similar features. Like Zfas1 , ZFAS1 is highly expressed in the mammary gland and is down-regulated in breast tumors compared to normal tissue. We propose a functional role for Zfas1/ ZFAS1 in the regulation of alveolar development and epithelial cell differentiation in the mammary gland, which, together with its dysregulation in human breast cancer, suggests ZFAS1 as a putative tumor suppressor gene.
Publisher: American Association for Cancer Research (AACR)
Date: 14-07-2023
DOI: 10.1158/1078-0432.23685612.V1
Abstract: Characteristics of 12 case-control datasets from the ENIGMA consortium partners.
Publisher: Oxford University Press (OUP)
Date: 25-02-2010
DOI: 10.1093/BIOINFORMATICS/BTQ088
Abstract: Motivation: High-density single nucleotide polymorphism (SNP) genotyping arrays are efficient and cost effective platforms for the detection of copy number variation (CNV). To ensure accuracy in probe synthesis and to minimize production costs, short oligonucleotide probe sequences are used. The use of short probe sequences limits the specificity of binding targets in the human genome. The specificity of these short probeset sequences has yet to be fully analysed against a normal reference human genome. Sequence similarity can artificially elevate or suppress copy number measurements, and hence reduce the reliability of affected probe readings. For the purpose of detecting narrow CNVs reliably down to the width of a single probeset, sequence similarity is an important issue that needs to be addressed. Results: We surveyed the Affymetrix Human Mapping SNP arrays for probeset sequence similarity against the reference human genome. Utilizing sequence similarity results, we identified a collection of fine-scaled putative CNVs between gender from autosomal probesets whose sequence matches various loci on the sex chromosomes. To detect these variations, we utilized our statistical approach, Dectecting REcurrent Copy number change using rank-order Statistics (DRECS), and showed that its performance was superior and more stable than the t-test in detecting CNVs. Through the application of DRECS on the HapMap population datasets with multi-matching probesets filtered, we identified biologically relevant SNPs in aberrant regions across populations with known association to physical traits, such as height, covered by the span of a single probe. This provided empirical confirmation of the existence of naturally occurring narrow CNVs as well as the sensitivity of the Affymetrix SNP array technology in detecting them. Availability: The MATLAB implementation of DRECS is available at ww2.cs.mu.oz.au/∼gwong/DRECS/index.html Contact: gwong@csse.unimelb.edu.au Supplementary information: Supplementary information is available at Bioinformatics online.
Publisher: Oxford University Press (OUP)
Date: 02-04-2012
DOI: 10.1093/BIOINFORMATICS/BTS146
Abstract: Motivation: In light of the increasing adoption of targeted resequencing (TR) as a cost-effective strategy to identify disease-causing variants, a robust method for copy number variation (CNV) analysis is needed to maximize the value of this promising technology. Results: We present a method for CNV detection for TR data, including whole-exome capture data. Our method calls copy number gains and losses for each target region based on normalized depth of coverage. Our key strategies include the use of base-level log-ratios to remove GC-content bias, correction for an imbalanced library size effect on log-ratios, and the estimation of log-ratio variations via binning and interpolation. Our methods are made available via CONTRA (COpy Number Targeted Resequencing Analysis), a software package that takes standard alignment formats (BAM/SAM) and outputs in variant call format (VCF4.0), for easy integration with other next-generation sequencing analysis packages. We assessed our methods using s les from seven different target enrichment assays, and evaluated our results using simulated data and real germline data with known CNV genotypes. Availability and implementation: Source code and s le data are freely available under GNU license (GPLv3) at contra-cnv.sourceforge.net/ Contact: Jason.Li@petermac.org Supplementary information: Supplementary data are available at Bioinformatics online.
Publisher: Springer Science and Business Media LLC
Date: 15-04-2019
DOI: 10.1038/S41467-018-08053-5
Abstract: Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.
No related grants have been discovered for Ian Campbell.