ORCID Profile
0000-0003-1639-5003
Current Organisation
University of British Columbia
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Publisher: American Association for Cancer Research (AACR)
Date: 15-02-2023
DOI: 10.1158/1055-9965.EPI-22-0941
Abstract: Better understanding of prognostic factors in tubo-ovarian high-grade serous carcinoma (HGSC) is critical, as diagnosis confers an aggressive disease course. Variation in tumor DNA methylation shows promise predicting outcome, yet prior studies were largely platform-specific and unable to evaluate multiple molecular features. We analyzed genome-wide DNA methylation in 1,040 frozen HGSC, including 325 previously reported upon, seeking a multi-platform quantitative methylation signature that we evaluated in relation to clinical features, tumor characteristics, time to recurrence/death, extent of CD8+ tumor-infiltrating lymphocytes (TIL), gene expression molecular subtypes, and gene expression of the ATP-binding cassette transporter TAP1. Methylation signature was associated with shorter time to recurrence, independent of clinical factors (N = 715 new set, hazard ratio (HR), 1.65 95% confidence interval (CI), 1.10–2.46 P = 0.015 N = 325 published set HR, 2.87 95% CI, 2.17–3.81 P = 2.2 × 10−13) and remained prognostic after adjustment for gene expression molecular subtype and TAP1 expression (N = 599 HR, 2.22 95% CI, 1.66–2.95 P = 4.1 × 10−8). Methylation signature was inversely related to CD8+ TIL levels (P = 2.4 × 10−7) and TAP1 expression (P = 0.0011) and was associated with gene expression molecular subtype (P = 5.9 × 10−4) in covariate-adjusted analysis. Multi-center analysis identified a novel quantitative tumor methylation signature of HGSC applicable to numerous commercially available platforms indicative of shorter time to recurrence/death, adjusting for other factors. Along with immune cell composition analysis, these results suggest a role for DNA methylation in the immunosuppressive microenvironment. This work aids in identification of targetable epigenome processes and stratification of patients for whom tailored treatment may be most beneficial.
Publisher: Springer Science and Business Media LLC
Date: 24-04-2017
DOI: 10.1038/NG.3849
Abstract: We studied the whole-genome point mutation and structural variation patterns of 133 tumors (59 high-grade serous (HGSC), 35 clear cell (CCOC), 29 endometrioid (ENOC), and 10 adult granulosa cell (GCT)) as a substrate for class discovery in ovarian cancer. Ab initio clustering of integrated point mutation and structural variation signatures identified seven subgroups both between and within histotypes. Prevalence of foldback inversions identified a prognostically significant HGSC group associated with inferior survival. This finding was recapitulated in two independent cohorts (n = 576 cases), transcending BRCA1 and BRCA2 mutation and gene expression features of HGSC. CCOC cancers grouped according to APOBEC deamination (26%) and age-related mutational signatures (40%). ENOCs were ided by cases with microsatellite instability (28%), with a distinct mismatch-repair mutation signature. Taken together, our work establishes the potency of the somatic genome, reflective of erse DNA repair deficiencies, to stratify ovarian cancers into distinct biological strata within the major histotypes.
Publisher: Massachusetts Medical Society
Date: 19-01-2012
Publisher: American Association for Cancer Research (AACR)
Date: 20-06-2023
DOI: 10.1158/1078-0432.CCR-22-3815
Abstract: Endometrioid ovarian carcinoma (ENOC) is the second most-common type of ovarian carcinoma, comprising 10%–20% of cases. Recently, the study of ENOC has benefitted from comparisons to endometrial carcinomas including defining ENOC with four prognostic molecular subtypes. Each subtype suggests differential mechanisms of progression, although tumor-initiating events remain elusive. There is evidence that the ovarian microenvironment may be critical to early lesion establishment and progression. However, while immune infiltrates have been well studied in high-grade serous ovarian carcinoma, studies in ENOC are limited. We report on 210 ENOC, with clinical follow-up and molecular subtype annotation. Using multiplex IHC and immunofluorescence, we examine the prevalence of T-cell lineage, B-cell lineage, macrophages, and populations with programmed cell death protein 1 or programmed death-ligand 1 across subtypes of ENOC. Immune cell infiltrates in tumor epithelium and stroma showed higher densities in ENOC subtypes with known high mutation burden (POLEmut and MMRd). While molecular subtypes were prognostically significant, immune infiltrates were not (overall survival P & 0.2). Analysis by molecular subtype revealed that immune cell density was prognostically significant in only the no specific molecular profile (NSMP) subtype, where immune infiltrates lacking B cells (TILB minus) had inferior outcome (disease-specific survival: HR, 4.0 95% confidence interval, 1.1–14.7 P & 0.05). Similar to endometrial carcinomas, molecular subtype stratification was generally superior to immune response in predicting outcomes. Subtype stratification is critical for better understanding of ENOC, in particular the distribution and prognostic significance of immune cell infiltrates. The role of B cells in the immune response within NSMP tumors warrants further study.
