ORCID Profile
0000-0003-3610-2511
Current Organisation
Peter MacCallum Cancer Centre
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Publisher: Oxford University Press (OUP)
Date: 05-05-2010
DOI: 10.1093/JNCI/DJQ057
Publisher: Springer Science and Business Media LLC
Date: 29-09-2010
DOI: 10.1007/S10689-010-9383-0
Abstract: The responsibility for informing at-risk relatives of the availability of genetic testing for breast/ovarian cancer gene (BRCA1 or BRCA2) mutations currently falls on the probands. This study explored the support needs of in iduals from families with identified BRCA1 or BRCA2 mutations when communicating about genetic risk and genetic testing with at-risk family members. Thirty-nine semi-structured telephone interviews were conducted with in iduals from families with identified BRCA mutations. Interview responses were cross-tabulated by s le characteristics using the qualitative research analysis software NVivo8. The development of educational materials, which in iduals could use when communicating the risks of carrying a BRCA gene mutation with their relatives, was identified as a specific need. Many participants expressed a preference for a staged approach, where relatives are notified of their increased risk and the availability of genetic testing risk either face-to-face or via a letter, with additional educational sources, including brief written information or access to a website, made available for those wishing to access more in-depth information. This research identified a need for the development of educational/informational resources to support in iduals with identified breast/ovarian cancer mutations to communicate with their at-risk relatives about genetic risk and genetic testing availability.
Publisher: Mary Ann Liebert Inc
Date: 03-2008
Publisher: Elsevier BV
Date: 03-2013
DOI: 10.1038/GIM.2012.115
Abstract: The Kathleen Cuningham Foundation Consortium for Research into Familial Aspects of Breast Cancer (kConFab) is a large-scale research study that notifies participants when new, personally relevant, information is discovered. In 2009, the (kConFab) instituted an intensive notification process to ensure at-risk in iduals were effectively notified. This study (i) evaluated the impact of intensive notification on genetic testing uptake (ii) identified those most likely to undergo testing postnotification and (iii) identified those most likely to acknowledge that they had been notified. Clinical/demographic data were retrieved from the (kConFab) database. Logistic regression analyses were conducted to identify potential predictors of testing uptake and notification acknowledgment using IBM SPSS. A total of 155 of 1,812 in iduals underwent testing after standard notification (8.6%). In comparison, 23/291 in iduals (7.9%) notified using the "intensive" approach underwent testing (χ(2) = 0.14 P = 0.71). After controlling for notification process, females and participants with a previous cancer were most likely to have undergone testing (P < 0.006). Older in iduals (50+ years) were most likely to acknowledge they had been notified (P = 0.038). Increasing the intensity of participant follow-up did not increase genetic testing uptake. The challenge to effectively notify participants, and increase the proportion whose risk is managed clinically, remains, particularly for males and in iduals unaffected by cancer.Genet Med 2013:15(3):187-194.
Publisher: Springer Science and Business Media LLC
Date: 08-2013
DOI: 10.1186/BCR3463
Publisher: Oxford University Press (OUP)
Date: 05-11-2008
DOI: 10.1093/JNCI/DJN345
Abstract: X chromosome inactivation, which silences gene expression from one of the two X chromosomes in females, is usually random. Skewed X inactivation has been implicated in both the expression and the suppression of X-linked disease phenotypes and has been reported to occur more frequently in breast and ovarian cancer patients, including BRCA1 or BRCA2 mutation carriers, than in control subjects. We assessed the pattern of X chromosome inactivation using methylation-specific polymerase chain reaction lification of the exon 1 microsatellite region of the X-linked androgen receptor (AR) gene in DNA from blood s les obtained from control subjects without a personal history of breast or ovarian cancer (n = 735), ovarian cancer patients (n = 313), familial breast cancer patients who did not carry mutations in BRCA1 or BRCA2 (n = 235), and affected and unaffected carriers of mutations in BRCA1 (n = 260) or BRCA2 (n = 63). We defined the pattern of X chromosome inactivation as skewed when the same X chromosome was active in at least 90% of cells. The association between skewed X inactivation and disease and/or BRCA mutation status was assessed by logistic regression analysis. The association between skewed X inactivation and age at cancer diagnosis was assessed by Cox proportional hazards regression analysis. All statistical tests were two-sided. The age-adjusted frequency of skewed X inactivation was not statistically significantly higher in ovarian cancer or familial breast cancer case subjects compared with control subjects. Skewed X inactivation was higher in BRCA1 mutation carriers than in control subjects (odds ratio [OR] = 2.7, 95% confidence interval [CI] = 1.1 to 6.2 P = .02), particularly among unaffected women (OR = 6.1, 95% CI = 1.5 to 31.8 P = .005). Among BRCA1 mutation carriers, those with skewed X inactivation were older at diagnosis of breast or ovarian cancer than those without skewed X inactivation (hazard ratio [HR] of breast or ovarian cancer = 0.37, 95% CI = 0.14 to 0.95 P = .04). Among BRCA2 mutation carriers, skewed X inactivation also occurred more frequently in unaffected carriers than in those diagnosed with breast or ovarian cancer (OR = 5.2, 95% CI = 0.5 to 28.9 P = .08) and was associated with delayed age at onset (HR = 0.59, 95% CI = 0.37 to 0.94 P = .03). Skewed X inactivation occurs at an increased frequency in BRCA1 (and possibly BRCA2) mutation carriers compared with control subjects and is associated with a statistically significant increase in age at diagnosis of breast and ovarian cancer.
Publisher: Wiley
Date: 09-09-2007
DOI: 10.1007/S10897-007-9105-4
Abstract: Some women at increased familial risk of breast cancer experience elevated levels of cancer-specific worry, which can possibly act as a barrier to screening, and may be a significant factor in decisions regarding risk-reducing surgery. The aim of this study was to comprehensively examine predictors of cancer-specific worry in high risk women and to test a model which proposes that perceived breast cancer risk mediates the impact of other factors on worry. 1,437 unaffected women from high risk breast cancer families completed questionnaires and interviews. Path analysis was used to test the model of potential predictors of cancer worry, including familial, personal and psychological variables, mediated via perceived cancer risk. Levels of cancer-specific worry were generally low despite an average perceived risk of 50.3%. The goodness-of-fit of the proposed model was poor, explaining only 9% of the variance for perceived risk and 10% of the variance for cancer specific worry. An alternative model of a direct relationship between all of the predictor variables and cancer worry, explained 24% of the variation in cancer worry. General anxiety, perceived risk, the stressful impact of recent cancer related events, a relative risk greater than 10, being closer in age to the youngest breast cancer diagnosis in family, and knowledge of personal mutation status, all independently contributed to cancer worry. Addressing general affective responses, experiences of recent cancer related events, in addition to education about personal risk, should be considered in counselling women with elevated cancer worry. Risk perception appears to act independently of other factors in its formulation and impact on cancer worry. Further research on the way in which women come to perceive their risk is indicated.
Publisher: Springer Science and Business Media LLC
Date: 17-06-2014
DOI: 10.1038/NCOMMS5051
Publisher: Wiley
Date: 05-03-2015
DOI: 10.1007/S10897-015-9824-X
Abstract: Little is known about the process of psychosocial adaptation to familial risk in tested and untested in iduals at increased familial risk of cancer. This paper presents findings from a qualitative study of 36 women participating in the Kathleen Cuningham Consortium for Research into Familial Breast cancer (kConFab) Psychosocial study. Facilitators and challenges in psychosocial adaptation were identified through semi-structured interviews. The women, who were either tested (carriers or non-carriers of breast cancer susceptibility mutations) or untested (ineligible for testing or eligible but delayed or declined testing), described personal, support network and healthcare characteristics that impacted on the adaptation process. Challenges in one domain could be overcome by facilitators in other domains and key differences relating to whether women had undergone testing, or not, were identified. Tested and untested women with an increased familial risk of breast cancer may benefit from support tailored to their mutation testing status in order to enhance adaptation.
Publisher: Springer Science and Business Media LLC
Date: 06-2005
DOI: 10.1007/S10689-004-6129-X
Abstract: Prospective collection of epidemiological, psychosocial and outcome data in large breast cancer family cohorts should provide less biased data than retrospective studies regarding penetrance of breast cancer and modifiers of genetic risk. The Kathleen Cuningham Foundation for Research into Breast Cancer (kConFab) recently commenced 3-yearly follow-up on over 750 families with multiple cases of breast cancer. Clinical follow-up was by mailed self-report questionnaire to all participants, while psychosocial follow-up was only of unaffected women and consisted of two components: a mailed questionnaire and an interview regarding stressful life events. To date, 1928 of 2748 (70%) participants returned the clinical follow-up questionnaire (10% opted out, 16% were non-responders, and 4% were not contactable). Of the unaffected females who returned the clinical follow-up questionnaire, 91% participated in the psychosocial follow-up. In multivariate analyses, sex, personal cancer status, marital status, age and educational status were independent predictors of response to the clinical follow-up questionnaire, and number of female children, age, and family history of breast cancer were independent predictors of response to the psychosocial follow-up. A first round of 3-yearly clinical and psychosocial follow-up using a mailed questionnaire was feasible in this cohort. High response rates were achieved by employing intensive tracing and reminder strategies. The predictors of response for the clinical and psychosocial follow-up components of this study should be considered in designing similar follow-up strategies for other family cancer cohorts.
Publisher: Springer Science and Business Media LLC
Date: 25-10-2006
DOI: 10.1007/S10549-006-9415-5
Abstract: Assays to determine the pathogenicity of unclassified sequence variants in disease-associated genes include the analysis of lymphoblastoid cell lines (LCLs). We assessed the ability of several assays of LCLs to distinguish carriers of germline BRCA1 and BRCA2 gene mutations from mutation-negative controls to determine their utility for use in a diagnostic setting. Post-ionising radiation cell viability and micronucleus formation, and telomere length were assayed in LCLs carrying BRCA1 or BRCA2 mutations, and in unaffected mutation-negative controls. Post-irradiation cell viability and micronucleus induction assays of LCLs from in iduals carrying pathogenic BRCA1 mutations, unclassified BRCA1 sequence variants or wildtype BRCA1 sequence showed significant phenotypic heterogeneity within each group. Responses were not consistent with predicted functional consequences of known pathogenic or normal sequences. Telomere length was also highly heterogeneous within groups of LCLs carrying pathogenic BRCA1 or BRCA2 mutations, and normal BRCA1 sequences, and was not predictive of mutation status. Given the significant degree of phenotypic heterogeneity of LCLs after gamma-irradiation, and the lack of association with BRCA1 or BRCA2 mutation status, we conclude that the assays evaluated in this study should not be used as a means of differentiating pathogenic and non-pathogenic sequence variants for clinical application. We suggest that a range of normal controls must be included in any functional assays of LCLs to ensure that any observed differences between s les reflect the genotype under investigation rather than generic inter-in idual variation.
Publisher: Springer New York
Date: 2016
Publisher: Elsevier BV
Date: 03-2015
DOI: 10.1016/J.EURURO.2014.08.007
Abstract: Intraductal carcinoma of the prostate (IDC-P) is a distinct clinicopathologic entity associated with aggressive prostate cancer (PCa). PCa patients carrying a breast cancer 2, early onset (BRCA2) germline mutation exhibit highly aggressive tumours with poor prognosis. To investigate the presence and implications of IDC-P in men with a strong family history of PCa who either carry a BRCA2 pathogenic mutation or do not carry the mutation (BRCAX). Patient-derived xenografts (PDXs) were generated from three germline BRCA2 mutation carriers and one BRCAX patient. Specimens were examined for histologic evidence of IDC-P. Whole-genome copy number analysis (WG-CNA) was performed on IDC-P from a primary and a matched PDX specimen. The incidence of IDC-P and association with overall survival for BRCA2 and BRCAX patients were determined using Kaplan-Meier analysis. PDXs from BRCA2 tumours showed increased incidence of IDC-P compared with sporadic PCa (p=0.015). WG-CNA confirmed that the genetic profile of IDC-P from a matched (primary and PDX) BRCA2 tumour was similar. The incidence of IDC-P was significantly increased in BRCA2 carriers (42%, n=33, p=0.004) but not in BRCAX patients (25.8%, n=62, p=0.102) when both groups were compared with sporadic cases (9%, n=32). BRCA2 carriers and BRCAX patients with IDC-P had significantly worse overall and PCa-specific survival compared with BRCA2 carriers and BRCAX patients without IDC-P (hazard ratio [HR]: 16.9, p=0.0064 and HR: 3.57, p=0.0086, respectively). PDXs revealed IDC-P in patients with germline BRCA2 mutations or BRCAX classification, identifying aggressive tumours with poor survival even when the stage and grade of cancer at diagnosis were similar. Further studies of the prognostic significance of IDC-P in sporadic PCa are warranted. Intraductal carcinoma of the prostate is common in patients with familial prostate cancer and is associated with poor outcomes. This finding affects genetic counselling and identifies patients in whom earlier multimodality treatment may be required.
Publisher: Springer Science and Business Media LLC
Date: 28-06-2007
DOI: 10.1038/NATURE05887
Publisher: Springer Science and Business Media LLC
Date: 04-12-2007
DOI: 10.1007/S10549-007-9832-0
Abstract: RAD51D is a homolog of the RAD51 protein, which is known to be an important component of the DNA repair pathway. A rare missense variant in the RAD51D gene, E233G (c.A>G), has been reported to be more prevalent in breast cancer cases from specific multiple-case breast cancer families, with an odds ratio of 2.6 (95% confidence interval (CI): 1.12-6.03). We assessed whether this variant was associated with breast cancer risk using two studies: a population-based case-control-family study based on 1,110 cases and 629 controls, and a clinic-based study based on 390 cases from multiple-case breast cancer families. We conducted case-control analyses and modified segregation analyses of carrier families. The carrier frequencies (95% CI) of the RAD51D variant were 4.1% (2.4-6.6) for clinic-based cases, 3.9% (2.8-5.2) for population-based cases, and 3.7% (2.3-5.4) for population-based controls, and were not significantly higher in case groups than controls (P=0.7 and P=0.8, respectively). After genotyping the relatives of cases who carried the variant, modified segregation analyses of these families were conducted, and the estimated hazard ratio for breast cancer corresponding to the E233G variant was 1.30 (95% CI: 0.66-2.58 P=0.4) for familial breast cancer families and 1.28 (95% CI: 0.47-3.43 P=0.6) for families unselected for family history. Therefore, despite being well powered to detect moderate risks, no evidence for an association between the E233G variant and breast cancer risk was observed in any setting. Larger studies would be required to determine if this variant is associated with a smaller risk of breast cancer.
Publisher: Springer Science and Business Media LLC
Date: 18-11-2009
Publisher: Oxford University Press (OUP)
Date: 13-07-2015
DOI: 10.1093/IJE/DYV118
Publisher: American Association for Cancer Research (AACR)
Date: 08-2006
Publisher: Springer Science and Business Media LLC
Date: 02-2008
DOI: 10.1186/BCR1858
Publisher: BMJ
Date: 02-2005
Publisher: American Association for Cancer Research (AACR)
Date: 2006
DOI: 10.1158/1055-9965.EPI-05-0709
Abstract: This is by far the largest study of its kind to date, and further suggests that AIB1 does not play a substantial role in modifying the phenotype of BRCA1 and BRCA2 carriers. The AIB1 gene encodes the AIB1/SRC-3 steroid hormone receptor coactivator, and lification of the gene and/or protein occurs in breast and ovarian tumors. A CAG/CAA repeat length polymorphism encodes a stretch of 17 to 29 glutamines in the HR-interacting carboxyl-terminal region of the protein which is somatically unstable in tumor tissues and cell lines. There is conflicting evidence regarding the role of this polymorphism as a modifier of breast cancer risk in BRCA1 and BRCA2 carriers. To further evaluate the evidence for an association between AIB1 glutamine repeat length and breast cancer risk in BRCA1 and BRCA2 mutation carriers, we have genotyped this polymorphism in 1,090 BRCA1 and 661 BRCA2 mutation carriers from Australia, Europe, and North America. There was no evidence for an increased risk associated with AIB1 glutamine repeat length. Given the large s le size, with more than adequate power to detect previously reported effects, we conclude that the AIB1 glutamine repeat does not substantially modify risk of breast cancer in BRCA1 and BRCA2 mutation carriers. (Cancer Epidemiol Biomarkers Prev 2006 (1):76–9)
Publisher: Elsevier BV
Date: 09-2014
DOI: 10.1038/MODPATHOL.2013.231
Abstract: Male breast cancer is poorly understood with a large proportion arising in the familial context particularly with the BRCA2 germline mutation. As phenotypic and genotypic differences between sporadic and familial male breast cancers have been noted, we investigated the importance of a hypoxic drive in these cancers as this pathway has been shown to be of importance in familial female breast cancer. Expression of two major hypoxia-induced proteins, the hypoxia-inducible factor-1α (HIF1A) and the carbonic anhydrase IX (CA9), examined within a large cohort including 61 familial (3 BRCA1, 28 BRCA2, 30 BRCAX) and 225 sporadic male breast cancers showed that 31% of all male breast cancers expressed either HIF1A (25%) and/or CA9 (8%) in the combined cohort. Expression of HIF1A correlated with an increased incidence of a second-major malignancy (P=0.04), histological tumor type (P=0.005) and basal phenotype (P=0.02). Expression of CA9 correlated with age (P=0.004) in sporadic cases and an increased tumor size (P=0.003). Expression of HIF1A was prognostic for disease-specific survival in sporadic male breast cancers (HR: 3.8, 95% CI: 1.5-9.8, P=0.006) but not within familial male breast cancer, whereas CA9 was only prognostic in familial male breast cancers (HR: 358.0, 95% CI: 9.3-13781.7, P=0.002) and not in sporadic male breast cancer. This study found that hypoxic drive is less prevalent in male breast cancer compared with female breast cancer, possibly due to a different breast microenvironment. The prognostic impact of HIF1A is greatest in sporadic male breast cancers with an alternate dominant mechanism for the oncogenic drivers suggested in high risk familial male breast cancers.