Publisher: BMJ Publishing Group Ltd
Date: 09-2019
Publisher: Public Library of Science (PLoS)
Date: 08-06-2017
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.C.6532976.V1
Abstract: AbstractPurpose: To identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes. Experimental Design: We profiled 421 primary CCOCs that passed quality control using a targeted deep sequencing panel of 163 putative CCOC driver genes and whole transcriptome sequencing of 211 of these tumors. Molecularly defined subgroups were identified and tested for association with clinical characteristics and overall survival. Results: We detected a putative somatic driver mutation in at least one candidate gene in 95% (401/421) of CCOC tumors including i ARID1A /i (in 49% of tumors), i PIK3CA /i (49%), i TERT /i (20%), and i TP53 /i (16%). Clustering of cancer driver mutations and RNA expression converged upon two distinct subclasses of CCOC. The first was dominated by i ARID1A /i -mutated tumors with enriched expression of canonical CCOC genes and markers of platinum resistance the second was largely comprised of tumors with i TP53 /i mutations and enriched for the expression of genes involved in extracellular matrix organization and mesenchymal differentiation. Compared with the i ARID1A /i -mutated group, women with i TP53 /i -mutated tumors were more likely to have advanced-stage disease, no antecedent history of endometriosis, and poorer survival, driven by their advanced stage at presentation. In women with i ARID1A /i -mutated tumors, there was a trend toward a lower rate of response to first-line platinum-based therapy. Conclusions: Our study suggests that CCOC consists of two distinct molecular subclasses with distinct clinical presentation and outcomes, with potential relevance to both traditional and experimental therapy responsiveness. i a href="lincancerres/article/doi/10.1158/1078-0432.CCR-22-2365" target="_blank" See related commentary by Lheureux, p. 4838 /a /i /
Publisher: Wiley
Date: 25-01-2013
DOI: 10.1002/PATH.4135
Abstract: Our group recently described recurrent somatic mutations of the miRNA processing gene DICER1 in non-epithelial ovarian cancer. Mutations appeared to be clustered around each of four critical metal-binding residues in the RNase IIIB domain of DICER1. This domain is responsible for cleavage of the 3' end of the 5p miRNA strand of a pre-mRNA hairpin. To investigate the effects of these cancer-associated 'hotspot' mutations, we engineered mouse DICER1-deficient ES cells to express wild-type and an allelic series of the mutant DICER1 variants. Global miRNA and mRNA profiles from cells carrying the metal-binding site mutations were compared to each other and to wild-type DICER1. The miRNA and mRNA profiles generated through the expression of the hotspot mutations were virtually identical, and the DICER1 hotspot mutation-carrying cells were distinct from both wild-type and DICER1-deficient cells. Further, miRNA profiles showed that mutant DICER1 results in a dramatic loss in processing of mature 5p miRNA strands but were still able to create 3p strand miRNAs. Messenger RNA (mRNA) profile changes were consistent with the loss of 5p strand miRNAs and showed enriched expression for predicted targets of the lost 5p-derived miRNAs. We therefore conclude that cancer-associated somatic hotspot mutations of DICER1, affecting any one of four metal-binding residues in the RNase IIIB domain, are functionally equivalent with respect to miRNA processing and are hypomorphic alleles, yielding a global loss in processing of mature 5p strand miRNA. We further propose that this resulting 3p strand bias in mature miRNA expression likely underpins the oncogenic potential of these hotspot mutations.
Publisher: Public Library of Science (PLoS)
Date: 10-09-2010
Publisher: Spandidos Publications
Date: 26-06-2012
Abstract: Cytokine expression in a tumor microenvironment can impact both host defense against the tumor and tumor cell survival. In this study, we sought to clarify whether the cytokine gene expression profile could have clinical associations with ovarian cancer. We analyzed the expression of 16 cytokine genes (IL-1α, IL-1β, IL-2, IL-4, IL-5, IL-8, IL-10, IL-12p35, IL-12p40, IL-15, IFN-γ, TNF-α, IL-6, HLA-DRA, HLA-DPA1 and CSF1) in 50 ovarian carcinomas. Hierarchical clustering analysis of these tumors was carried out using Cluster software and differentially expressed genes were examined between clear cell carcinoma (CCC) and other subtypes. Following this examination we evaluated the biological significance of IL-6 knockdown in CCC. Unsupervised hierarchical clustering analysis of cytokine gene expression revealed two distinct clusters. The relationship between the two clusters and clinical parameters showed statistically significant differences in CCC compared to other histologies. CCC showed a dominant Th-2 cytokine expression pattern driven largely by IL-6 expression. Inhibition of IL-6 in CCC cells suppressed Stat3 signaling and rendered cells sensitive to cytotoxic agents. The unique cytokine expression pattern found in CCC may be involved in the pathogenesis of this subtype. In particular, high IL-6 expression appears likely to be driven by the tumor cells, fueling an autocrine pathway involving IL-6 expression and Stat3 activation and may influence survival when exposed to cytotoxic chemotherapy. Modulation of IL-6 expression or its related signaling pathway may be a promising strategy of treatment for CCC.
Publisher: Future Medicine Ltd
Date: 03-2014
DOI: 10.2217/NNM.13.220
Abstract: Epithelial ovarian cancers are a group of at least five histologically and clinically distinct diseases, yet at this time patients with these different diseases are all treated with the same platinum and taxane-based chemotherapeutic regimen. With increased knowledge of histotype-specific differences that correlate with treatment responses and resistance, novel treatment strategies will be developed for each distinct disease. Type-specific or resistance-driven molecularly targeted agents will provide some specificity over traditional chemotherapies and it is argued here that nanoscaled drug delivery systems, in particular lipid-based formulations, have the potential to improve the delivery and specificity of pathway-specific drugs and broad-spectrum cytotoxic chemotherapeutics. An overview of the current understanding of ovarian cancers and the evolving clinical management of these diseases is provided. This overview is needed as it provides the context for understanding the current role of drug delivery systems in the treatment of ovarian cancer and the need to design formulations for treatment of clinically distinct forms of ovarian cancer.
Publisher: Annual Reviews
Date: 09-2010
DOI: 10.1146/ANNUREV-GENOM-082509-141536
Abstract: Cancer profiling studies have had a profound impact on our understanding of the biology of cancers in a number of ways, including providing insights into the biological heterogeneity of specific cancer types, identification of novel oncogenes and tumor suppressors, and defining pathways that interact to drive the growth of in idual cancers. Several large-scale genomic studies are underway that aim to catalog all biologically significant mutational events in each cancer type, and these findings will allow researchers to understand how mutational networks function within in idual tumors. The identification of molecular predictive and prognostic tools to facilitate treatment decisions is an important step for in idualized patient therapy and, ultimately, in improving patient outcomes. Whereas there are still significant challenges to implementing genomic testing and targeted therapy into routine clinical practice, rapid technological advancements provide hope for overcoming these obstacles.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: Springer Science and Business Media LLC
Date: 05-08-2019
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494876.V1
Abstract: Supplementary Figure 1: Methylation Signature Approximation
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: Elsevier BV
Date: 12-2017
DOI: 10.1016/J.YGYNO.2017.10.016
Abstract: APELA is a small, secreted peptide that can function as a ligand for the G-protein coupled receptor, Apelin Receptor (APLNR, APJ). APELA plays an essential role in endoderm differentiation and cardiac development during embryogenesis. We investigated whether APELA exerts any functions in cancer progression. The Cancer Genome Atlas (TCGA) RNA sequencing datasets, microarray from an OCCC mouse model, and RNA isolated from fresh frozen and FFPE patient tissue were used to assess APELA expression. APELA knockout ovarian clear cell carcinoma (OCCC) cell lines were generated using CRISPR/Cas9. APELA was expressed in various ovarian cancer histotypes and was especially elevated in OCCC. Disruption of APELA expression in OCCC cell lines suppressed cell growth and migration, and altered cell-cycle progression. Moreover, addition of human recombinant APELA peptide to the OCCC cell line OVISE promoted cell growth and migration. Interestingly, OVISE cells do not express APLNR, suggesting that APELA can function through an APLNR-independent pathway. Furthermore, APELA affected cell growth and cell cycle progression in a p53-dependent manner. In addition, APELA knockdown induced p53 expression in cancer cell lines. Our findings uncover a potential oncogenic role for APELA in promoting ovarian tumour progression and provide a possible therapeutic strategy in ovarian cancer by targeting APELA.