Publisher: Springer Science and Business Media LLC
Date: 24-04-2017
DOI: 10.1038/NG.3841
Publisher: American Society of Clinical Oncology (ASCO)
Date: 09-2013
Abstract: To determine whether adjuvant tamoxifen treatment for breast cancer (BC) is associated with reduced contralateral breast cancer (CBC) risk for BRCA1 and/or BRCA2 mutation carriers. Analysis of pooled observational cohort data, self-reported at enrollment and at follow-up from the International BRCA1, and BRCA2 Carrier Cohort Study, Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer, and Breast Cancer Family Registry. Eligible women were BRCA1 and BRCA2 mutation carriers diagnosed with unilateral BC since 1970 and no other invasive cancer or tamoxifen use before first BC. Hazard ratios (HRs) for CBC associated with tamoxifen use were estimated using Cox regression, adjusting for year and age of diagnosis, country, and bilateral oophorectomy and censoring at contralateral mastectomy, death, or loss to follow-up. Of 1,583 BRCA1 and 881 BRCA2 mutation carriers, 383 (24%) and 454 (52%), respectively, took tamoxifen after first BC diagnosis. There were 520 CBCs over 20,104 person-years of observation. The adjusted HR estimates were 0.38 (95% CI, 0.27 to 0.55) and 0.33 (95% CI, 0.22 to 0.50) for BRCA1 and BRCA2 mutation carriers, respectively. After left truncating at recruitment to the cohort, adjusted HR estimates were 0.58 (95% CI, 0.29 to 1.13) and 0.48 (95% CI, 0.22 to 1.05) based on 657 BRCA1 and 426 BRCA2 mutation carriers with 100 CBCs over 4,392 person-years of prospective follow-up. HRs did not differ by estrogen receptor status of the first BC (missing for 56% of cases). This study provides evidence that tamoxifen use is associated with a reduction in CBC risk for BRCA1 and BRCA2 mutation carriers. Further follow-up of these cohorts will provide increased statistical power for future prospective analyses.
Publisher: Springer Science and Business Media LLC
Date: 23-03-2010
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: Springer Science and Business Media LLC
Date: 27-03-2017
DOI: 10.1038/NG.3826
Publisher: Springer Science and Business Media LLC
Date: 15-05-2012
DOI: 10.1038/BJC.2012.160
Publisher: Informa UK Limited
Date: 02-12-2015
Publisher: Springer Science and Business Media LLC
Date: 02-2012
DOI: 10.1186/BCR3121
Publisher: Springer Science and Business Media LLC
Date: 25-09-2011
DOI: 10.1038/NM.2459
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: Springer Science and Business Media LLC
Date: 24-06-2011
Abstract: Detection of mutations by DNA sequencing can be facilitated by scanning methods to identify licons which may have mutations. Current scanning methods used for the detection of germline sequence variants are laborious as they require post-PCR manipulation. High resolution melting (HRM) is a cost-effective rapid screening strategy, which readily detects heterozygous variants by melting curve analysis of PCR products. It is well suited to screening genes such as BRCA1 and BRCA2 as germline pathogenic mutations in these genes are always heterozygous. Assays for the analysis of all coding regions and intron-exon boundaries of BRCA1 and BRCA2 were designed, and optimised. A final set of 94 assays which ran under identical lification conditions were chosen for BRCA1 (36) and BRCA2 (58). Significant attention was placed on primer design to enable reproducible detection of mutations within the licon while minimising unnecessary detection of polymorphisms. Deoxyinosine residues were incorporated into primers that overlay intronic polymorphisms. Multiple 384 well plates were used to facilitate high throughput. 169 BRCA1 and 239 BRCA2 known sequence variants were used to test the licons. We also performed an extensive blinded validation of the protocol with 384 separate patient DNAs. All heterozygous variants were detected with the optimised assays. This is the first HRM approach to screen the entire coding region of the BRCA1 and BRCA2 genes using one set of reaction conditions in a multi plate 384 well format using specifically designed primers. The parallel screening of a relatively large number of s les enables better detection of sequence variants. HRM has the advantages of decreasing the necessary sequencing by more than 90%. This markedly reduced cost of sequencing will result in BRCA1 and BRCA2 mutation testing becoming accessible to in iduals who currently do not undergo mutation testing because of the significant costs involved.
Publisher: Oxford University Press (OUP)
Date: 06-02-2002
Abstract: The ATM gene encoding a putative protein kinase is mutated in ataxia-telangiectasia (A-T), an autosomal recessive disorder with a predisposition for cancer. Studies of A-T families suggest that female heterozygotes have an increased risk of breast cancer compared with noncarriers. However, neither linkage analyses nor mutation studies have provided supporting evidence for a role of ATM in breast cancer predisposition. Nevertheless, two recurrent ATM mutations, T7271G and IVS10-6T-->G, reportedly increase the risk of breast cancer. We examined these two ATM mutations in a population-based, case-control series of breast cancer families and multiple-case breast cancer families. Five hundred twenty-five or 262 case patients with breast cancer and 381 or 68 control subjects, respectively, were genotyped for the T7271G and IVS10-6T-->G ATM mutations, as were index patients from 76 non-BRCA1/2 multiple-case breast cancer families. Linkage and penetrance were analyzed. ATM protein expression and kinase activity were analyzed in lymphoblastoid cell lines from mutation carriers. All statistical tests were two-sided. In case and control subjects unselected for family history of breast cancer, one case patient had the T7271G mutation, and none had the IVS10-6T-->G mutation. In three multiple-case families, one of these two mutations segregated with breast cancer. The estimated average penetrance of the mutations was 60% (95% confidence interval [CI] = 32% to 90%) to age 70 years, equivalent to a 15.7-fold (95% CI = 6.4-fold to 38.0-fold) increased relative risk compared with that of the general population. Expression and activity analyses of ATM in heterozygous cell lines indicated that both mutations are dominant negative. At least two ATM mutations are associated with a sufficiently high risk of breast cancer to be found in multiple-case breast cancer families. Full mutation analysis of the ATM gene in such families could help clarify the role of ATM in breast cancer susceptibility.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2010
DOI: 10.1158/1055-9965.EPI-10-0374
Abstract: Background: Truncating mutations in ATM have been shown to increase the risk of breast cancer but the effect of missense variants remains contentious. Methods: We have genotyped five polymorphic (minor allele frequency, 0.9-2.6%) missense single nucleotide polymorphisms (SNP) in ATM (S49C, S707P, F858L, P1054R, and L1420F) in 26,101 breast cancer cases and 29,842 controls from 23 studies in the Breast Cancer Association Consortium. Results: Combining the data from all five SNPs, the odds ratio (OR) was 1.05 for being a heterozygote for any of the SNPs and 1.51 for being a rare homozygote for any of the SNPs with an overall trend OR of 1.06 (Ptrend = 0.04). The trend OR among bilateral and familial cases was 1.12 (95% confidence interval, 1.02-1.23 Ptrend = 0.02). Conclusions: In this large combined analysis, these five missense ATM SNPs were associated with a small increased risk of breast cancer, explaining an estimated 0.03% of the excess familial risk of breast cancer. Impact: Testing the combined effects of rare missense variants in known breast cancer genes in large collaborative studies should clarify their overall contribution to breast cancer susceptibility. Cancer Epidemiol Biomarkers Prev 19(9) 2143–51. ©2010 AACR.
Publisher: Wiley
Date: 31-03-2023
DOI: 10.1111/HIS.14906
Abstract: To catalogue and compare the pattern of metastatic disease in germline BRCA1/2 pathogenic mutation carriers and non‐carriers with breast, ovarian and prostate cancer from a rapid autopsy programme. The number of metastases in the major body systems and the proportion of participants with metastases were documented in 50 participants (19 germline mutation carriers). Analysis was conducted on the participants’ pattern of disease for the different cancers and mutation subgroups. The four commonly affected organ systems were the digestive (liver only) (82%), respiratory (76%), gastrointestinal (65%) and reticuloendothelial (42%). There were significant differences in the pattern of metastatic breast cancer in BRCA1/2 germline carriers compared with non‐carriers. Breast cancer carriers had significantly fewer organ systems involved (median n = 3, range = 1–3) compared with non‐carriers (median n = 9, range = 1–7) ( P = 0.03). BRCA1/2 carriers with ovarian carcinomas had significantly more organ systems with metastatic carcinoma (median n = 10, range = 3–8) than non‐carriers (median n = 5, range = 3–5) ( P 0.001). There were no significant differences in the number of involved systems in BRCA2 carriers compared with non‐carriers with prostate cancer ( P = 1.0). There was an absence of locoregional disease (6.5%) compared with distant disease (93.5%) among the three cancer subtypes ( P 0.001). The majority of metastatic deposits (97%) collected during the autopsy were identified by recent diagnostic imaging. Even though a major limitation of this study is that our numbers are small, especially in the breast cancer carrier group, the metastatic patterns of breast and ovarian cancers may be impacted by BRCA1/2 carrier status, suggesting that tumours derived from patients with these mutations use different mechanisms of dissemination. The findings may focus clinical diagnostic imaging for monitoring metastases where whole‐body imaging resources are scant.
Publisher: Wiley
Date: 02-09-2010
DOI: 10.1002/GCC.20816
Abstract: The heterogeneity of multiple case breast cancer families that do not carry mutations in BRCA1 or BRCA2 (non-BRCA1/2 families) poses a challenge to the identification of breast cancer susceptibility genes. The aim of this study was to determine whether intrafamilial concordance in breast cancer pathology could identify subgroups of non-BRCA1/2 families with consistent genotypic features. Invasive breast cancers were reviewed from 84 in iduals belonging to 30 multiple-case families BRCA1 (n = 9), BRCA2 (n = 10), and non-BRCA1/2 (n = 11). Hierarchical cluster analysis based on histopathology and age at first diagnosis was then used to specify three subgroups designated Clusters 1-3. The genomic features of non-BRCA1/2 families were examined by genome wide linkage and FGFR2 SNP genotyping, according to whether they showed cluster-concordant or cluster-mixed familial pathology. The majority of pathogenic BRCA1 mutation carriers (80%) fell into a single cluster. In contrast pathogenic BRCA2 mutation carriers were distributed across all three clusters and within families, cluster groups were also generally mixed. Most non-BRCA1/2 mutation carriers belonged to Cluster 3 (71%). Genome wide linkage data from five non-BRCA1/2 Cluster 3-concordant families were compared with four mixed cluster non-BRCA1/2 families. This revealed a number of distinct linkage peaks, including some regions previously associated with breast cancer susceptibility. The distribution of low risk alleles in FGFR2 was not different between these two subgroups (P = 0.237). The pattern of breast cancer pathology concordance amongst family members may assist the investigation of breast cancer susceptibility in multiple case families.
Publisher: Springer Science and Business Media LLC
Date: 11-12-2008
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488654.V1
Abstract: Supplementary Figures S1-S13
Publisher: Springer Science and Business Media LLC
Date: 27-08-2010
DOI: 10.1007/S10549-010-1123-5
Abstract: Exposure to estrogen has a major effect on breast cancer risk. A polymorphism (-34 T > C rs743572) in the cytochrome P450c17alpha gene (CYP17A1) encoding an enzyme which controls estrogen levels was reportedly associated with breast cancer risk in average risk populations. The effect of this polymorphism on breast or ovarian cancer risk for BRCA1 and BRCA2 mutation carriers has not been thoroughly investigated. With this aim, 2,221 BRCA1 and BRCA2 mutation carriers (1,313 with breast cancer, 279 with ovarian cancer, and 695 asymptomatic carriers), with either BRCA1 (n = 1693) or BRCA2 (n = 528) germline mutations from seven centers were genotyped for the -34 T > C CYP17 polymorphism. Genotyping was accomplished using Taqman allelic discrimination, matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOF MS) or PCR-based restriction-fragment length polymorphism analysis, and limited sequencing. Data were analyzed using Cox proportional hazards models. The hazard ratios (HRs) for breast cancer was 1.02 (95% CI 0.89-1.17, p = 0.74) and 1.10 (95% CI 0.72-1.67, p = 0.66) for BRCA1 and BRCA2 mutation carriers, respectively. The HRs for ovarian cancer were 1.17 (0.94-1.46, p = 0.17) and 0.91 (0.31-2.67, p = 0.86) for BRCA1 and BRCA2 mutation carriers, respectively. Results remained unaltered when the Israeli cohort (primarily Ashkenazim) was evaluated separately. In conclusion, there was no overall evidence for an association of the -34 T > C CYP17 polymorphism with either breast or ovarian cancer risk in BRCA1 or BRCA2 mutation carriers.
Publisher: Public Library of Science (PLoS)
Date: 27-12-2016
Publisher: Springer Science and Business Media LLC
Date: 16-05-2009
Publisher: Public Library of Science (PLoS)
Date: 27-07-2016
Publisher: Wiley
Date: 25-09-2006
DOI: 10.1002/GCC.20381
Abstract: Mutations in ATM are responsible for the autosomal recessive disorder ataxia telangiectasia. Heterozygous mutations in ATM have been associated with an elevated risk of breast cancer. We previously reported one breast cancer family in which ATM 7271T>G (V2424G) segregated with disease, and apparently acted in a dominant negative manner. We now report the screening of 782 multiple-case breast cancer families that identified two additional index cases with ATM 7271T>G. Phylogenetic sequence analysis showed that V2424 is a highly conserved residue, and that the 2424G variant is likely to interfere with function. To elucidate the consequences of this mutation, we expression profiled wild-type, heterozygous, and homozygous lymphoblastoid cell lines (LCLs) from Scottish and Australian families using an oligonucleotide microarray. Cluster analysis revealed 77 genes that were differentially expressed in homozygous and heterozygous V2424G cells (compared to wild-type) and 11 genes differentially expressed in the homozygous cells. We also evaluated the profiles of LCLs after exposure to ionizing radiation (IR) and identified 77 genes that were differentially expressed in wild-type cells, but not in homozygous or heterozygous V2424G cells. We validated the expression differences by RT-PCR in additional heterozygous V2424G LCLs from another breast cancer family. We found no consistent cytotoxicity or abrogation of ATM kinase activity after IR in seven heterozygous V2424G LCLs, compared to wild-type LCLs, but did find an increase in the number of chromosomal aberrations. These data suggest that the V2424G missense mutation acts largely as a dominant negative in terms of the associated expression profiles.
Publisher: Springer Science and Business Media LLC
Date: 09-02-2016
Publisher: BMJ
Date: 27-05-2005
Publisher: American Society of Clinical Oncology (ASCO)
Date: 04-2008
Abstract: Rare missense substitutions and in-frame deletions of BRCA1 and BRCA2 genes present a challenge for genetic counseling of in iduals carrying such unclassified variants. We assessed the value of tumor immunohistochemical markers in conjunction with genetic and evolutionary approaches for investigating the clinical significance of unclassified variants. We studied 10 BRCA1 and 12 BRCA2 variants identified in Australian families with breast cancer. Analyses assumed a prior probability based on revised cross-species sequence alignment methods assessing amino acid evolutionary conservation and position, combined with likelihoods from data on co-occurrence with pathogenic mutations in the same gene, segregation analysis, and immunohistochemistry. We specifically explored the value of estrogen receptor, cytokeratin 5/6, and cytokeratin 14 as tumor markers of BRCA1 mutation status. Posterior probabilities classified 72% of variants. BRCA1 variants IVS18+1 G T (del exon 18) and 5632 T A (V1838E) were classified as pathogenic, with % posterior probability of being deleterious, and tumor histopathology was particularly important for their classification. BRCA2 variant classification was improved over previous studies, largely by incorporating the prior probability of pathogenicity based on amino acid cross-species sequence alignments. Variant classification was considerably improved by analysis of estrogen receptor, cytokeratin 5/6, and cytokeratin 14 tumor expression, and use of updated methods estimating the clinical relevance of amino acid evolutionary conservation and position. These methodologies may assist genetic counseling of in iduals with unclassified sequence variants.
Publisher: BMJ
Date: 20-07-2009
Abstract: The role of FOXP1 in sporadic breast cancers has been widely studied but its role in familial breast cancers is yet unexplored. To investigate FOXP1 expression in different molecular subtypes of familial breast cancers and to correlate its expression with clinicopathological parameters, oestrogen receptors (ER) and survival. Immunohistochemical staining for FOXP1 was performed in 126 familial breast carcinomas comprising 35 BRCA1, 34 BRCA2 and 57 BRCAX. Nuclear FOXP1 expression ranged from focal weak to widespread strong expression. Expression of FOXP1 was higher in familial breast cancers (54%) compared with sporadic cancers (46%) (p .001). There was a significant correlation between FOXP1 with ERα (p = 0.038) and ERβ (p = 0.007) in familial breast cancers. FOXP1 was more highly expressed in familial breast cancers compared with sporadic cancers for luminal (p = 0.021) and basal (p .001), but not HER2 and null phenotypes (both p .05). The absence of FOXP1 expression was associated with a shorter relapse-free (p = 0.025) and overall survival (p = 0.009) in familial breast cancer. Negativity for FOXP1 was associated with a significantly worse overall survival in BRCA2 cancers (p = 0.021) and there was a non-significant separation of the survival curves for BRCA1 cancers (p = 0.183). No differences in survival were seen for BRCAX cancers (p = 0.762). Results suggest that FOXP1 demonstrates different expression patterns in familial breast cancers than sporadic tumours, even in tumours showing similar phenotypes. They also suggest a different role of FOXP1 as a tumour suppressor in familial tumours, which is unrelated to ER expression and may impact on therapeutic options.
Publisher: Springer Science and Business Media LLC
Date: 08-2007
DOI: 10.1186/BCR1759
Publisher: Wiley
Date: 26-10-2006
DOI: 10.1111/J.1365-2559.2006.02538.X
Abstract: Germline variants in the ataxia telangiectasia mutated (ATM) gene have been implicated in increased breast cancer risk. The aim of this study was to determine whether the histopathology of breast cancers occurring in ATM variant carriers is distinctive or resembles the described BRCA1 mutation-associated phenotype. The histopathological features of breast cancers occurring in ATM variant carriers from multiple-case breast cancer families were compared with matched controls. The test group included 21 cases of in situ and/or invasive cancer from carriers of either the IVS10-6T-->G, 2424V-->G or 1420L-->F ATM variants in the absence of BRCA1 or BRCA2 mutations. An additional four invasive cancers from carriers of a pathogenic BRCA1 mutation in the context of a familial ATM variant were also examined. The histopathology of breast cancers in ATM variant-only carriers was not significantly different from controls and known features of BRCA1 mutation-associated cancer were rarely seen. In contrast, these features were prominent in the small group of cases with a pathogenic BRCA1 mutation. Breast cancer occurring in carriers of ATM variants is not associated with distinctive histopathological features and does not resemble the tumour phenotype commonly observed in BRCA1 mutation carriers.