Publisher: American Association for Cancer Research (AACR)
Date: 14-08-2012
DOI: 10.1158/0008-5472.CAN-12-0203
Abstract: High-grade serous cancer (HGSC), the most common subtype of ovarian cancer, often becomes resistant to chemotherapy, leading to poor patient outcomes. Intratumoral heterogeneity occurs in nearly all solid cancers, including ovarian cancer, contributing to the development of resistance mechanisms. In this study, we examined the spatial and temporal genomic variation in HGSC using high-resolution single-nucleotide polymorphism arrays. Multiple metastatic lesions from in idual patients were analyzed along with 22 paired pretreatment and posttreatment s les. We documented regions of differential DNA copy number between multiple tumor biopsies that correlated with altered expression of genes involved in cell polarity and adhesion. In the paired primary and relapse cohort, we observed a greater degree of genomic change in tumors from patients that were initially sensitive to chemotherapy and had longer progression-free interval compared with tumors from patients that were resistant to primary chemotherapy. Notably, deletion or downregulation of the lipid transporter LRP1B emerged as a significant correlate of acquired resistance in our analysis. Functional studies showed that reducing LRP1B expression was sufficient to reduce the sensitivity of HGSC cell lines to liposomal doxorubicin, but not to doxorubicin, whereas LRP1B overexpression was sufficient to increase sensitivity to liposomal doxorubicin. Together, our findings underscore the large degree of variation in DNA copy number in spatially and temporally separated tumors in HGSC patients, and they define LRP1B as a potential contributor to the emergence of chemotherapy resistance in these patients. Cancer Res 72(16) 4060–73. ©2012 AACR.
Publisher: Wiley
Date: 10-2021
DOI: 10.1002/CJP2.243
Abstract: The World Health Organization endorses molecular subclassification of endometrial endometrioid carcinomas (EECs). Our objectives were to test the sensitivity of tumor morphology in capturing p53 abnormal (p53abn) cases and to model the impact of p53abn on changes to ESGO/ESTRO/ESP (European Society of Gynaecological Oncology/European Society for Radiotherapy and Oncology/European Society of Pathology) risk stratification. A total of 292 consecutive endometrial carcinoma resections received at Foothills Medical Centre, Calgary, Canada (2019–2021) were retrieved and assigned to ESGO risk groups with and without p53 status. Three pathologists reviewed the representative H& E‐stained slides, predicted the p53 status, and indicated whether p53 immunohistochemistry (IHC) would be ordered. Population‐based survival for endometrial carcinomas diagnosed during 2008–2016 in Alberta was obtained from the Alberta Cancer Registry. The cohort consisted mostly of grade 1/2 endometrioid carcinomas (EEC1/2 N = 218, 74.6%). One hundred and fifty‐two EEC1/2 (52.1% overall) were stage IA and 147 (50.3%) were low risk by ESGO. The overall prevalence of p53abn and subclonal p53 was 14.5 and 8.3%, respectively. The average sensitivity of predicting p53abn among observers was 83.6%. Observers requested p53 IHC for 39.4% with 98.5% sensitivity to detect p53abn (99.6% negative predictive value). Nuclear features including smudged chromatin, pleomorphism, atypical mitoses, and tumor giant cells accurately predicted p53abn. In 7/292 (2.4%), p53abn upgraded ESGO risk groups (2 to intermediate risk, 5 to high risk). EEC1/2/stage IA patients had an excellent disease‐specific 5‐year survival of 98.5%. Pathologists can select cases for p53 testing with high sensitivity and low risk of false negativity. Molecular characterization of endometrial carcinomas has great potential to refine ESGO risk classification for a small subset but offers little value for approximately half of endometrial carcinomas, namely, EEC1/2/stage IA cases.