Publisher: BMJ
Date: 03-11-2015
Publisher: Public Library of Science (PLoS)
Date: 08-06-2015
Publisher: BMJ
Date: 04-10-2010
Publisher: Springer Science and Business Media LLC
Date: 11-03-2017
Publisher: Springer Science and Business Media LLC
Date: 17-07-2001
DOI: 10.1186/BCR319
Abstract: Mutations in BRCA1 and BRCA2 account for approximately 50% of breast cancer families with more than four affected cases, whereas exonic mutations in p53, PTEN, CHK2 and ATM may account for a very small proportion. It was recently reported that an intronic variant of p53--G13964C--occurred in three out of 42 (7.1%) 'hereditary' breast cancer patients, but not in any of 171 'sporadic' breast cancer control in iduals (P = 0.0003). If this relatively frequent occurrence of G13964C in familial breast cancer and absence in control in iduals were confirmed, then this would suggest that the G13964C variant plays a role in breast cancer susceptibility. We genotyped 71 familial breast cancer patients and 143 control in iduals for the G13964C variant using polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) analysis. Three (4.2% 95% confidence interval [CI] 0-8.9%) G13964C heterozygotes were identified. The variant was also identified in 5 out of 143 (3.5% 95% CI 0.6-6.4%) control in iduals without breast cancer or a family history of breast cancer, however, which is no different to the proportion found in familial cases (P = 0.9). The present study would have had 80% power to detect an odds ratio of 4.4, and we therefore conclude that the G13946C polymorphism is not a 'high-risk' mutation for familial breast cancer.
Publisher: Elsevier BV
Date: 04-2006
DOI: 10.1080/00313020600561526
Abstract: Comparison between BRCA1-associated and sporadic ovarian carcinomas is a potential method to identify candidate modifier gene/s involved in the carcinogenic pathway of either or both groups. A previous study identified a significant difference in the frequency of copy number gain at 2q24-q32 by comparing BRCA1-associated and sporadic ovarian tumour specimens using comparative genomic hybridisation (CGH). The present study aimed to investigate the reported allelic imbalance at 2q24-32 by lification of several microsatellite markers at the region by quantitative microsatellite analysis (QuMA) using Taqman at the same region identified as a site of allelic imbalance. The copy number of the genomic region in 2q24-32 was established in 21 BRCA1-associated ovarian carcinomas and 14 sporadic cases using quantitative microsatellite polymerase chain reaction (PCR). Statistical analysis was performed using permutation test analysis. A significant loss at D2S156 marker (2q24.2) (p = 0.026) compared with the other three markers at 2q24-32 was found in the sporadic cohort but not in the BRCA1-associated group (p = 0.385). Our data do not support the association between copy number gain at 2q24-32 and BRCA1 mutation status in ovarian cancers reported previously. The novel finding of the present study was significant loss at 2q24.2 in sporadic ovarian cancers.
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2006
Publisher: Public Library of Science (PLoS)
Date: 24-08-2016
Publisher: Springer Science and Business Media LLC
Date: 2012
Publisher: American Society of Clinical Oncology (ASCO)
Date: 11-2013
Abstract: Limited data suggest that germline BRCA1 mutations are associated with occult primary ovarian insufficiency and that BRCA1 and BRCA2 mutation carriers might have earlier natural menopause (NM) than their noncarrier relatives. Eligible women were mutation carriers and noncarriers from families segregating a BRCA1 or BRCA2 mutation. Data were self-reported using uniform questionnaires at cohort entry and every 3 years thereafter. NM was defined as the cessation of menses for 12 months without another cause. Cox proportional hazards analysis modeled time from birth to NM, adjusting for multiple potential confounders. Analysis time was censored at the earliest of the following: last follow-up, bilateral oophorectomy, hysterectomy, commencement of hormone therapy, insertion of intrauterine device, or any cancer diagnosis. Hazard ratios (HRs) were estimated as a measure of how likely mutation carriers are, relative to noncarriers, to reach NM at a given age. A total of 1,840 women were eligible for analysis. Overall only 19% reached NM. A lower proportion of BRCA1 and BRCA2 mutation carriers reached NM compared with noncarriers. Conversely, a higher proportion of mutation carriers were censored at cancer diagnosis or oophorectomy than noncarriers. The adjusted HR estimates for NM were 1.03 (95% CI, 0.75 to 1.40 P = .9) for 445 BRCA1 mutation carriers and 559 noncarrier relatives and 1.01 (95% CI, 0.71 to 1.42 P = .9) for 374 BRCA2 mutation carriers and 462 noncarrier relatives. We found no evidence that BRCA1 and BRCA2 mutation carriers are at higher risk of NM at a given age than their noncarrier relatives.
Publisher: Oxford University Press (OUP)
Date: 07-2009
DOI: 10.1093/JNCI/DJP167
Publisher: Wiley
Date: 2005
DOI: 10.1002/PON.835
Abstract: There has been an ongoing debate in the literature on the extent to which women with a family history of breast cancer are at risk of psychological morbidity. This study compares psychological morbidity in 557 women participating in a large Australian registry of high-risk breast cancer families (kConFab) with 2 age and education matched s les, 1494 general practitioner attendees and 158 members of a twin registry. Participants completed the Somatic and Psychological Health Report (SPHERE). There were no significant differences between the three groups on psychological distress (F(2, 670) = 1.77, p = 0.17). Unsurprisingly, GP attendees reported more symptoms of somatic distress than the kConFab group (t411 = 2.89, p = 0.004) there were no differences between the twins and the kConFab group on somatic distress (t174 = 0.40, p = 0.687). Clinically significant anxiety/depression, a combination of psychological and somatic distress, therefore was significantly higher in GP attendees (28%) than the kConFab and twin s les (both 20%). These results refute the hypothesis that women with a family history of breast cancer are at greater psychological risk.
Publisher: Springer Science and Business Media LLC
Date: 10-2014
DOI: 10.1007/S10689-013-9687-Y
Abstract: This study assessed the sociodemographic, medical and psychological predictors of accuracy of perceived risk in women at increased genetic risk for ovarian cancer. Women participating in a large cohort study who were at increased risk of ovarian and fallopian tube cancer, had no personal history of cancer and had ≥1 ovary in situ at cohort enrollment, were eligible. Women completed self-administered questionnaires and attended an interview at enrollment. Of 2,868 women unaffected with cancer at cohort enrollment, 561 were eligible. 335 women (59.8 %) overestimated their ovarian cancer risk, while 215 women (38.4 %) accurately estimated their risk, and 10 (1.8 %) underestimated it. Women who did not know their mutation status were more likely to overestimate their risk (OR 1.74, 95 % CI 1.10, 2.77, p = 0.018), as were those with higher cancer-specific anxiety (OR 1.05, 95 % CI 1.02, 1.08, p < 0.001) and/or a mother who had been diagnosed with ovarian cancer (OR 1.98, 95 % CI 1.23, 3.18, p = 0.005). Amongst the group of women who did not know their mutation status, 63.3 % overestimated their risk and the mean perceived lifetime risk of developing ovarian cancer was 42.1 %, compared to a mean objective risk of 6.4 %. A large number of women at increased risk for ovarian cancer overestimate their risk. This is of concern especially in women who are at moderately increased risk only for this sub-group of women, interventions are needed to reduce potentially unnecessary psychological distress and minimise engagement in unnecessary surgery or screening.
Publisher: Hindawi Limited
Date: 02-2010
DOI: 10.1002/HUMU.21181
Publisher: Public Library of Science (PLoS)
Date: 28-01-2014
Publisher: Springer Science and Business Media LLC
Date: 28-03-2015
DOI: 10.1007/S10865-015-9632-7
Abstract: Risk comprehension in in iduals at increased familial risk of cancer is suboptimal and little is known about how risk is understood and managed by at-risk in iduals who do not undergo genetic testing. We qualitatively studied these issues in 36 unaffected women from high-risk breast cancer families, including both women who had and had not undergone genetic testing. Data were collected through semi-structured interviews and data analysis was guided by Grounded Theory. Risk comprehension and risk management were largely influenced by the in idual's experience of coming from a high-risk family, with both tested and untested women relying heavily on their intuition. Although women's cognitive understanding of their risk appeared generally accurate, this objective risk information was considered of secondary value. The findings could be used to guide the development and delivery of information about risk and risk management to genetically tested and untested in iduals at increased risk of hereditary cancer.
Publisher: Springer Science and Business Media LLC
Date: 28-04-2011
DOI: 10.1007/S10549-011-1539-6
Abstract: Although a significant proportion of familial aggregation of breast cancer remains unexplained, many of the currently known breast cancer susceptibility genes, including BRCA1, BRCA2 and TP53, play a role in maintaining genome integrity by engaging in DNA repair. RAD51L1 is one of the five RAD51 paralogs involved in homologous recombination (HR) repair of DNA double-strand breaks (DSBs) it also interacts directly with p53. Deleterious mutations have been found in one RAD51 paralog, RAD51C (RAD51L2), in non-BRCA1/2 breast and ovarian cancer families, which suggests that all five paralogs are strong candidate breast cancer susceptibility genes. A genome-wide association study (GWAS) has already identified a single nucleotide polymorphism (SNP) deep within intron 10 of RAD51L1 as a risk locus for breast cancer. Based on its biological functions and association with RAD51C, there is reason to suggest that RAD51L1 (RAD51B/REC2) may also contain high risk mutations in the gene that give rise to multiple-case breast cancer families. In order to investigate this hypothesis, we have used high resolution melt (HRM) analysis to screen RAD51L1 for germline mutations in 188 non-BRCA1/2 multiple-case breast cancer families and 190 controls. We identified a total of seven variants: one synonymous, three intronic, and three previously identified SNPs, but no truncating or nonsense changes. Therefore, our results suggest that RAD51L1 is unlikely to represent a high-penetrance breast cancer susceptibility gene.
Publisher: Springer Science and Business Media LLC
Date: 28-05-2010
Abstract: Genetic screening of breast cancer patients and their families have identified a number of variants of unknown clinical significance in the breast cancer susceptibility genes, BRCA1 and BRCA2 . Evaluation of such unclassified variants may be assisted by web-based bioinformatic prediction tools, although accurate prediction of aberrant splicing by unclassified variants affecting exonic splice enhancers (ESEs) remains a challenge. This study used a combination of RT-PCR analysis and splicing reporter minigene assays to assess five unclassified variants in the BRCA2 gene that we had previously predicted to disrupt an ESE using bioinformatic approaches. Analysis of BRCA2 c.8308 G A (p.Ala2770Thr) by mRNA analysis, and BRCA2 c.8962A G (p.Ser2988Gly), BRCA2 c.8972G A (p.Arg2991His), BRCA2 c.9172A G (p.Ser3058Gly), and BRCA2 c.9213G T (p.Glu3071Asp) by a minigene assay, revealed no evidence for aberrant splicing. These results illustrate the need for improved methods for predicting functional ESEs and the potential consequences of sequence variants contained therein.
Publisher: Hindawi Limited
Date: 02-08-2012
DOI: 10.1002/HUMU.22159
Abstract: Mutations in the BRCA1 gene confer a substantial increase in breast cancer risk, yet routine clinical genetic screening is limited to the coding regions and intron-exon boundaries, precluding the identification of mutations in noncoding and untranslated regions (UTR). As 3'UTR mutations can influence cancer susceptibility by altering protein and microRNA (miRNA) binding regions, we screened the BRCA1 3'UTR for mutations in a large series of BRCA-mutation negative, population and clinic-based breast cancer cases, and controls. Fifteen novel BRCA1 3'UTR variants were identified, the majority of which were unique to either cases or controls. Using luciferase reporter assays, three variants found in cases, c.* 528G>C, c.* 718A>G, and c.* 1271T>C and four found in controls, c.* 309T>C, c.* 379G>A, c.* 823C>T, and c.* 264C>T, reduced 3'UTR activity (P T and c.* 1139G>T, increased 3'UTR activity (P G, c.* 800T>C, and c.* 1340_1342delTGT, were predicted to create new miRNA binding sites and c.* 1340_1342delTGT caused a reduction (25%, P = 0.0007) in 3'UTR reporter activity when coexpressed with the predicted targeting miRNA, miR-103. This is the most comprehensive identification and analysis of BRCA1 3'UTR variants published to date.
Publisher: Springer Science and Business Media LLC
Date: 22-04-2010
Publisher: Public Library of Science (PLoS)
Date: 27-03-2013
Publisher: Elsevier BV
Date: 06-2008
DOI: 10.1080/00313020802035899
Abstract: In recent years histopathology has made an important contribution to the study of familial breast cancer, largely on the basis of the distinctive cancer phenotype commonly identified in BRCA1-mutation carriers. The aim of this study was to identify this phenotype amongst index cases from families in the kConFab familial breast cancer resource with no known pathogenic mutation ('BRCAX' families). The histopathology of breast cancer from 180 in iduals was reviewed: 132 members of in idual BRCAX families, 26 BRCA1 and 15 BRCA2 mutation carriers and seven mutation negative in iduals from families with a known pathogenic mutation. BRCAX breast cancers were a heterogeneous group with 25.8% grade 1, 37.9% grade 2 and 36.4% grade 3. Overall, 45/180 (25%) cases were designated 'BRCA1-phenotype' including 22/132 (16.7%) BRCAX cases, 18/26 (69.2%) BRCA1 and 5/15 (33.3%) BRCA2 mutation carriers. For BRCAX cases, a BRCA1 phenotype designation was negatively correlated with age. Characteristic breast cancer pathology is not diagnostic of a germline BRCA1 mutation, but it does indicate a pathogenic mechanism that occurs with increased frequency in BRCA1 mutation carriers. In BRCAX families, BRCA1 tumour phenotype may signal the presence of an unidentified BRCA1 mutation. However, this finding must be interpreted with regard to limits of the association between histopathology and genotype, and the importance of clinical context.
Publisher: Wiley
Date: 26-10-2017
DOI: 10.1111/BJU.14043
Abstract: To determine the relevance of intraductal carcinoma of the prostate (IDC-P) in advanced prostate cancer by first examining whether IDC-P was originally present in patients who later developed advanced prostate cancer and then using patient-derived xenografts (PDXs) to investigate the response of IDC-P to androgen deprivation therapy (ADT). We conducted a retrospective pathology review of IDC-P in primary prostate biopsy or surgery specimens from 38 men who subsequently developed advanced prostate cancer. Overall survival was calculated using the Kaplan-Meier method. To demonstrate the response of IDC-P to ADT, we established PDXs from seven patients with familial and/or high-risk sporadic prostate cancer. After castration and testosterone restoration of host mice, we measured the volume and proliferation of IDC-P within PDX grafts. We found that IDC-P was a prominent feature in the primary prostate specimens, present in 63% of specimens and often co-existing with poorly differentiated adenocarcinoma. Overall survival was similar in patients with or without IDC-P. In the PDXs from all seven patients, IDC-P was identified and present at a similar volume to adenocarcinoma. Residual IDC-P lesions persisted after host castration and, similar to castrate-tolerant adenocarcinoma, testosterone restoration led to tumour regeneration. The study showed that IDC-P is prevalent in aggressive prostate cancer and contains cells that can withstand androgen deprivation. Thus, IDC-P appears functionally relevant in advanced prostate cancer. The presence of IDC-P may be a trigger to develop innovative clinical management plans.
Publisher: Springer Science and Business Media LLC
Date: 06-2005
DOI: 10.1007/S10689-004-2102-Y
Abstract: A recent report based on 68 families, including 17 with mutations in BRCA1, suggested that there was an excess of female offspring born to BRCA1 mutation carriers. We have examined the gender ratio among offspring of 511 mutation carriers from 116 BRCA1 families, 77 and 39 from Australia and the United States, respectively. We found no evidence for a significant deviation from the expected proportion of female offspring in the Australian pedigrees, but there was an excess of female offspring in pedigrees from the USA. Ascertainment bias probably explains this bias, rather than a link with X-chromosome inactivation as previously suggested, because the families from the USA were ascertained for the purposes of linkage studies whereas those from Australia were ascertained through Familial Cancer Clinics to which they had been referred for clinical genetic counseling and mutation testing.
Publisher: American Medical Association (AMA)
Date: 25-01-2012
DOI: 10.1001/JAMA.2012.20
Publisher: American Association for Cancer Research (AACR)
Date: 05-2011
DOI: 10.1158/1055-9965.EPI-10-0909
Abstract: Background: Inherited BRCA1 and BRCA2 (BRCA1/2) mutations confer elevated breast cancer risk. Knowledge of factors that can improve breast cancer risk assessment in BRCA1/2 mutation carriers may improve personalized cancer prevention strategies. Methods: A cohort of 5,546 BRCA1 and 2,865 BRCA2 mutation carriers was used to evaluate risk of breast cancer associated with BARD1 Cys557Ser. In a second nonindependent cohort of 1,537 of BRCA1 and 839 BRCA2 mutation carriers, BARD1 haplotypes were also evaluated. Results: The BARD1 Cys557Ser variant was not significantly associated with risk of breast cancer from single SNP analysis, with a pooled effect estimate of 0.90 (95% CI: 0.71–1.15) in BRCA1 carriers and 0.87 (95% CI: 0.59–1.29) in BRCA2 carriers. Further analysis of haplotypes at BARD1 also revealed no evidence that additional common genetic variation not captured by Cys557Ser was associated with breast cancer risk. Conclusion: Evidence to date does not support a role for BARD1 variation, including the Cy557Ser variant, as a modifier of risk in BRCA1/2 mutation carriers. Impact: Interactors of BRCA1/2 have been implicated as modifiers of BRCA1/2-associated cancer risk. Our finding that BARD1 does not contribute to this risk modification may focus research on other genes that do modify BRCA1/2-associated cancer risk. Cancer Epidemiol Biomarkers Prev 20(5) 1032–8. ©2011 AACR.
Publisher: Elsevier BV
Date: 12-2007
DOI: 10.1086/522611
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: 12-2012
DOI: 10.1007/S10689-012-9585-8
Abstract: Bilateral risk-reducing salpingo-oophorectomy (RRSO) has been shown to significantly reduce the risk of ovarian cancer. This study assessed factors predicting uptake of RRSO. Women participating in a large multiple-case breast cancer family cohort study who were at increased risk for ovarian and fallopian tube cancer (i.e. BRCA1 or BRCA2 mutation carrier or family history including at least one first- or second-degree relative with ovarian or fallopian tube cancer), with no personal history of cancer and with at least one ovary in situ at cohort enrolment, were eligible for this study. Women who knew they did not carry the BRCA1 or BRCA2 mutation segregating in their family (true negatives) were excluded. Sociodemographic, biological and psychosocial factors, including cancer-specific anxiety, perceived ovarian cancer risk, optimism and social support, were assessed using self-administered questionnaires and interviews at cohort enrolment. RRSO uptake was self-reported every three years during systematic follow-up. Of 2,859 women, 571 were eligible. Mean age was 43.3 years 62 women (10.9 %) had RRSO a median of two years after cohort entry. Factors predicting RRSO were: being parous (OR 3.3, p = 0.015) knowing one's mutation positive status (OR 2.9, p < 0.001) and having a mother and/or sister who died from ovarian cancer (OR 2.5, p = 0.013). Psychological variables measured at cohort entry were not associated with RRSO. These results suggest that women at high risk for ovarian cancer make decisions about RRSO based on risk and in idual socio-demographic characteristics, rather than in response to psychological factors such as anxiety.
Publisher: Elsevier BV
Date: 03-2009
DOI: 10.1016/J.EJCA.2008.09.023
Abstract: Few data exist regarding the use of complementary and alternative medicine (CAM) by unaffected women at high risk of breast cancer. Self-reported CAM use by women from multiple-case breast cancer families was obtained by questionnaire. Factors associated with CAM use were assessed using multiple logistic regression. Of 892 women, 55% (n=489) used CAM, 6% (n=53) specifically to prevent cancer. CAM use was independently associated with tertiary education level (OR 2.56, 95% CI 1.83-3.58, p<0.001), greater physical activity (OR 1.05 per hour of physical activity/week, 95% CI 1.00-1.10, p=0.049), greater anxiety (OR 1.92, 95% CI 1.16-3.16, p=0.01), not currently smoking (OR 0.64, 95% CI 0.42-0.97, p=0.037) and lower perceived BC risk (OR 0.82 per 20 percentage points, 95% CI 0.72-0.94, p=0.005). The majority of high-risk women use CAM, but mostly for reasons other than cancer prevention. Most predictors of CAM use are consistent with the limited literature for women at high risk for cancer.
Publisher: Springer Science and Business Media LLC
Date: 08-2009
DOI: 10.1038/NM.2000
Abstract: Basal-like breast cancers arising in women carrying mutations in the BRCA1 gene, encoding the tumor suppressor protein BRCA1, are thought to develop from the mammary stem cell. To explore early cellular changes that occur in BRCA1 mutation carriers, we have prospectively isolated distinct epithelial subpopulations from normal mammary tissue and preneoplastic specimens from in iduals heterozygous for a BRCA1 mutation. We describe three epithelial subsets including basal stem rogenitor, luminal progenitor and mature luminal cells. Unexpectedly, we found that breast tissue from BRCA1 mutation carriers harbors an expanded luminal progenitor population that shows factor-independent growth in vitro. Moreover, gene expression profiling revealed that breast tissue heterozygous for a BRCA1 mutation and basal breast tumors were more similar to normal luminal progenitor cells than any other subset, including the stem cell-enriched population. The c-KIT tyrosine kinase receptor (encoded by KIT) emerged as a key marker of luminal progenitor cells and was more highly expressed in BRCA1-associated preneoplastic tissue and tumors. Our findings suggest that an aberrant luminal progenitor population is a target for transformation in BRCA1-associated basal tumors .
Publisher: Mary Ann Liebert Inc
Date: 10-2003
DOI: 10.1089/154099903322447738
Abstract: Because of the uncertain efficacy of breast cancer screening in women at increased risk of developing breast cancer, bilateral prophylactic oophorectomy and mastectomy are considered management options for high-risk women. Data on the attitudes to prophylactic strategies of high-risk women who have not attended specialist clinics are needed to ascertain the need for patient education and provide the basis for planning of support services. Three hundred seventy-one women unaffected by cancer and with unknown mutation status from families with a dominantly inherited susceptibility to breast cancer, recruited through a large Australian population-based, epidemiological study, were assessed using a mailed self-administered questionnaire with validated measures of psychological outcome. Sixteen percent of women reported considering prophylactic mastectomy, and 1% had already had the procedure. Among women with a family history of breast/ovarian cancer, 33% had considered and 5% had already had a prophylactic oophorectomy. Twenty-three percent of women reported considering taking tamoxifen if it were shown to prevent breast cancer. Consideration of prophylactic oophorectomy (OR = 1.51 for a 10% change in perceived risk, 95% CI 1.14-1.99, p = 0.0045) and tamoxifen (OR = 1.14 for a 10% change in perceived risk, 95% CI 1.002-1.30, p = 0.047) were positively associated with perceived cancer risk. Attitudes to prophylactic surgery and psychological distress levels in high-risk women participating in an epidemiological study appear to be comparable to those of women attending familial cancer clinics and indicate that women attending high-risk clinics may be representative of the larger population of women at increased risk.
Publisher: Springer Science and Business Media LLC
Date: 09-03-2015
DOI: 10.1038/NG.3242
Publisher: American Association for Cancer Research (AACR)
Date: 05-2009
DOI: 10.1158/1055-9965.EPI-08-0745
Abstract: Previous studies have suggested that minor alleles for ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 may influence breast cancer risk, but the evidence is inconclusive due to their small s le size. These polymorphisms were genotyped in more than 30,000 breast cancer cases and 30,000 controls, primarily of European descent, from 30 studies in the Breast Cancer Association Consortium. We calculated odds ratios (OR) and 95% confidence intervals (95% CI) as a measure of association. We found that the minor alleles for these polymorphisms were not related to invasive breast cancer risk overall in women of European descent: ECCR4 per-allele OR (95% CI) = 0.99 (0.97-1.02), minor allele frequency = 27.5% TNF 1.00 (0.95-1.06), 5.0% CASP10 1.02 (0.98-1.07), 6.5% PGR 1.02 (0.99-1.06), 15.3% and BID 0.98 (0.86-1.12), 1.7%. However, we observed significant between-study heterogeneity for associations with risk for single-nucleotide polymorphisms (SNP) in CASP10, PGR, and BID. Estimates were imprecise for women of Asian and African descent due to small numbers and lower minor allele frequencies (with the exception of BID SNP). The ORs for each copy of the minor allele were not significantly different by estrogen or progesterone receptor status, nor were any significant interactions found between the polymorphisms and age or family history of breast cancer. In conclusion, our data provide persuasive evidence against an overall association between invasive breast cancer risk and ERCC4 rs744154, TNF rs361525, CASP10 rs13010627, PGR rs1042838, and BID rs8190315 genotypes among women of European descent. (Cancer Epidemiol Biomarkers Prev 2009 (5):1610–6)
Publisher: Springer Science and Business Media LLC
Date: 25-04-2015
Publisher: Oxford University Press (OUP)
Date: 06-01-2009
DOI: 10.1093/HMG/DDN429
Publisher: Springer Science and Business Media LLC
Date: 06-2006
DOI: 10.1186/BCR1415
Publisher: Wiley
Date: 06-04-2015
DOI: 10.1111/BJU.12792
Abstract: To ascertain whether D'Amico risk classification is an accurate discriminator of prostate cancer mortality risk in BRCA2 pathogenic mutation carriers and non-carriers from a familial breast cancer cohort. From family cancer pedigrees of patients evaluated through a familial breast cancer cohort all related men with a diagnosis of prostate cancer were identified. Genotyping of each patient or of the dominant familial BRCA2 mutation was undertaken in each instance. Prostate cancers were analysed by BRCA2 carrier vs non-carrier status for their clinical progression and survival according to their D'Amico risk groups. For patients who were BRCA2-mutation positive, there was no significant difference in cancer-specific survival (CSS) between those patients who were graded as having D'Amico high- or intermediate-risk disease. For patients who were BRCA2-mutation negative, but were identified via a family cancer pedigree, there was no statistically significant difference in CSS between D'Amico high- and intermediate-risk prostate cancers. Patients with D'Amico high-risk disease who were BRCA2-mutation carriers had substantially increased disease-specific mortality compared with high-risk non-carriers (hazard ratio 2.94, P = 0.004). D'Amico risk classification has limitations in predicting variations in prostate cancer-specific mortality for this group of patients.
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: Springer Science and Business Media LLC
Date: 27-04-2016
DOI: 10.1038/NCOMMS11375
Abstract: Common variants in 94 loci have been associated with breast cancer including 15 loci with genome-wide significant associations ( P × 10 −8 ) with oestrogen receptor (ER)-negative breast cancer and BRCA1 -associated breast cancer risk. In this study, to identify new ER-negative susceptibility loci, we performed a meta-analysis of 11 genome-wide association studies (GWAS) consisting of 4,939 ER-negative cases and 14,352 controls, combined with 7,333 ER-negative cases and 42,468 controls and 15,252 BRCA1 mutation carriers genotyped on the iCOGS array. We identify four previously unidentified loci including two loci at 13q22 near KLF5 , a 2p23.2 locus near WDR43 and a 2q33 locus near PPIL3 that display genome-wide significant associations with ER-negative breast cancer. In addition, 19 known breast cancer risk loci have genome-wide significant associations and 40 had moderate associations ( P .05) with ER-negative disease. Using functional and eQTL studies we implicate TRMT61B and WDR43 at 2p23.2 and PPIL3 at 2q33 in ER-negative breast cancer aetiology. All ER-negative loci combined account for ∼11% of familial relative risk for ER-negative disease and may contribute to improved ER-negative and BRCA1 breast cancer risk prediction.
Publisher: American Association for Cancer Research (AACR)
Date: 15-05-2008
DOI: 10.1158/1078-0432.CCR-07-5237
Abstract: Purpose: Prostate cancer risk is increased for men carrying a pathogenic germline mutation in BRCA2, and perhaps BRCA1. Our primary aim was to test for loss of heterozygosity (LOH) at the locus of the mutation in prostate cancers from men who a carry pathogenic germline mutation in BRCA1 or BRCA2, and to assess clinical and pathologic features of these tumors. Experimental Design: From 1,243 kConFab families: (a) 215 families carried a pathogenic BRCA1 mutation, whereas 188 families carried a pathogenic BRCA2 mutation (b) of the 158 men diagnosed with prostate cancer (from 137 families), 8 were confirmed to carry the family-specific BRCA1 mutation, whereas 20 were confirmed to carry the family-specific BRCA2 mutation and (c) 10 cases were eliminated from analysis because no archival material was available. The final cohort comprised 4 and 14 men with a BRCA1 and BRCA2 mutation, respectively. We examined LOH at the BRCA1 and BRCA2 genes using multiplex ligation-dependent probe lification of DNA from microdissected tumor. Results: LOH at BRCA2 was observed in 10 of 14 tumors from BRCA2 mutation carriers (71%), whereas no LOH at BRCA1 was observed in four tumors from BRCA1 mutation carriers (P = 0.02). Under the assumption that LOH occurs only because the cancer was caused by the germline mutation, carriers of BRCA2 mutations are at 3.5-fold (95% confidence interval, 1.8-12) increased risk of prostate cancer. A high Gleason was the only distinct clinical feature. Conclusions: These observations are consistent with the idea that BRCA2, but not BRCA1, is a tumor suppressor of prostate cancer.
Publisher: Wiley
Date: 09-03-2004
DOI: 10.1023/B:JOGC.0000018822.56297.A6
Abstract: Forty-seven unaffected women from high-risk breast cancer families who had received results for hereditary breast/ovarian predisposition genes between 1 month and 5 years ago were interviewed regarding their experiences. Women responded to open-ended questions. The initial emotional turmoil reported by most was generally short lived. However, the impact of genetic testing went beyond the in idual to the extended family and social context, particularly in the short-term. A common theme was the difficulty associated with ulging a result to family members, who were also adjusting to their own result. The majority of carriers reported advantages that were both physical (options for surveillance programs and prophylactic surgery) and emotional (reduced uncertainty, increased awareness of options and knowledge about risk, preparation time). Most carriers reported no change in lifestyle although some reported discovering their mutation status as a positive life-changing experience. Implications for genetic counseling and further research are discussed.
Publisher: Springer Science and Business Media LLC
Date: 09-01-2017
DOI: 10.1038/NCOMMS13671
Abstract: Germline mutations in the BRCA2 tumour suppressor are associated with both an increased lifetime risk of developing prostate cancer (PCa) and increased risk of aggressive disease. To understand this aggression, here we profile the genomes and methylomes of localized PCa from 14 carriers of deleterious germline BRCA2 mutations ( BRCA2 -mutant PCa). We show that BRCA2 -mutant PCa harbour increased genomic instability and a mutational profile that more closely resembles metastastic than localized disease. BRCA2 -mutant PCa shows genomic and epigenomic dysregulation of the MED12L / MED12 axis, which is frequently dysregulated in metastatic castration-resistant prostate cancer (mCRPC). This dysregulation is enriched in BRCA2 -mutant PCa harbouring intraductal carcinoma (IDC). Microdissection and sequencing of IDC and juxtaposed adjacent non-IDC invasive carcinoma in 10 patients demonstrates a common ancestor to both histopathologies. Overall we show that localized castration-sensitive BRCA2 -mutant tumours are uniquely aggressive, due to de novo aberration in genes usually associated with metastatic disease, justifying aggressive initial treatment.
Publisher: Public Library of Science (PLoS)
Date: 04-2015
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-01-2008
Abstract: Women from BRCA mutation–positive families who do not carry the family-specific mutation are generally at average cancer risk and therefore do not require intensive risk management. Participants were female noncarriers from BRCA mutation–positive families who had responded to 3 yearly follow-up questionnaires and had chosen to either receive or not receive their genetic test result. In the former group, undertaking mammography younger than age 40 years or more than once every 2 years, clinical breast examination (CBE) more than yearly, breast self-examination (BSE) more than monthly, or any transvaginal ultrasound (TVU) or CA-125 was considered overscreening. Screening behaviors of women who did and did not know their genetic test result were compared. Logistic regression and nonparametric analyses were performed to identify demographic and psychosocial factors (respectively) associated with overscreening. Of 325 eligible women, 116 knew their mutation status and 209 did not. For the first group, proportions overscreening were mammography, 53% CBE, 10% BSE, 11% TVU, 7% and CA-125, 10%. There were no significant differences in screening behaviors between the groups. In those aware of their mutation status, parous women were more likely to overuse mammography (odds ratio [OR] = 4.4 95% CI, 1.1 to 17 P = .03) and women with one or more first-degree relative with ovarian cancer (OC) were more likely to overuse OC screening (TVU: OR = 6.00 95% CI, 1.0 to 35.1 P = .047, and CA-125: OR = 6.50 95% CI, 1.49 to 28.4 P = .013). The reasons for overuse of screening (particularly mammography) by mutation noncarriers require additional elucidation given the potential for harm.
Publisher: Springer Science and Business Media LLC
Date: 04-2012
DOI: 10.1186/BCR3169
Publisher: Springer Science and Business Media LLC
Date: 09-11-2012
Publisher: Elsevier BV
Date: 09-1985
DOI: 10.1016/0277-5379(85)90286-X
Abstract: A monoclonal antibody, designated OM-1, was raised against ovarian serous papillary cystadenocarcinoma (stage IV) cells. This antibody was found to react strongly with primary and metastatic ovarian serous cystadenocarcinomas and endometrioid carcinomas but the antigen detected was either absent or at very low levels in ovarian mucinous adenocarcinomas, clear cell carcinomas, benign serous and mucinous cystadenomas and Brenner tumours. The OM-1 antibody gave no detectable reaction with 93 other human tumours, including ex les of breast and colon adenocarcinomas. In normal tissues the OM-1 antibody reacted with normal sebaceous gland cells, lung type II pneumocytes and placental syncytial trophoblasts. In the normal ovary OM-1 reactivity was confined to extremely weak staining of the surface epithelium. No reaction with any other ovarian cell type could be detected. No evidence of reaction with other normal cell populations present in 24 adult and seven foetal tissues was found. The antigen detected is compared with other ovarian tumour-associated antigens. The OM-1 antibody is likely to prove of value in the detection and diagnosis of ovarian carcinoma.
Publisher: Springer Science and Business Media LLC
Date: 26-06-2008
DOI: 10.1007/S10549-007-9627-3
Abstract: Association studies aimed at identifying breast cancer susceptibility variants in the progesterone receptor (PGR) gene have been previously reported in the literature with conflicting results, ranging from a protective effect conferred by the PROGINS allele in German Caucasian women, to an increased risk for the leucine variant of the Val660Leu (rs1042838) polymorphism in East Anglian cases. We report the results of genotype and haplotype analyses of five PGR polymorphisms, +44C/T (rs518162), +331G/A (rs10895068), V660L (rs1042838), H770H (rs1042839) and Q886Q (rs500760), conducted on 1,847 Australian breast cancer cases (including 276 cases from a cohort of multiple-case breast cancer families) and 833 controls. Genotype and haplotype analyses of the five polymorphisms showed no evidence of an association with breast cancer (p>0.3). We also conducted a meta-analysis of the V660 L (rs1042838) polymorphism on our and six other published studies including 10,205 cases and 11,320 controls. Compared to the VV homozygotes, VL heterozygotes and LL homozygotes were associated with a non-significant increased risk for breast cancer [Odds ratio (OR)VL, 1.06 95% confidence intervals (95% CI), 0.97-1.15, ORLL, 1.05 95% CI, 0.75-1.49]. Analysis of a per-leucine allele risk under a codominant model, however, suggested a significant leucine-allele dose effect, ORper-L, 1.07 95% CI, 1.02-1.13, p=0.01. We conclude that the leucine allele of the V660L SNP may be associated with a small increase in breast cancer risk, while the other four PGR SNPs, +44C/T (rs518162), +331G/A (rs10895068), H770H (rs1042839) and Q886Q (rs500760), do not substantially increase breast cancer risk.