Publisher: American Association for Cancer Research (AACR)
Date: 13-07-2023
DOI: 10.1158/1078-0432.23676035.V1
Abstract: Supplementary Figures S1-S4
Publisher: Springer Science and Business Media LLC
Date: 08-01-2019
DOI: 10.1038/S41419-018-1276-4
Abstract: Osteosarcoma is a malignant bone sarcoma characterized by extensive genomic disruption and a propensity for metastatic spread. Osteoid production suggests a close relationship with normal osteoblasts, and the latter are the presumptive cell of origin of this disease. The HACE1 gene, localized to human chromosome 6q21, encodes the HACE1 HECT E3 ligase, a tumor suppressor in erse tumors that acts in part by targeting the activated form of RAC1 GTPase for proteasomal degradation. Disruption or loss of 6q21 is relatively common in osteosarcomas, and Hace1−/−/Tp53 +/ − mice frequently develop osteosarcomas, in contrast to Tp53 +/− mice, which do not. This suggests an unexplored link between HACE1 loss and osteosarcoma. Here we compared HACE1 expression in normal osteoblasts and osteosarcoma cell lines in vitro by western blotting and quantitative RT-PCR, and in human osteosarcoma specimens by immunohistochemistry. Both HACE1 transcript and protein levels were reduced in osteosarcoma compared to osteoblasts in vitro. Reduced HACE1 expression in osteosarcoma tumors was observed in 76% of cases and associated with high-grade lesions. Further, clonally derived pairs of high and low metastatic osteosarcoma cell lines showed significant downregulation in the high compared to corresponding low metastatic cells. Ectopic expression of HACE1 markedly inhibited anchorage-independent growth and cell motility of HACE1 osteosarcoma cell lines, and was associated with reduced RAC1 activation and decreased reactive oxygen species (ROS). Finally, HACE1 overexpression blocked osteosarcoma xenograft growth and dramatically reduced pulmonary metastases. These findings point to a potential tumor suppressor function for HACE1 in osteosarcoma.
Publisher: Springer Science and Business Media LLC
Date: 19-05-2015
Publisher: Elsevier BV
Date: 09-2020
Publisher: American Association for Cancer Research (AACR)
Date: 13-07-2023
DOI: 10.1158/1078-0432.C.6740546.V1
Abstract: AbstractPurpose: Endometrioid ovarian carcinoma (ENOC) is the second most-common type of ovarian carcinoma, comprising 10%–20% of cases. Recently, the study of ENOC has benefitted from comparisons to endometrial carcinomas including defining ENOC with four prognostic molecular subtypes. Each subtype suggests differential mechanisms of progression, although tumor-initiating events remain elusive. There is evidence that the ovarian microenvironment may be critical to early lesion establishment and progression. However, while immune infiltrates have been well studied in high-grade serous ovarian carcinoma, studies in ENOC are limited. Experimental Design: We report on 210 ENOC, with clinical follow-up and molecular subtype annotation. Using multiplex IHC and immunofluorescence, we examine the prevalence of T-cell lineage, B-cell lineage, macrophages, and populations with programmed cell death protein 1 or programmed death-ligand 1 across subtypes of ENOC. Results: Immune cell infiltrates in tumor epithelium and stroma showed higher densities in ENOC subtypes with known high mutation burden ( i POLE /i mut and MMRd). While molecular subtypes were prognostically significant, immune infiltrates were not (overall survival i P /i 0.2). Analysis by molecular subtype revealed that immune cell density was prognostically significant in only the i no specific molecular profile /i (NSMP) subtype, where immune infiltrates lacking B cells (TIL sub B minus /sub ) had inferior outcome (disease-specific survival: HR, 4.0 95% confidence interval, 1.1–14.7 i P /i 0.05). Similar to endometrial carcinomas, molecular subtype stratification was generally superior to immune response in predicting outcomes. Conclusions: Subtype stratification is critical for better understanding of ENOC, in particular the distribution and prognostic significance of immune cell infiltrates. The role of B cells in the immune response within NSMP tumors warrants further study. /
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.C.6532976