Publisher: Impact Journals, LLC
Date: 22-10-2016
Publisher: Springer Science and Business Media LLC
Date: 04-2012
DOI: 10.1186/BCR3176
Publisher: Springer Science and Business Media LLC
Date: 08-07-2015
Publisher: Elsevier BV
Date: 03-2010
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: 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: 2012
Publisher: Hindawi Limited
Date: 03-11-2011
DOI: 10.1002/HUMU.21628
Publisher: Springer Science and Business Media LLC
Date: 27-05-2015
DOI: 10.1038/NATURE14410
Abstract: Patients with high-grade serous ovarian cancer (HGSC) have experienced little improvement in overall survival, and standard treatment has not advanced beyond platinum-based combination chemotherapy, during the past 30 years. To understand the drivers of clinical phenotypes better, here we use whole-genome sequencing of tumour and germline DNA s les from 92 patients with primary refractory, resistant, sensitive and matched acquired resistant disease. We show that gene breakage commonly inactivates the tumour suppressors RB1, NF1, RAD51B and PTEN in HGSC, and contributes to acquired chemotherapy resistance. CCNE1 lification was common in primary resistant and refractory disease. We observed several molecular events associated with acquired resistance, including multiple independent reversions of germline BRCA1 or BRCA2 mutations in in idual patients, loss of BRCA1 promoter methylation, an alteration in molecular subtype, and recurrent promoter fusion associated with overexpression of the drug efflux pump MDR1.
Publisher: Springer Science and Business Media LLC
Date: 11-08-2009
DOI: 10.1007/S10549-009-0497-8
Abstract: The purpose of this study is to determine the prevalence and predictors of contralateral risk-reducing mastectomy (CRRM) in Australasian women at high familial risk of a second primary breast cancer (BC). Participants were women with unilateral BC and a strong family history of the disease, including BRCA1/2 mutation carriers. Data were collected through interview, self-administered questionnaire and review of pathology and surgical reports. Associations between CRRM and potential predictors were assessed using multivariate logistic regression. Of 1,018 women (median follow-up 11.1 years), 154 (15%) underwent CRRM, 43% of these within 12 months of initial BC surgery. More likely to undergo CRRM were women who were younger at BC diagnosis (odds ratio [OR] = 0.94 per year of age, P < 0.001), were diagnosed more recently (OR = 1.16 per calendar year, P < 0.001), underwent mastectomy as initial definitive BC treatment (OR = 5.2, P < 0.001) and underwent risk-reducing salpingo-oophorectomy (OR = 3.4, P < 0.001). BRCA1/2 mutation status, axillary nodal status and receipt of chemotherapy were not independently associated with CRRM uptake. A contralateral BC event (invasive or in situ) occurred in 177 (20.5%) of the 864 women who did not have CRRM, compared with one chest wall event (0.6%) in the 154 women post-CRRM. The contralateral event rate was 15.1 per 1,000 women-years for non-CRRM women and 0.7 per 1,000 women-years for CRRM women P < 0.0001. Younger women with more recently diagnosed BC treated with mastectomy are more likely to elect CRRM. Neither BRCA1/2 mutation status, nor the competing risk of BC recurrence and death, appears to influence decision making.
Publisher: Springer Science and Business Media LLC
Date: 21-06-2016
Publisher: BMJ
Date: 05-2005
Publisher: Springer Science and Business Media LLC
Date: 22-03-2011
Publisher: BMJ
Date: 19-09-2011
Publisher: Springer Science and Business Media LLC
Date: 29-03-2009
DOI: 10.1038/NG.354
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488651
Abstract: Supplementary Methods
Publisher: Springer Science and Business Media LLC
Date: 20-12-2008
DOI: 10.1007/S10549-007-9848-5
Abstract: Germline mutations in BRCA1 or BRCA2 confer an increased lifetime risk of developing breast or ovarian cancer, but variable penetrance suggests that cancer susceptibility is influenced in part by modifier genes. Microarray expression profiling was conducted for 69 irradiated lymphoblastoid cell lines derived from healthy controls, or from cancer-affected women with a strong family history of breast and ovarian cancer carrying pathogenic mutations in BRCA1 or BRCA2, or with no BRCA1/2 mutations (BRCAX). Genes discriminating between BRCA1, BRCA2 or BRCAX and controls were stratified based on irradiation response and/or cell cycle involvement. Gene lists were aligned against genes tagged with single nucleotide polymorphisms (SNPs) determined by the Cancer Genetic Markers of Susceptibility (CGEMS) Breast Cancer Whole Genome Association Scan to be nominally associated with breast cancer risk. Irradiation responsive genes whose expression correlated with BRCA1 and/or BRCA2 mutation status were more likely to be tagged by risk-associated SNPs in the CGEMS dataset (BRCA1, P = 0.0005 BRCA2, P = 0.01). In contrast, irradiation responsive genes correlating with BRCAX status were not enriched in the CGEMS dataset. Classification of expression data by involvement in cell cycle processes did not enrich for genes tagged by risk-associated SNPs, for BRCA1, BRCA2 or BRCAX groups. Using a novel combinatorial approach, we have identified a subset of irradiation responsive genes as high priority candidate BRCA1/2 modifier genes. Similar approaches may be used to identify genes and underlying genetic risk factors that interact with exogenous stimulants to cause or modify any disease, without a priori knowledge of the pathways involved.
Publisher: Oxford University Press (OUP)
Date: 10-2011
DOI: 10.1093/JNCIMONOGRAPHS/LGR042
Abstract: In 2005, 100,514 Australians were diagnosed with cancer, and over 10,000 of these cancers will be due to heritable causes. The impact of familial cancer by definition extends beyond the in idual, affecting tens of thousands of parents, siblings, and children. The study of familial cancer causes has arguably made the greatest single contribution to our understanding of cancer biology. This knowledge is used clinically to guide investment in screening and prevention, as well as being translated into new treatments.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488654
Abstract: Supplementary Figures S1-S13
Publisher: Springer Science and Business Media LLC
Date: 17-02-2016
Publisher: Hindawi Limited
Date: 10-05-2010
DOI: 10.1002/HUMU.21267
Publisher: Springer Science and Business Media LLC
Date: 30-10-2009
Publisher: Springer Science and Business Media LLC
Date: 09-2009
Publisher: Springer Science and Business Media LLC
Date: 25-08-2009
Publisher: Springer Science and Business Media LLC
Date: 21-03-2012
Publisher: Oxford University Press (OUP)
Date: 11-07-2016
DOI: 10.1093/HMG/DDW223
Publisher: American Association for Cancer Research (AACR)
Date: 02-2015
DOI: 10.1158/1078-0432.CCR-14-2497
Abstract: Purpose: To analyze the effect of germline mutations in BRCA1 and BRCA2 on mortality in patients with ovarian cancer up to 10 years after diagnosis. Experimental Design: We used unpublished survival time data for 2,242 patients from two case–control studies and extended survival time data for 4,314 patients from previously reported studies. All participants had been screened for deleterious germline mutations in BRCA1 and BRCA2. Survival time was analyzed for the combined data using Cox proportional hazard models with BRCA1 and BRCA2 as time-varying covariates. Competing risks were analyzed using Fine and Gray model. Results: The combined 10-year overall survival rate was 30% [95% confidence interval (CI), 28%–31%] for non-carriers, 25% (95% CI, 22%–28%) for BRCA1 carriers, and 35% (95% CI, 30%–41%) for BRCA2 carriers. The HR for BRCA1 was 0.53 at time zero and increased over time becoming greater than one at 4.8 years. For BRCA2, the HR was 0.42 at time zero and increased over time (predicted to become greater than 1 at 10.5 years). The results were similar when restricted to 3,202 patients with high-grade serous tumors and to ovarian cancer–specific mortality. Conclusions: BRCA1/2 mutations are associated with better short-term survival, but this advantage decreases over time and in BRCA1 carriers is eventually reversed. This may have important implications for therapy of both primary and relapsed disease and for analysis of long-term survival in clinical trials of new agents, particularly those that are effective in BRCA1/2 mutation carriers. Clin Cancer Res 21(3) 652–7. ©2014 AACR.
Publisher: Springer Science and Business Media LLC
Date: 12-2014
DOI: 10.1038/BJC.2014.511
Publisher: Wiley
Date: 15-05-1986
Abstract: The molecular nature of SGA, the ovarian-carcinoma-associated antigen defined by the MAb OM-1, has been determined. The cell-surface form of the SGA molecule is a glycoprotein with p1 less than 4.2, which on PAGE analysis has an apparent MW of approximately 360 kDa. This was the only OM-1-reactive species found on the cell surface. The apparent MW was unaffected by reducing conditions. The predominant cytoplasmic form of SGA is a non-glycosylated 170-kDa molecule with p1 6.5. Pulse-chase experiments were complicated by the extremely slow rate of SGA synthesis. However, the data indicate that the SGA molecule is synthesized as a 190-kDa protein, cleaved to yield a 170-kDa non-glycosylated intracellular form which is slowly glycosylated to the 360-kDa cell-surface species. Western blotting experiments revealed the presence of the 360-kDa glycosylated molecule in human ovarian cell culture supernatants.
Publisher: Springer Science and Business Media LLC
Date: 06-04-2016
Publisher: Springer Science and Business Media LLC
Date: 10-06-2009
DOI: 10.1007/S10549-008-0083-5
Abstract: The p27(kip1) protein functions as an inhibitor of cyclin dependent kinase-2, and shows loss of expression in a large percentage of BRCA1 and BRCA2 breast cancer cases. We investigated the association between CDKN1B gene variants and breast cancer risk in 2359 female BRCA1 and BRCA2 mutation carriers from Australia, the UK, and the USA. S les were genotyped for five single nucleotide polymorphisms, including coding variant rs2066827 (V109G). Cox regression provided no convincing evidence that any of the polymorphisms modified disease risk for BRCA1 or BRCA2 carriers, either alone or as a haplotype. Borderline associations were observed for homozygote carriers of the rs3759216 rare allele, but were opposite in effect for BRCA1 and BRCA2 carriers (adjusted hazard ratio (HR) 0.72 (95% CI = 0.53-0.99 P = 0.04 for BRCA1, HR 1.47 (95% CI = 0.99-2.18 P = 0.06 for BRCA2). The 95% confidence intervals for per allele risk estimates excluded a twofold risk, indicating that common CDKN1B polymorphisms do not markedly modify breast cancer risk among BRCA1 or BRCA2 carriers.
Publisher: Cambridge University Press (CUP)
Date: 04-2011
Abstract: There is evidence that tamoxifen treatment of BRCA1 and BRCA2 carriers for prior breast cancer increases risk of endometrioid subtype endometrial cancer (EC), and suggestive evidence that BRCA1 and BRCA2 mutation carriers may be predisposed to EC in the absence of tamoxifen exposure. We assessed the association of EC with BRCA1 or BRCA2 mutation status in Australasian breast-ovarian families. Report of at least one case of EC was significantly greater in BRCA1 -positive families (35/218 (16%) p = .03) and non-significantly greater in BRCA2 -positive families (23/189 (12%) p = .6), compared to high-risk breast cancer families without a BRCA1/2 mutation (86/796 (11%)). EC was the first/concurrent cancer for 41% of EC cases with multiple cancer diagnoses from BRCA1/2 families, and early onset for most of these diagnoses. Mutation status was imputed for ungeno-typed in iduals from 57 BRCA1/2 pedigrees reporting EC using BRCAPRO. Effects of genotype on EC diagnosis age, and interaction with tamoxifen therapy, were assessed using Cox proportional hazards regression analysis. EC risk was non-significantly marginally greater for BRCA1 carriers (hazard ratio = 1.25, 95%CI = 0.65–2.41), and BRCA2 carriers (HR = 1.12, 95%CI = 0.51–2.45), compared to non-carrier family members. Tamoxifen therapy was highly significantly associated with EC (HR = 6.68, 95%CI = 3.12–15.15 p = 1.7 x 10 -6 ) in BRCA1/2 families, with no evidence for interaction between tamoxifen therapy and BRCA1/2 genotype. Our family-based study supports a 7-fold increase in EC risk with tamoxifen exposure for female family members from BRCA1/2 families. Early onset EC in carriers without tamoxifen use suggests that further study is required to assess association of modest EC risk with BRCA1/2 mutation status alone.
Publisher: Wiley
Date: 11-2009
Publisher: Wiley
Date: 10-07-2003
DOI: 10.1034/J.1399-0004.2003.00097.X
Abstract: Prophylactic mastectomy (PM) is a risk-management option for women at high familial risk of breast cancer (BC). This study describes the PM experience of women enrolled in a large observational cohort study involving families with a history of hereditary breast cancer. Within 357 multiple-case BC families [119 (33%) BRCA1 or BRCA2 mutation positive], identified via family cancer clinics, 49 cases of PM [21 (43%) BRCA1 or BRCA2 mutation positive] were identified and their clinical, pathological and genetic features reviewed. Families with at least one incidence of PM displayed stronger breast/ovarian cancer histories than did families without PM. Median age at time of PM was 45 years (range 28-58). Ten cases (21%) were bilateral PMs in unaffected women and 39 cases were contralateral PMs in women with prior invasive BC (71%) or ductal carcinoma in situ (DCIS) (8%). Most (88%) underwent total mastectomy. Unnecessary axillary surgery occurred in eight subjects (16%). Malignant histology was found in three PM specimens (6%). Prior to genetic testing, PM was performed in two women who were subsequently shown not to carry the mutation specific to their family. Optimal utilization of genetic testing to guide surgical decision making, appropriate surgical technique and careful pathology examination of PM specimens, are important issues to consider prior to PM in women at high familial risk of BC.
Publisher: Springer Science and Business Media LLC
Date: 23-07-2014
DOI: 10.1038/NATURE13545
Publisher: Springer Science and Business Media LLC
Date: 23-12-2006
DOI: 10.1007/S10549-006-9461-Z
Abstract: Most of the known breast cancer susceptibility genes (BRCA1, BRCA2, CHEK2 and ATM) are involved in the damage response pathway. Other members of this pathway are therefore good candidates for additional breast cancer susceptibility genes. ATR, along with ATM, plays a central role in DNA damage recognition and Chk1 relays checkpoint signals from both ATR and ATM. PPP2R1B and PPP2R5B code for subunits of protein phosphatase 2A (PP2A), which regulates autophosphorylation of ATM. In addition, EIF2S6/Int-6, which was originally identified as a common integration site for the mouse mammary tumour virus in virally induced mouse mammary tumours, is a candidate breast cancer susceptibility gene because of its putative role in maintaining chromosome stability. To investigate the role of ATR, CHK1, PPP2R1B, PPP2R5B and EIF2S6/Int-6, we carried out mutation analysis of these genes in the index cases from non-BRCA1/BRCA2 breast cancer families. We also screened sporadic breast tumours for somatic mutations in PPP2R1B and PPP2R5B. Although we identified many novel variants, we found no evidence that highly penetrant germline mutations in these five genes contribute to familial breast cancer susceptibility.
Publisher: Springer Science and Business Media LLC
Date: 2007
Publisher: Springer Science and Business Media LLC
Date: 06-2013
DOI: 10.1038/BJC.2013.277
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488645
Abstract: Supplementary Tables S1-S11
Publisher: American Society of Clinical Oncology (ASCO)
Date: 10-08-2016
Abstract: CHEK2*1100delC is a well-established breast cancer risk variant that is most prevalent in European populations however, there are limited data on risk of breast cancer by age and tumor subtype, which limits its usefulness in breast cancer risk prediction. We aimed to generate tumor subtype- and age-specific risk estimates by using data from the Breast Cancer Association Consortium, including 44,777 patients with breast cancer and 42,997 controls from 33 studies genotyped for CHEK2*1100delC. CHEK2*1100delC genotyping was mostly done by a custom Taqman assay. Breast cancer odds ratios (ORs) for CHEK2*1100delC carriers versus noncarriers were estimated by using logistic regression and adjusted for study (categorical) and age. Main analyses included patients with invasive breast cancer from population- and hospital-based studies. Proportions of heterozygous CHEK2*1100delC carriers in controls, in patients with breast cancer from population- and hospital-based studies, and in patients with breast cancer from familial- and clinical genetics center–based studies were 0.5%, 1.3%, and 3.0%, respectively. The estimated OR for invasive breast cancer was 2.26 (95%CI, 1.90 to 2.69 P = 2.3 × 10 −20 ). The OR was higher for estrogen receptor (ER)–positive disease (2.55 [95%CI, 2.10 to 3.10 P = 4.9 × 10 −21 ]) than it was for ER-negative disease (1.32 [95%CI, 0.93 to 1.88 P = .12] P interaction = 9.9 × 10 −4 ). The OR significantly declined with attained age for breast cancer overall (P = .001) and for ER-positive tumors (P = .001). Estimated cumulative risks for development of ER-positive and ER-negative tumors by age 80 in CHEK2*1100delC carriers were 20% and 3%, respectively, compared with 9% and 2%, respectively, in the general population of the United Kingdom. These CHEK2*1100delC breast cancer risk estimates provide a basis for incorporating CHEK2*1100delC into breast cancer risk prediction models and into guidelines for intensified screening and follow-up.
Publisher: Public Library of Science (PLoS)
Date: 28-10-2010
Publisher: American Association for Cancer Research (AACR)
Date: 09-2013
DOI: 10.1158/1055-9965.EPI-13-0189
Abstract: Background: The effects of low-dose medical radiation on breast cancer risk are uncertain, and few studies have included genetically susceptible women, such as those who carry germline BRCA1 and BRCA2 mutations. Methods: We studied 454 BRCA1 and 273 BRCA2 mutation carriers ages younger than 50 years from three breast cancer family registries in the United States, Canada, and Australia/New Zealand. We estimated breast cancer risk associated with diagnostic chest X-rays by comparing mutation carriers with breast cancer (cases) with those without breast cancer (controls). Exposure to chest X-rays was self-reported. Mammograms were not considered in the analysis. Results: After adjusting for known risk factors for breast cancer, the ORs for a history of diagnostic chest X-rays, excluding those for tuberculosis or pneumonia, were 1.16 [95% confidence interval (CI), 0.64–2.11] for BRCA1 mutations carriers and 1.22 (95% CI, 0.62–2.42) for BRCA2 mutations carriers. The OR was statistically elevated for BRCA2 mutation carriers with three to five diagnostic chest X-rays (P = 0.01) but not for those with six or more chest X-rays. Few women reported chest fluoroscopy for tuberculosis or chest X-rays for pneumonia the OR estimates were elevated, but not statistically significant, for BRCA1 mutation carriers. Conclusions: Our findings do not support a positive association between diagnostic chest X-rays and breast cancer risk before the ages of 50 years for BRCA1 or BRCA2 mutation carriers. Impact: Given the increasing use of diagnostic imaging involving higher ionizing radiation doses, further studies of genetically predisposed women are warranted. Cancer Epidemiol Biomarkers Prev 22(9) 1547–56. ©2013 AACR.
Publisher: Springer Science and Business Media LLC
Date: 05-10-2015
DOI: 10.1007/S10689-014-9759-7
Abstract: This study prospectively investigated long-term psychosocial outcomes for women who opted for risk-reducing mastectomy (RRM) and/or risk-reducing salpingo-oophorectomy (RRSO). Unaffected women from high-risk breast cancer families who had completed baseline questionnaires for an existing study and subsequently underwent RRM and/or RRSO, completed measures of perceived breast and ovarian cancer risk, anxiety, depression, cancer-related anxiety, body image, sexual functioning, menopausal symptoms, use of hormone replacement therapy and decision regret 3 years post-surgery. Outcomes were compared to age- and risk-matched controls. Participants (N = 233) were 17 women who had RRM (39 controls), 38 women who had RRSO (94 controls) and 15 women who had RRM + RRSO (30 controls). Women who underwent RRM and those who underwent RRM + RRSO reported reductions in perceived breast cancer risk and perceived breast and ovarian cancer risk respectively, compared to their respective controls. RRM women reported greater reductions in cancer-related anxiety compared with both controls and RRSO women. RRSO women reported more sexual discomfort than controls and more urogenital menopausal symptoms than controls and RRM only women. No differences in general anxiety, depression or body image were observed. Regret was associated with greater reductions in body image since surgery and more sexual discomfort, although overall regret levels were low. Women who undergo RRM experience psychological benefits associated with reduced breast cancer risk. Although women who undergo RRSO experience some deterioration in sexual and menopausal symptoms, they do not regret their surgery decision. It is vital that women considering these procedures receive detailed information about potential psychosocial consequences.
Publisher: Springer Science and Business Media LLC
Date: 15-05-2008
DOI: 10.1007/S10549-008-0045-Y
Abstract: BARD1 was first identified as a BRCA1-interacting protein with tumour-suppressor functions. Some association studies suggested that the BARD1 Cys557Ser variant might be associated with increased risk of breast cancer, but the evidence remains uncertain. We found that the BARD1 Cys557Ser variant was carried by 50 of 1,136 cases (4.4%) and 30 of 623 controls (5.0%) from the population-based Australian Breast Cancer Family Study, 14 of 324 (4.3%) cases from the Kathleen Cuningham Foundation Consortium for Research into Familial Breast Cancer (kConFab), and 30 of 760 controls (4.0%) from the Australian Ovarian Cancer Study. Case-control comparisons showed no evidence that the variant frequency differed by case-control status (P >or= 0.3). Segregation analysis of 14 kConFab variant-carrying families containing 157 genotyped in iduals provided no evidence of segregation with disease. We conclude that the BARD1 Cys557Ser variant is not associated with breast cancer risk.
Publisher: Springer Science and Business Media LLC
Date: 29-11-2010
DOI: 10.1186/BCR2785
Publisher: American Association for Cancer Research (AACR)
Date: 07-2011
DOI: 10.1158/1940-6207.CAPR-10-0397
Abstract: The role of a germ-line BRCA2 mutation in the development of prostate cancer is established, but the clinical presentation linked to outcome for this group of men has not been well described. A total of 148 men from 1,423 families were ascertained from the kConFab consortium. Each participant met the following criteria: (i) a verified case of prostate cancer (ii) confirmed as either a carrier or noncarrier of a family-specific BRCA pathogenic mutation (iii) comprehensive clinical and treatment data were available. Clinical data were linked to treatment received and overall survival was analyzed by Kaplan–Meier. Prostate cancer in men from breast cancer-prone families has a high risk of disease progression, irrespective of mutation status. BRCA2 mutation carriers have an increased risk of death and prostate cancer-related death [HR (95% CI) 4.5 (2.12–9.52), P = 8.9 × 10−5] by comparison with noncarriers. Serum PSA readings taken prior to diagnosis in 90% of all men, age adjusted, were above clinical significance. Following D'Amico risk stratification, 77.5% of BRCA2 mutation carriers and 58.7% of noncarriers had high-risk disease. BRCA2 mutation status was also an independent prognostic indicator of overall survival. Furthermore, there was a poor overall survival outcome for both the BRCA2 mutation carriers and noncarriers given curative-intent treatment. All men in breast cancer-prone families are at risk of developing aggressive prostate cancer. This information is significant and should be included in discussions with genetic counselors and medical professionals when discussing prostate cancer treatment options for men in these families, irrespective of mutation status. Cancer Prev Res 4(7) 1002–10. ©2011 AACR.
Publisher: Oxford University Press (OUP)
Date: 19-05-2011
DOI: 10.1093/HMG/DDR228
Publisher: Springer Science and Business Media LLC
Date: 2005
DOI: 10.1186/BCR971
Publisher: Springer Science and Business Media LLC
Date: 21-10-2005
DOI: 10.1186/BCR1336
Publisher: Elsevier BV
Date: 05-2016
Publisher: Wiley
Date: 04-10-2012
Publisher: Wiley
Date: 10-08-2006
DOI: 10.1111/J.1399-0004.2006.00665.X
Abstract: This study prospectively evaluated the utilization of cancer risk management strategies in a multi-institutional cohort of BRCA1 and BRCA2 mutation carriers using a self-report questionnaire. Of 142 unaffected female mutation carriers, 70 (49%) had elected to receive their mutation result. Of those who knew their mutation result, 11% underwent bilateral mastectomy (BM), 29% had bilateral oophorectomy (BO), 78% performed regular breast self-examination (BSE), and 80%, 89%, 67%, and 0% had at least annual clinical breast examination (CBE), mammography, transvaginal ultrasound (TVU), and CA125, respectively. A further 20%, 7%, 0%, 21%, and 75%, respectively, reported never having had these tests. For women who elected not to receive their mutation result, 0% underwent BM, 6% underwent BO, and 77%, 42%, 56%, 7%, and 0% had regular BSE, CBE, mammography, TVU, and CA125, respectively. Only one woman used chemoprevention outside a clinical trial. Uptake of prophylactic surgery and screening was associated with knowing one's mutation status (for all behaviors except BSE), age (for BO and CBE) and residence (for mammography). In this cohort, the minority of mutation carriers utilized risk-reducing surgery or chemoprevention and a substantial minority were not undergoing regular cancer-screening tests.
Publisher: Springer Science and Business Media LLC
Date: 20-06-2016
DOI: 10.1038/NM.4118
Abstract: In iduals who have mutations in the breast-cancer-susceptibility gene BRCA1 (hereafter referred to as BRCA1-mutation carriers) frequently undergo prophylactic mastectomy to minimize their risk of breast cancer. The identification of an effective prevention therapy therefore remains a 'holy grail' for the field. Precancerous BRCA1(mut/+) tissue harbors an aberrant population of luminal progenitor cells, and deregulated progesterone signaling has been implicated in BRCA1-associated oncogenesis. Coupled with the findings that tumor necrosis factor superfamily member 11 (TNFSF11 also known as RANKL) is a key paracrine effector of progesterone signaling and that RANKL and its receptor TNFRSF11A (also known as RANK) contribute to mammary tumorigenesis, we investigated a role for this pathway in the pre-neoplastic phase of BRCA1-mutation carriers. We identified two subsets of luminal progenitors (RANK(+) and RANK(-)) in histologically normal tissue of BRCA1-mutation carriers and showed that RANK(+) cells are highly proliferative, have grossly aberrant DNA repair and bear a molecular signature similar to that of basal-like breast cancer. These data suggest that RANK(+) and not RANK(-) progenitors are a key target population in these women. Inhibition of RANKL signaling by treatment with denosumab in three-dimensional breast organoids derived from pre-neoplastic BRCA1(mut/+) tissue attenuated progesterone-induced proliferation. Notably, proliferation was markedly reduced in breast biopsies from BRCA1-mutation carriers who were treated with denosumab. Furthermore, inhibition of RANKL in a Brca1-deficient mouse model substantially curtailed mammary tumorigenesis. Taken together, these findings identify a targetable pathway in a putative cell-of-origin population in BRCA1-mutation carriers and implicate RANKL blockade as a promising strategy in the prevention of breast cancer.
Publisher: Springer Science and Business Media LLC
Date: 04-04-2010
DOI: 10.1007/S10549-010-0868-1
Abstract: This study applied the self-regulation model to examine cognitive and emotional predictors of screening in unaffected women with a strong family history of breast cancer. 748 unaffected female members of an Australian registry of multiple-case breast cancer families formed the s le. Participants completed a baseline psychosocial questionnaire and a screening questionnaire 3 years later. Multinomial logistic regression was employed to determine predictors of under- and over-screening according to national guidelines. At follow-up 16% of women under-screened and 10% over-screened with mammography 55% under-screened with clinical breast examination (CBE) and 9% over-screened with breast self-examination (BSE). Of the women found screening according to guidelines for mammography 72% reported ever having received specific recommendations for mammography screening from a health professional. Compared to appropriate screeners, under-screeners on mammography were less likely to have received a screening recommendation (as were under-screeners on CBE), were younger and reported lower perceived breast cancer risk, but were at higher relative risk (RR) of breast cancer and were more likely to report elevated depression. Over-screeners on mammography were more likely to be younger and have a lower RR of breast cancer. Over-screeners on BSE reported elevated cancer-specific anxiety, were less likely to be university educated and more likely to have received a recommendation for BSE. Under- and over-screening is common in women with a strong family history of breast cancer. Evaluation of interventions targeting perceived risk of breast cancer, anxiety and depression are needed to ensure women obtain accurate advice from relevant specialists and enact screening recommendations.
Publisher: American Association for Cancer Research (AACR)
Date: 10-2006
DOI: 10.1158/1055-9965.EPI-06-0258
Abstract: Background: Understanding the effect of oral contraceptives on risk of breast cancer in BRCA1 or BRCA2 mutation carriers is important because oral contraceptive use is a common, modifiable practice. Methods: We studied 497 BRCA1 and 307 BRCA2 mutation carriers, of whom 195 and 128, respectively, had been diagnosed with breast cancer. Case-control analyses were conducted using unconditional logistic regression with adjustments for family history and familial relationships and were restricted to subjects with a reference age under 50 years. Results: For BRCA1 mutation carriers, there was no significant association between risk of breast cancer and use of oral contraceptives for at least 1 year [odds ratio (OR), 0.77 95% confidence interval (95% CI), 0.53-1.12] or duration of oral contraceptive use (Ptrend = 0.62). For BRCA2 mutation carriers, there was no association with use of oral contraceptives for at least 1 year (OR, 1.62 95% CI, 0.90-2.92) however, there was an association of elevated risk with oral contraceptive use for at least 5 years (OR, 2.06 95% CI, 1.08-3.94) and with duration of use (ORtrend per year of use, 1.08 P = 0.008). Similar results were obtained when we considered only use of oral contraceptives that first started in 1975 or later. Conclusions: We found no evidence overall that use of oral contraceptives for at least 1 year is associated with breast cancer risk for BRCA1 and BRCA2 mutation carriers before age 50. For BRCA2 mutation carriers, use of oral contraceptives may be associated with an increased risk of breast cancer among women who use them for at least 5 years. Further studies reporting results separately for BRCA1 and BRCA2 mutation carriers are needed to resolve this important issue. (Cancer Epidemiol Biomarkers Prev 2006 (10):1863–70)
Publisher: Elsevier BV
Date: 2016
DOI: 10.1038/GIM.2016.43
Publisher: Hindawi Limited
Date: 2005
DOI: 10.1002/HUMU.9379
Abstract: Genetic screening of women from multiple-case breast cancer families and other research-based endeavors have identified an extensive collection of germline variations of BRCA1 and BRCA2 that can be classified as deleterious and have clinical relevance. For some variants, such as those in the conserved intronic splice site regions which are highly likely to alter splicing, it is not possible to classify them based on the identified DNA sequence variation alone. We studied 11 multiple-case breast cancer families carrying seven distinct splice site region genetic alterations in BRCA1 or BRCA2 (BRCA1, c.IVS6-2delA, c.IVS9-2A>C, c.IVS4-1G>T, c.IVS20+1G>A and BRCA2, c.IVS17-1G>C, c.IVS20+1G>A, c.IVS7-1G>A) and applied SpliceSiteFinder to predict possible changes in efficiency of splice donor and acceptor sites, characterized the transcripts, and estimated the average age-specific cumulative risk (penetrance) using a modified segregation analysis. SpliceSiteFinder predicted and we identified transcipts that illustrated that all variants caused exon skipping, and all but two led to frameshifts. The risks of breast cancer to age 70 yrs, averaged over all variants, over BRCA1 variants alone, and over BRCA2 variants alone, were 73% (95% confidence interval 47-93), 64% (95%CI 28-96) and 79% (95%CI 48-98) respectively (all P<0.0001). Therefore five of these seven consensus splice site variants of BRCA1 and BRCA2 produce a transcript similar to that of other previously described deleterious exonic variants and are associated with similar high lifetime risks.
Publisher: Springer Science and Business Media LLC
Date: 31-10-2007
Publisher: Elsevier BV
Date: 06-2009
Publisher: Wiley
Date: 15-08-1987
Abstract: The human breast cancer cell line PMC42 responds to the addition of epidermal growth factor (EGF) by proliferation and increased frequency of attachment of cell-organoid structures to the culture vessel. Antibodies to fibronectin and laminin reacted strongly, by immunoperoxidase, with the membranes of cells from organoids that became adherent following addition of EGF. This reaction was weak with membranes of cells of non-adherent organoids in cultures containing EGF and was negative with membranes of cells of free-floating organoids from cultures without EGF. An increase in biosynthetic labelling with 35S-methionine was found in cell lysates and supernatants of PMC42 cells cultured in the presence of EGF compared with control cells grown without EGF. One-dimensional SDS-polyacrylamide gel electrophoresis and 2-dimensional NEPHGE-PAGE of labelled cell proteins showed increased synthesis of several cellular proteins and the appearance in EGF-treated cells of 2 proteins which were not detected in cells from control cultures lacking EGF. Immunoprecipitation experiments using antibodies to fibronectin and laminin with lysates of 35S-methionine labelled PMC42 cells cultured with EGF showed strong immunoprecipitation at Mr 200 and 400 with anti-laminin, and at Mr 200 and 96 with anti-fibronectin. These immunoprecipitates were blocked specifically by purified laminin or fibronectin, respectively. No immunoprecipitates were detected with these antibodies in lysates from cells grown without EGF. EGF thus stimulates increased adherence of cultured PMC42 cell-organoid structures together with increased membrane expression of the cell-adhesive proteins laminin and fibronectin. These effects may play a role in normal development and neoplastic behaviour of breast epithelia.
Publisher: Springer Science and Business Media LLC
Date: 30-08-2011
DOI: 10.1038/MP.2011.101
Publisher: Springer Science and Business Media LLC
Date: 02-07-2015
Publisher: Elsevier BV
Date: 04-2005
DOI: 10.1016/J.YGYNO.2004.12.030
Abstract: BRCA1 mutations predispose to cancer in hormone responsive tissues. A predominance of estrogen receptor (ER)-negative breast cancers in BRCA1 mutation carriers and potential interactions between ERalpha and BRCA1 suggest a link between hormones and BRCA1. However, the expression pattern of ERalpha and other hormone receptors in BRCA1-associated ovarian cancer was unknown. Twenty-two BRCA1-associated ovarian cancer cases were matched with sporadic cases (no family history of ovarian or breast cancer) for FIGO stage, grade, histologic subtype, and patient age and hormone receptor expression was measured immunohistochemically. ERalpha expression was similar in BRCA1-associated ovarian cancer compared with matched sporadic counterparts, in contrast with previous findings in BRCA1-linked breast cancer. There was also no significant difference in expression of progesterone receptors and androgen receptor between the matched cases in the two groups. However, differences were noted in the relative expression of receptor isotypes, in particular, levels of ERalpha and ERbeta were positively correlated in sporadic tumors but inversely related in BRCA1-associated tumors. Similar hormone receptor expression in BRCA1-associated ovarian cancer and matched sporadic counterparts may be further evidence that at least a proportion of sporadic ovarian tumors and BRCA1-associated tumors develop through similar pathways.
Publisher: Springer Science and Business Media LLC
Date: 06-10-2008
DOI: 10.1007/S10689-007-9162-8
Abstract: Mutations in the DNA mismatch repair gene MSH2 lead to increased replication error and microsatellite instability and account for a substantial proportion of hereditary non-polyposis colorectal cancer (Lynch syndrome). A recent international collaborative genome-wide linkage scan (GWS) for breast cancer susceptibility loci found some evidence for there being a breast cancer susceptibility gene in a genomic region on chromosome 2p close to MSH2. We sought to investigate the possibility that mutations in MSH2 might explain the multiple cases of breast cancer in some families that were included in the international GWS. DNA s les from the affected probands of 59 multiple-case breast cancer families, many of whom gave LOD scores >0.5 in the MSH2 region, were screened for large genomic alterations in MSH2 via the Multiplex Ligation-dependent Probe Amplification (MLPA) assay and for coding region mutations via exonic sequencing. Several of the families also contained cases of colorectal cancer in addition to breast cancer and had been included in the GWS that had identified a positive LOD score on chromosome 2p. Using MLPA, c.1236C > T was identified in one proband but this variant was not predicted to create an alternate acceptor/donor site within exon 7 MSH2 using in silico analyses. A c.1734T > C was identified in a second proband via exonic sequencing but testing of the variant in other family members did not support segregation of this variant with disease. Extensive screening of 59 multiple-case breast cancer families did not identify any coding region mutations or larger genomic alterations in MSH2 that might implicate MSH2 as a breast cancer susceptibility gene.
Publisher: Springer Science and Business Media LLC
Date: 09-11-2016
Publisher: Springer Science and Business Media LLC
Date: 26-09-2012
Publisher: Elsevier BV
Date: 12-2004
DOI: 10.1016/J.YGYNO.2004.08.035
Abstract: Mutation of the BRCA1 gene, which has incomplete penetrance, is involved in ovarian cancer development. Cell cycle check point inactivation via acquired somatic mutations in the check point regulatory genes, particularly p53, may be required for BRCA1-linked ovarian tumorigenesis. In the few studies directly comparing p53 mutations in BRCA1-linked and sporadic ovarian cancers, data have been contradictory. This study aimed to clarify the role of p53 mutation in BRCA1-associated and sporadic ovarian cancer by comparing two, large, matched cohorts from two different populations who developed BRCA1-linked or sporadic ovarian cancers. Forty-eight BRCA1-associated ovarian tumor s les (22 from Australia and 26 from Norway) were collected and matched with 48 sporadic ovarian cancers for tumor stage, grade, histological subtype, and patient age. Expression of p53 protein was measured by immunohistochemistry (IHC). Consistent with the presence of a mutated p53 protein, the majority of BRCA1-associated (79%) and sporadic (73%) ovarian carcinomas from Australia and Norway overexpressed p53 protein. There was no significant difference between BRCA1-linked ovarian cancers and their sporadic counterparts with regard to p53 protein expression (P = 0.5). Our results suggest that p53 inactivation is associated with both BRCA1-associated and sporadic ovarian tumorigenesis, and that BRCA1-linked and sporadic ovarian cancers may develop through a similar carcinogenic pathway.
Publisher: Springer Science and Business Media LLC
Date: 11-2004
Publisher: Springer Science and Business Media LLC
Date: 12-2009
DOI: 10.1007/S11568-010-9138-X
Abstract: Multiple lines of evidence suggest regulatory variation to play an important role in phenotypic evolution and disease development, but few regulatory polymorphisms have been characterized genetically and molecularly. Recent technological advances have made it possible to identify bona fide regulatory sequences experimentally on a genome-wide scale and opened the window for the biological interrogation of germ-line polymorphisms within these sequences. In this study, through a forward genetic analysis of bona fide p53 binding sites identified by a genome-wide chromatin immunoprecipitation and sequence analysis, we discovered a SNP (rs1860746) within the motif sequence of a p53 binding site where p53 can function as a regulator of transcription. We found that the minor allele (T) binds p53 poorly and has low transcriptional regulation activity as compared to the major allele (G). Significantly, the homozygosity of the minor allele was found to be associated with an increased risk of ER negative breast cancer (OR = 1.47, P = 0.038) from the analysis of five independent breast cancer s les of European origin consisting of 6,127 breast cancer patients and 5,197 controls. rs1860746 resides in the third intron of the PRKAG2 gene that encodes the γ subunit of the AMPK protein, a major sensor of metabolic stress and a modulator of p53 action. However, this gene does not appear to be regulated by p53 in lymphoblastoid cell lines nor in a cancer cell line. These results suggest that either the rs1860746 locus regulates another gene through distant interactions, or that this locus is in linkage disequilibrium with a second causal mutation. This study shows the feasibility of using genomic scale molecular data to uncover disease associated SNPs, but underscores the complexity of determining the function of regulatory variants in human populations.
Publisher: Elsevier BV
Date: 10-2016
Publisher: Springer Science and Business Media LLC
Date: 12-09-2016
DOI: 10.1038/NBT.3674
Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2006
DOI: 10.1158/0008-5472.CAN-05-3546
Abstract: Classification of rare missense variants as neutral or disease causing is a challenge and has important implications for genetic counseling. A multifactorial likelihood model for classification of unclassified variants in BRCA1 and BRCA2 has previously been developed, which uses data on co-occurrence of the unclassified variant with pathogenic mutations in the same gene, cosegregation of the unclassified variant with affected status, and Grantham analysis of the fit between the missense substitution and the evolutionary range of variation observed at its position in the protein. We have further developed this model to take into account relevant features of BRCA1- and BRCA2-associated tumors, such as the characteristic histopathology and immunochemical profiles associated with pathogenic mutations in BRCA1, and the fact that ∼80% of tumors from BRCA1 and BRCA2 carriers undergo inactivation of the wild-type allele by loss of heterozygosity. We examined 10 BRCA1 and 15 BRCA2 unclassified variants identified in Australian, multiple-case breast cancer families. By a combination of genetic, in silico, and histopathologic analyses, we were able to classify one BRCA1 variant as pathogenic and six BRCA1 and seven BRCA2 variants as neutral. Five of these neutral variants were also found in at least 1 of 180 healthy controls, suggesting that screening a large number of appropriate controls might be a useful adjunct to other methods for evaluation of unclassified variants. (Cancer Res 2006 66(4): 2019-27)
Publisher: Springer Science and Business Media LLC
Date: 28-10-2016
Publisher: Public Library of Science (PLoS)
Date: 19-02-2010
Publisher: Wiley
Date: 14-09-2010
Publisher: Springer Science and Business Media LLC
Date: 11-05-2011
Abstract: The gene CHEK2 encodes a checkpoint kinase playing a key role in the DNA damage pathway. Though CHEK2 has been identified as an intermediate breast cancer susceptibility gene, only a small proportion of high-risk families have been explained by genetic variants located in its coding region. Alteration in gene expression regulation provides a potential mechanism for generating disease susceptibility. The detection of differential allelic expression (DAE) represents a sensitive assay to direct the search for a functional sequence variant within the transcriptional regulatory elements of a candidate gene. We aimed to assess whether CHEK2 was subject to DAE in lymphoblastoid cell lines (LCLs) from high-risk breast cancer patients for whom no mutation in BRCA1 or BRCA2 had been identified. We implemented an assay based on high-resolution melting (HRM) curve analysis and developed an analysis tool for DAE assessment. We observed allelic expression imbalance in 4 of the 41 LCLs examined. All four were carriers of the truncating mutation 1100delC. We confirmed previous findings that this mutation induces non-sense mediated mRNA decay. In our series, we ruled out the possibility of a functional sequence variant located in the promoter region or in a regulatory element of CHEK2 that would lead to DAE in the transcriptional regulatory milieu of freely proliferating LCLs. Our results support that HRM is a sensitive and accurate method for DAE assessment. This approach would be of great interest for high-throughput mutation screening projects aiming to identify genes carrying functional regulatory polymorphisms.
Publisher: Elsevier BV
Date: 04-2008
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: Springer Science and Business Media LLC
Date: 04-12-2009
DOI: 10.1007/S10549-009-0653-1
Abstract: Extensive expression profiling studies have shown that sporadic breast cancer is composed of five clinically relevant molecular subtypes. However, although BRCA1-related tumours are known to be predominantly basal-like, there are few published data on other classes of familial breast tumours. We analysed a cohort of 75 BRCA1, BRCA2 and non-BRCA1/2 breast tumours by gene expression profiling and found that 74% BRCA1 tumours were basal-like, 73% of BRCA2 tumours were luminal A or B, and 52% non-BRCA1/2 tumours were luminal A. Thirty-four tumours were also analysed by single nucleotide polymorphism-comparative genomic hybridization (SNP-CGH) arrays. Copy number data could predict whether a tumour was basal-like or luminal with high accuracy, but could not predict its mutation class. Basal-like BRCA1 and basal-like non-BRCA1 tumours were very similar, and contained the highest number of chromosome aberrations. We identified regions of frequent gain containing potential driver genes in the basal (8q and 12p) and luminal A tumours (1q and 17q). Regions of homozygous loss associated with decreased expression of potential tumour suppressor genes were also detected, including in basal tumours (5q and 9p), and basal and luminal tumours (10q). This study highlights the heterogeneity of familial tumours and the clinical consequences for treatment and prognosis.
Publisher: Springer Science and Business Media LLC
Date: 28-09-2015
DOI: 10.1038/NG.3412
Publisher: American Association for Cancer Research (AACR)
Date: 11-2010
DOI: 10.1158/1055-9965.EPI-10-0517
Abstract: Background: The genes caspase-8 (CASP8) and caspase-10 (CASP10) functionally cooperate and play a key role in the initiation of apoptosis. Suppression of apoptosis is one of the major mechanisms underlying the origin and progression of cancer. Previous case-control studies have indicated that the polymorphisms CASP8 D302H and CASP10 V410I are associated with a reduced risk of breast cancer in the general population. Methods: To evaluate whether the CASP8 D302H (CASP10 V410I) polymorphisms modify breast or ovarian cancer risk in BRCA1 and BRCA2 mutation carriers, we analyzed 7,353 (7,227) subjects of white European origin provided by 19 (18) study groups that participate in the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA). A weighted cohort approach was used to estimate hazard ratios (HR) and 95% confidence intervals (95% CI). Results: The minor allele of CASP8 D302H was significantly associated with a reduced risk of breast cancer (per-allele HR, 0.85 95% CI, 0.76-0.97 Ptrend = 0.011) and ovarian cancer (per-allele HR, 0.69 95% CI, 0.53-0.89 Ptrend = 0.004) for BRCA1 but not for BRCA2 mutation carriers. The CASP10 V410I polymorphism was not associated with breast or ovarian cancer risk for BRCA1 or BRCA2 mutation carriers. Conclusions: CASP8 D302H decreases breast and ovarian cancer risk for BRCA1 mutation carriers but not for BRCA2 mutation carriers. Impact: The combined application of these and other recently identified genetic risk modifiers could in the future allow better in idual risk calculation and could aid in the in idualized counseling and decision making with respect to preventive options in BRCA1 mutation carriers. Cancer Epidemiol Biomarkers Prev 19(11) 2859–68. ©2010 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488651.V1
Abstract: Supplementary Methods
Publisher: American Association for Cancer Research (AACR)
Date: 07-2007
DOI: 10.1158/1055-9965.EPI-07-0129
Abstract: The AURKA oncogene is associated with abnormal chromosome segregation and aneuploidy and predisposition to cancer. Amplification of AURKA has been detected at higher frequency in tumors from BRCA1 and BRCA2 mutation carriers than in sporadic breast tumors, suggesting that overexpression of AURKA and inactivation of BRCA1 and BRCA2 cooperate during tumor development and progression. The F31I polymorphism in AURKA has been associated with breast cancer risk in the homozygous state in prior studies. We evaluated whether the AURKA F31I polymorphism modifies breast cancer risk in BRCA1 and BRCA2 mutation carriers from the Consortium of Investigators of Modifiers of BRCA1/2. Consortium of Investigators of Modifiers of BRCA1/2 was established to provide sufficient statistical power through increased numbers of mutation carriers to identify polymorphisms that act as modifiers of cancer risk and can refine breast cancer risk estimates in BRCA1 and BRCA2 mutation carriers. A total of 4,935 BRCA1 and 2,241 BRCA2 mutation carriers and 11 in iduals carrying both BRCA1 and BRCA2 mutations was genotyped for F31I. Overall, homozygosity for the 31I allele was not significantly associated with breast cancer risk in BRCA1 and BRCA2 carriers combined [hazard ratio (HR), 0.91 95% confidence interval (95% CI), 0.77-1.06]. Similarly, no significant association was seen in BRCA1 (HR, 0.90 95% CI, 0.75-1.08) or BRCA2 carriers (HR, 0.93 95% CI, 0.67-1.29) or when assessing the modifying effects of either bilateral prophylactic oophorectomy or menopausal status of BRCA1 and BRCA2 carriers. In summary, the F31I polymorphism in AURKA is not associated with a modified risk of breast cancer in BRCA1 and BRCA2 carriers. (Cancer Epidemiol Biomarkers Prev 2007 (7):1416–21)
Publisher: AMPCo
Date: 11-2013
DOI: 10.5694/MJA13.10848
Abstract: To estimate the prevalence of the use of cancer risk-reducing measures among Australian BRCA1 and BRCA2 mutation carriers. Prospective follow-up of female carriers of BRCA1 or BRCA2 mutations who had no personal history of cancer and were enrolled in a multiple-case breast cancer family cohort study (kConFab). Data, including cancer events and uptake of risk-reducing surgery and medication were collected by self-report at cohort entry and 3 yearly thereafter. Surgery was confirmed from pathology and medical records. Women were followed up from enrolment until cancer diagnosis, date of last follow-up, or death. Data were collected from 3 November 1997 to 21 May 2012. Uptake of risk-reducing surgery and/or medication. Of 175 BRCA1 and 150 BRCA2 mutation carriers (median age, 37 years at cohort enrolment), 69 (21%) underwent risk-reducing mastectomy, 125 (38%) underwent risk-reducing bilateral salpingo-oophorectomy and nine (3%) participated in a clinical trial of risk-reducing medication, during 2447 person-years of follow-up (median follow-up, 9 years). Sixty-eight women (21%) reported incident cancers, including 52 breast cancers and nine ovarian cancers (defined in this article as high-grade serous cancers of the ovary, fallopian tube or peritoneum). There is considerable scope to increase the uptake of cancer risk-reducing measures in Australian BRCA1 and BRCA2 mutation carriers. These findings should drive (i) future research into the factors contributing to low uptake in Australia and (ii) changes to policy and practice to help better translate genetic knowledge into reductions in cancer incidence.
Publisher: Springer Science and Business Media LLC
Date: 02-2005
Publisher: Oxford University Press (OUP)
Date: 19-03-2008
DOI: 10.1093/JNCI/DJN037
Abstract: Data from several studies have suggested that polymorphisms in A-kinase anchoring proteins (AKAPs), which are key components of signal transduction, contribute to carcinogenesis. To evaluate the impact of AKAP variants on breast cancer risk, we genotyped six nonsynonymous single-nucleotide polymorphisms that were predicted to be deleterious and found two (M463I, 1389G>T and N2792S, 8375A>G) to be associated with an allele dose-dependent increase in risk of familial breast cancer in a German population. We extended the analysis of AKAP9 M463I, which is in strong linkage disequilibrium with AKAP9 N2792S, to 9523 breast cancer patients and 13770 healthy control subjects from seven independent European and Australian breast cancer studies. All statistical tests were two-sided. The collaborative analysis confirmed the association of M463I with increased breast cancer risk. Among all breast cancer patients, the combined adjusted odds ratio (OR) of breast cancer for in iduals homozygous for the rare allele TT (frequency = 0.19) compared with GG homozygotes was 1.17 (95% confidence interval [CI] = 1.08 to 1.27, P = .0003), and the OR for TT homozygotes plus GT heterozygotes compared with GG homozygotes was 1.10 (95% CI = 1.04 to 1.17, P = .001). Among the combined subset of 2795 familial breast cancer patients, the respective ORs were 1.27 (95% CI = 1.12 to 1.45, P = .0003) and 1.16 (95% CI = 1.06 to 1.27, P = .001).
Publisher: Wiley
Date: 07-2010
DOI: 10.1002/PATH.2728
Abstract: Tissue s le acquisition is a limiting step in many studies. There are many thousands of formalin-fixed, paraffin-embedded archival blocks collected around the world, but in contrast relatively few fresh frozen s les in tumour banks. Once s les are fixed in formalin, the RNA is degraded and traditional methods for gene expression profiling are not suitable. In this study, we have evaluated the ability of the whole genome DASL (cDNA-mediated Annealing, Selection, extension, and Ligation) assay from Illumina to perform transcriptomic analysis of archived breast tumour tissue in formalin-fixed, paraffin-embedded (FFPE) blocks. We profiled 76 familial breast tumours from cases carrying a BRCA1, BRCA2 or ATM mutation, or from non-BRCA1/2 families. We found that replicate s les correlated well with each other (r(2) = 0.9-0.98). In 12/15 cases, the matched formalin-fixed and frozen s les predicted the same tumour molecular subtypes with confidence. These results demonstrate that the whole genome DASL assay is a valuable tool to profile degraded RNA from archival FFPE material. This assay will enable transcriptomic analysis of a large number of archival s les that are stored in pathology archives around the globe and consequently will have the potential to improve our understanding and characterization of many diseases.
Publisher: Elsevier BV
Date: 11-2002
DOI: 10.1046/J.1523-1747.2002.19513.X
Abstract: Human papillomavirus is a risk factor for vulvar cancer, whereas human papillomavirus-negative late onset vulvar carcinoma is associated with the dermatologic condition, lichen sclerosus. Human papillomavirus E6 protein targets TP53 for degradation and by inference it has been assumed that human papillomavirus-negative vulvar cancer is dependent upon the acquisition of p53 somatic mutations and subsequent allelic loss. To investigate this, TP53 expression, loss of heterozygosity, and p53 genomic sequence were examined in 29 cases of human papillomavirus-negative vulvar carcinoma with adjacent lichen sclerosus. We examined 37 cases of lichen sclerosus without vulvar carcinoma, 10 cases of nongenital lichen sclerosus, and 12 cases of normal vulvar epithelium served as controls. TP53 was evident in 72% of vulvar carcinoma, 48% in epithelium adjacent to vulvar carcinoma, but was minimal in normal s les. When lichen sclerosus cases were selected to exclude s les with absolutely no TP53 expression through probable failed antigen retrieval or homozygous p53 loss the number of epithelial cells expressing TP53 increased progressively from nongenital lichen sclerosus to lichen sclerosus without vulvar carcinoma, then to lichen sclerosus with vulvar carcinoma (p<0.0001). These data suggest elevated TP53 is a feature of vulvar lichen sclerosus. Seventy-four percent of vulvar carcinoma had chromosome 17p-linked loss of heterozygosity, whereas 47% of adjacent lichen sclerosus featured loss of heterozygosity, but only 31% of vulvar carcinoma had p53 mutations, a frequency less than reported previously. Seven percent of adjacent lichen sclerosus had mutations, showing for the first time the presence of an identical mutation to the matched vulvar carcinoma. These data, however, implicate p53 mutations as a later event in vulvar carcinoma and in marked contrast to the original expectation, our loss of heterozygosity data are consistent with loss of another locus (not p53) on 17p operating as a tumor suppressor in lichen sclerosus destined to develop vulvar carcinoma.
Publisher: Oxford University Press (OUP)
Date: 23-04-2010
DOI: 10.1093/HMG/DDQ174
Publisher: Springer Science and Business Media LLC
Date: 24-12-2011
DOI: 10.1007/S10689-011-9504-4
Abstract: Most studies of quality of life following risk-reducing bilateral salpingo-oophorectomy (RRSO) and mastectomy (RRM) for inherited breast and ovarian cancer susceptibility were conducted before counseling protocols were established and included women at varying times since surgery. This study aimed to overcome these deficiencies and to provide current data on outcomes for this growing group of women. Semi-structured interviews were used to explore the experiences of an Australian cohort of 40 high-risk women 3 years after they underwent RRM and/or RRSO. Data were analyzed using the method of constant comparison. 19/40 women underwent RRSO, 8/40 RRM and 13/40 both procedures. Two themes-looking different and feeling different-captured the psychosocial impact of surgery upon interviewees. All regarded RR surgery as a positive experience and were relieved at having their risks of cancer substantially reduced however, reducing risk by removing these body parts is not without costs. In addition to relief interviewees also reported experiencing a range of negative emotions and a range of unexpected bodily sensations following surgery and reflected upon both positive and negative changes in their appearance. Women said they had been unprepared for the lack of sensation in reconstructed breasts and/or the severity of menopausal symptoms, which often had a negative impact upon sexuality. At-risk women regard RR surgery as a positive way to manage cancer risk. However, although women who currently undergo RR surgery are informed about its sequelae, few are entirely prepared for the reality of undergoing this procedure. We recommend that women who undergo these procedures should be provided with information supported by psychosocial input before and after RR surgery.
Publisher: Oxford University Press (OUP)
Date: 02-09-2011
DOI: 10.1093/HMG/DDR388
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488645.V1
Abstract: Supplementary Tables S1-S11
Publisher: Elsevier BV
Date: 09-2000
DOI: 10.1016/S0022-3999(00)00156-2
Abstract: Review empirical evidence for a relationship between psychosocial factors and breast cancer development. Standardised quality assessment criteria were utilised to assess the evidence of psychosocial predictors of breast cancer development in the following domains: (a) stressful life events, (b) coping style, (c) social support, and (d) emotional and personality factors. Few well-designed studies report any association between life events and breast cancer, the exception being two small studies using the Life Events and Difficulties Schedule (LEDS) reporting an association between severely threatening events and breast cancer risk. Seven studies show anger repression or alexithymia are predictors, the strongest evidence suggesting younger women are at increased risk. There is no evidence that social support, chronic anxiety, or depression affects breast cancer development. With the exception of rationality/anti-emotionality, personality factors do not predict breast cancer risk. The evidence for a relationship between psychosocial factors and breast cancer is weak. The strongest predictors are emotional repression and severe life events. Future research would benefit from theoretical grounding and greater methodological rigour. Recommendations are given.
Publisher: Springer Science and Business Media LLC
Date: 02-2006
DOI: 10.1186/BCR1377
Publisher: Springer Science and Business Media LLC
Date: 29-02-2016
DOI: 10.1038/NG.3521
Publisher: Public Library of Science (PLoS)
Date: 29-06-2012
Publisher: American Association for Cancer Research (AACR)
Date: 30-04-2012
DOI: 10.1158/0008-5472.CAN-11-3157
Abstract: Few studies have evaluated the association between DNA methylation in white blood cells (WBC) and the risk of breast cancer. The evaluation of WBC DNA methylation as a biomarker of cancer risk is of particular importance as peripheral blood is often available in prospective cohorts and easier to obtain than tumor or normal tissues. Here, we used prediagnostic blood s les from three studies to analyze WBC DNA methylation of two ATM intragenic loci (ATMmvp2a and ATMmvp2b) and genome-wide DNA methylation in long interspersed nuclear element-1 (LINE1) repetitive elements. S les were from a case–control study derived from a cohort of high-risk breast cancer families (KConFab) and nested case–control studies in two prospective cohorts: Breakthrough Generations Study (BGS) and European Prospective Investigation into Cancer and Nutrition (EPIC). Bisulfite pyrosequencing was used to quantify methylation from 640 incident cases of invasive breast cancer and 741 controls. Quintile analyses for ATMmvp2a showed an increased risk of breast cancer limited to women in the highest quintile [OR, 1.89 95% confidence interval (CI), 1.36–2.64 P = 1.64 × 10−4]. We found no significant differences in estimates across studies or in analyses stratified by family history or menopausal status. However, a more consistent association was observed in younger than in older women and in idually significant in KConFab and BGS, but not EPIC. We observed no differences in LINE1 or ATMmvp2b methylation between cases and controls. Together, our findings indicate that WBC DNA methylation levels at ATM could be a marker of breast cancer risk and further support the pursuit of epigenome-wide association studies of peripheral blood DNA methylation. Cancer Res 72(9) 2304–13. ©2012 AACR.
Publisher: Proceedings of the National Academy of Sciences
Date: 15-01-2002
Abstract: The known susceptibility genes for breast cancer, including BRCA1 and BRCA2, only account for a minority of the familial aggregation of the disease. A recent study of 77 multiple case breast cancer families from Scandinavia found evidence of linkage between the disease and polymorphic markers on chromosome 13q21. We have evaluated the contribution of this candidate “BRCA3” locus to breast cancer susceptibility in 128 high-risk breast cancer families of Western European ancestry with no identified BRCA1 or BRCA2 mutations. No evidence of linkage was found. The estimated proportion (α) of families linked to a susceptibility locus at D13S1308, the location estimated by Kainu et al. [(2000) Proc. Natl. Acad. Sci. USA 97, 9603–9608], was 0 (upper 95% confidence limit 0.13). Adjustment for possible bias due to selection of families on the basis of linkage evidence at BRCA2 did not materially alter this result (α = 0, upper 95% confidence limit 0.18). The proportion of linked families reported by Kainu et al. (0.65) is excluded with a high degree of confidence in our dataset [heterogeneity logarithm of odds (HLOD) at α = 0.65 was −11.0]. We conclude that, if a susceptibility gene does exist at this locus, it can only account for a small proportion of non-BRCA1/2 families with multiple cases of early-onset breast cancer.
Publisher: Springer Science and Business Media LLC
Date: 23-09-2012
DOI: 10.1038/NG.2417
Publisher: Hindawi Limited
Date: 2005
DOI: 10.1002/HUMU.9344
Abstract: The ATM gene is mutated in ataxia-telangiectasia (AT). Heterozygote female relatives of AT cases have a 2-7fold increased risk of breast cancer. We previously reported high risks of breast cancer associated with certain ATM variants. To estimate the risks more precisely, we have examined two ATM variants, c.1066-6T>G (IVS10-6T>G) and c.4258C>T (p.Leu1420Phe), in additional cases and controls from the same Australian cohorts previously used to estimate the risk of breast cancer associated with c.1066-6T>G. A total of 775 and 84 population-based controls were genotyped for the c.1066-6T>G and c.4258C>T ATM variants respectively, as were index cases from 378 and 373 non-BRCA1/2 breast cancer families. Penetrance was estimated by Bayes factor analysis. The allele frequencies of ATM c.1066-6T>G and c.4258C>T estimated from controls were 0.005 (95% CI=0.002 to 0.009) and 0.012 (95% CI=0.001 to 0.042), respectively. We identified three new breast cancer families with c.1066-6T>G, and seven families with c.4258C>T. Combining with the two c.1066-6T>G families previously reported, the estimated penetrance to age 70 of c.1066-6T>G was 17.2% (95% CI=4.7% to 37.5%). For c.4258C>T, the estimated average penetrance was 4.8% (95% CI 1.7% to 10.1%). In conclusion, we found no evidence that the ATM c.4258C>T variant increases breast cancer risk, and little evidence that c.1066-6T>G confers an elevated risk. Analysis of additional families will be necessary to define more precisely the risk, if any, associated with c.1066-6T>G.
Publisher: Wiley
Date: 30-03-2006
DOI: 10.1002/GCC.20330
Publisher: Public Library of Science (PLoS)
Date: 05-05-2016
Publisher: BMJ
Date: 04-2010
Abstract: A study of Chinese women recently suggested that the minor allele of rs11655505 in the BRCA1 promoter (c.-2265C-->T) increases promoter activity and has a protective effect on breast cancer risk. We genotyped rs11655505 in 2912 female breast cancer cases and 2783 unaffected female controls from four Caucasian breast cancer studies. No evidence for an association between rs11655505 and breast cancer risk was found. Our study failed to confirm a role of rs11655505 in breast cancer risk. Larger studies are necessary to determine if there is a weak association between this SNP and breast cancer risk.
Publisher: Springer Science and Business Media LLC
Date: 20-05-2011
Publisher: Oxford University Press (OUP)
Date: 13-06-2014
DOI: 10.1093/HMG/DDU300
Publisher: Public Library of Science (PLoS)
Date: 23-05-2008
Publisher: Elsevier BV
Date: 05-2017
DOI: 10.1038/GIM.2016.147
Publisher: Hindawi Limited
Date: 06-2009
DOI: 10.1002/HUMU.20949
Publisher: Public Library of Science (PLoS)
Date: 13-10-2010
Publisher: Elsevier BV
Date: 06-2022
Publisher: Springer Science and Business Media LLC
Date: 14-05-2004
DOI: 10.1186/BCR803
Publisher: Springer Science and Business Media LLC
Date: 10-2006
Publisher: Springer Science and Business Media LLC
Date: 17-11-2009
Publisher: Springer Science and Business Media LLC
Date: 25-07-2011
DOI: 10.1186/BCR2919
Publisher: Wiley
Date: 2004
DOI: 10.1002/GCC.10321
Abstract: The breast cancer susceptibility genes BRCA1 and BRCA2 are responsible for a large proportion of familial breast and ovarian cancer, yet little is known of how disruptions in the functions of the proteins these genes encode increased cancer risk preferentially in hormone-dependent tissue. There is no information on whether a germ-line mutation in BRCA1 or BRCA2 causes disruptions in hormone-signaling pathways in the normal breast. In this study markers of hormone responsiveness were measured in prophylactically removed normal breast tissue (n = 31) in women bearing a germ-line pathogenic mutation in one of the BRCA genes. The estrogen receptor (ER) and proteins associated with ER action in hormone-sensitive tissues, namely, PS2 and the progesterone receptor (PR), were detected immunohistochemically. ER expression was not different in BRCA mutation carriers than in noncarriers, but there was a reduction in PS2 expression. PR expression was also reduced, and there was a striking lack of expression of the PRB isoform, which resulted in cases with PRA-only expression in BRCA1 and BRCA2 mutation carriers. The alterations in PS2 and PR expression were similar in the BRCA1 and BRCA2 carriers, demonstrating that although these proteins are structurally and functionally distinct, there is overlap in their interaction with hormone-signaling pathways. This study provides evidence for altered cell function arising from loss of function of one BRCA allele in the normal breast, leading to PS2 loss, preferential PRB loss, and expression of PRA alone. In breast cancer development, PRA overexpression becomes evident in premalignant lesions and is associated with features of poor prognosis in invasive disease and altered cell function in vitro. The results of this study suggest that heterozygosity for a germ-line mutation in BRCA1 or BRCA2 results in development of PRA predominance. This is likely to lead to changes in progesterone signaling in hormone-dependent tissues, which may be a factor in the increased risk of cancer in these tissues in women with germ-line BRCA1 or BRCA2 mutations.
Publisher: Springer Science and Business Media LLC
Date: 02-2017
Publisher: American Medical Association (AMA)
Date: 07-04-2015
Publisher: Elsevier BV
Date: 09-2016
Publisher: Wiley
Date: 17-06-2016
DOI: 10.1002/IJC.30150
Publisher: Springer Science and Business Media LLC
Date: 20-02-2008
DOI: 10.1038/EJHG.2008.13
Publisher: Springer Science and Business Media LLC
Date: 17-12-2010
DOI: 10.1007/S10549-010-1292-2
Abstract: ABCC11 is an ATP-binding cassette transporter responsible for the transport of a erse range of lipophilic compounds. A single nucleotide polymorphism (SNP) encoding an amino acid change has recently been shown to determine whether cerumen (earwax) is wet or dry. We hypothesised that this ABCC11 SNP may be associated with breast cancer risk because an association has been reported between wet earwax and increased risk of breast cancer. We therefore analysed the frequency of the functional SNP in 1342 cases and 2256 controls from two breast cancer studies of Caucasian women but found no evidence for an association with breast cancer risk.
Publisher: Elsevier BV
Date: 10-2009
Publisher: Oxford University Press (OUP)
Date: 19-04-2016
Publisher: Impact Journals, LLC
Date: 05-02-2017
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: Springer Science and Business Media LLC
Date: 03-01-2012
Publisher: Mary Ann Liebert Inc
Date: 06-2011
Abstract: Despite proven benefits, the uptake of genetic counseling and testing by at-risk family members of BRCA1 and BRCA2 mutation carriers remains low. This study aimed to examine at-risk in iduals' reported reasons for and against familial cancer clinic (FCC) attendance and genetic testing. Thirty-nine telephone interviews were conducted with relatives of high-risk mutation carriers, 23% (n = 9) of whom had not previously attended an FCC. Interview responses were analyzed using the frameworks of Miles and Huberman. The reasons most commonly reported for FCC attendance were for clarification of risk status and to gain access to testing. While disinterest in testing was one reason for FCC nonattendance, several in iduals were unaware of their risk (n = 3) or their eligibility to attend an FCC (n = 2), despite being notified of their risk status through their participation in a large-scale research project. In iduals' reasons for undergoing testing were in line with that reported elsewhere however, concerns about discrimination and insurance were not reported in nontestees. Current guidelines regarding notifying in iduals discovered to be at increased risk in a research, rather than clinical setting, take a largely nondirective approach. However, this study demonstrates that in iduals who receive a single letter notifying them of their risk may not understand/value the information they receive.
Publisher: Oxford University Press (OUP)
Date: 18-06-2014
DOI: 10.1093/HMG/DDU311
Publisher: Elsevier BV
Date: 09-2005
DOI: 10.1016/J.YGENO.2005.05.006
Abstract: Cross-species comparative genomics is a powerful strategy for identifying functional regulatory elements within noncoding DNA. In this paper, comparative analysis of human and mouse intronic sequences in the breast cancer susceptibility gene (BRCA1) revealed two evolutionarily conserved noncoding sequences (CNS) in intron 2, 5 kb downstream of the core BRCA1 promoter. The functionality of these elements was examined using homologous-recombination-based mutagenesis of reporter gene-tagged cosmids incorporating these regions and flanking sequences from the BRCA1 locus. This showed that CNS-1 and CNS-2 have differential transcriptional regulatory activity in epithelial cell lines. Mutation of CNS-1 significantly reduced reporter gene expression to 30% of control levels. Conversely mutation of CNS-2 increased expression to 200% of control levels. Regulation is at the level of transcription and shows promoter specificity. Both elements also specifically bind nuclear proteins in vitro. These studies demonstrate that the combination of comparative genomics and functional analysis is a successful strategy to identify novel regulatory elements and provide the first direct evidence that conserved noncoding sequences in BRCA1 regulate gene expression.
Publisher: Springer Science and Business Media LLC
Date: 12-01-2015
DOI: 10.1038/NG.3185
Publisher: Springer Science and Business Media LLC
Date: 18-08-2011
DOI: 10.1007/S10549-011-1733-6
Abstract: Published studies have reached contradictory conclusions regarding breast cancer risk for women from families segregating a BRCA1 or BRCA2 mutation who do not carry the family-specific mutation. Accurate estimation of breast cancer risk is crucial for appropriate counselling regarding risk management. The aim of this study is to prospectively assess whether breast cancer risk for mutation negative women from families segregating BRCA1 or BRCA2 mutations is greater than for women in the general population. Eligible women were 722 first-, second- and third-degree relatives of a BRCA1 or BRCA2 mutation carrier from 224 mutation positive (128 BRCA1, 96 BRCA2) families, had no personal cancer history at baseline, and had been tested and found not to carry the family-specific mutation. Self-reported family history of cancer, preventive interventions and verified cancer diagnoses were collected at baseline, and every 3 years thereafter. Median follow-up was 6.1 years (range 0.1-12.4 years). Time at risk of breast cancer was censored at cancer diagnosis or risk-reducing surgery. Standardised incidence ratios (SIR) were estimated by comparing observed to population incidences of invasive breast cancer using Australian Cancer Incidence and Mortality Books. Six cases of invasive breast cancer were observed. The estimated SIRs were 1.14 (95% CI: 0.51-2.53) overall (n = 722), 1.29 (95% CI: 0.58-2.88) when restricted to first- and second-degree relatives of an affected mutation carrier (n = 442) and 0.48 (95% CI: 0.12-1.93) when restricted to those with no family history of breast cancer in the non-mutation carrying parental lineage (n = 424). There was no evidence that mutation negative women from families segregating BRCA1 or BRCA2 mutations are at increased risk of breast cancer. Despite this being the largest prospective cohort to assess this issue, moderately increased breast cancer risk (2-fold) cannot be ruled out.
Publisher: Springer Science and Business Media LLC
Date: 15-06-2012
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: Hindawi Limited
Date: 13-06-2003
DOI: 10.1002/HUMU.10224
Abstract: Genetic testing for cancer predisposing mutations in BRCA1 and BRCA2 has been of benefit to many in iduals from breast and ovarian cancer-prone kindreds. However, a function has not been assigned to many of the domains that make up these complex proteins and hence, the significance of many sequence variants, including missense mutations, splice-site mutations, and in-frame deletions/insertions, remains unclear. We identified a putative splice site mutation (IVS6-2delA) in BRCA1 in a family attending a Familial Cancer Centre that had a significant history of both breast and ovarian cancer. This sequence variant was not novel but the exact effect on mRNA splicing and hence the biological impact of this sequence variation was unclear and therefore the finding was unable to be used in genetic counseling of the family. Via the construction of novel GFP-based expression fusion constructs, we demonstrated that this sequence variation prevented normal splicing of the BRCA1 transcript. By combining these data with an assessment of the histopathological features of the breast carcinomas in this family and mutation penetrance estimate we were able to conclude that this BRCA1 variant conveyed an increased risk of breast cancer.
Publisher: Informa UK Limited
Date: 20-03-2015
No related grants have been discovered for Heather Thorne.