Abstract: AbstractPurpose: To identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes. Experimental Design: We profiled 421 primary CCOCs that passed quality control using a targeted deep sequencing panel of 163 putative CCOC driver genes and whole transcriptome sequencing of 211 of these tumors. Molecularly defined subgroups were identified and tested for association with clinical characteristics and overall survival. Results: We detected a putative somatic driver mutation in at least one candidate gene in 95% (401/421) of CCOC tumors including i ARID1A /i (in 49% of tumors), i PIK3CA /i (49%), i TERT /i (20%), and i TP53 /i (16%). Clustering of cancer driver mutations and RNA expression converged upon two distinct subclasses of CCOC. The first was dominated by i ARID1A /i -mutated tumors with enriched expression of canonical CCOC genes and markers of platinum resistance the second was largely comprised of tumors with i TP53 /i mutations and enriched for the expression of genes involved in extracellular matrix organization and mesenchymal differentiation. Compared with the i ARID1A /i -mutated group, women with i TP53 /i -mutated tumors were more likely to have advanced-stage disease, no antecedent history of endometriosis, and poorer survival, driven by their advanced stage at presentation. In women with i ARID1A /i -mutated tumors, there was a trend toward a lower rate of response to first-line platinum-based therapy. Conclusions: Our study suggests that CCOC consists of two distinct molecular subclasses with distinct clinical presentation and outcomes, with potential relevance to both traditional and experimental therapy responsiveness. i a href="lincancerres/article/doi/10.1158/1078-0432.CCR-22-2365" target="_blank" See related commentary by Lheureux, p. 4838 /a /i /
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: Wiley
Date: 06-08-2013
DOI: 10.1002/PATH.4230
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488654.V1
Abstract: Supplementary Figures S1-S13
Publisher: Elsevier BV
Date: 12-2017
DOI: 10.1016/J.YGYNO.2017.09.032
Abstract: Endometrioid (ENOC) and clear cell ovarian carcinoma (CCOC) share a common precursor lesion, endometriosis, hence the designation endometriosis associated ovarian cancers (EAOC). Long interspersed nuclear element 1 (LINE-1 or L1), is a family of mobile genetic elements activated in many cancers capable of moving neighboring DNA through 3' transductions. Here we investigated the involvement of specific L1-mediated transductions in EAOCs. Through whole genome sequencing, we identified active L1-mediated transductions originating within the TTC28 gene in 34% (10/29) of ENOC and 31% (11/35) of CCOC cases. We used PCR and capillary sequencing to assess the presence of specific TTC28-L1 transductions in formalin-fixed paraffin-embedded (FFPE) blocks from six different anatomical sites (five tumors and one normal control) for four ENOC and three CCOC cases, and compared the results to the presence of single nucleotide variations (SNVs)/frame shift (fs) mutations detected using multiplex PCR and next generation sequencing. TTC28-L1 mediated transductions were identified in at least three tumor s lings in all cases, and were present in all five tumor s lings in 5/7 (71%) cases. In these cases, KRAS, PIK3CA, CTNNB1, ARID1A, and PTEN mutations were found across all tumor sites while other selected SNV/fs mutations of unknown significance were present at varying allelic frequencies. The TTC28-L1 transductions along with classical driver mutations were near ubiquitous across the tumors, suggesting that L1 activation likely occurred early in the development of EAOCs. TTC28-L1 transductions could potentially be used to determine clonal relationships and to track ovarian cancer progression.
Publisher: The American Association of Immunologists
Date: 05-2022
DOI: 10.4049/JIMMUNOL.208.SUPP.179.04
Abstract: Mucinous ovarian carcinoma (MOC) is a rare histotype of ovarian cancer. Women with advanced disease (FIGO stage III/IV) have very poor outcomes, with 5-year survival of & %. Little is known about the anti-tumor immune response in MOC, limiting potential immunotherapeutic options for patients. Immune data from 3 platforms were analysed. A NanoString mRNA expression panel with 39 immune-related genes (n=60 MOC, n=4198 other ovarian histotypes), a NanoString mRNA plexset with PD-1, PD-L1 (n=241 MOC, n=115 upper and lower gastrointestinal (GI) cancers), and 2 multicolor immunofluorescence (mcIF) panels (n=121 MOC) for CD68, PD-L1, PD-1, CD8 and FOXP3. Data overlapped all platforms for 22 MOC. Immune marker expression by ovarian cancer histotype was measured. Uni- and multivariable Cox Proportional Hazards assessed overall survival (OS) within MOC. Hierarchical clustering looked for subgroups of patients based on co-expression of immune genes. Compared to more common high-grade serous ovarian cancer (HGSC) and GI cancers, MOC were less immunologically active. High IGHM expression was associated with poorer OS (HR 1.31 (95% CI 1.02–1.69), p=0.033). High tumor densities of FOXP3 and PD-1 positive cells conferred poorer OS in a model with age, stage and site however, these and PD-L1 and CD68 were associated with grade. The 39 gene NanoString and mcIF datasets revealed 4 clusters, roughly translating to immune cold, moderate and hot (groups 3,4). mcIF analysis revealed a subset with PD-L1 expression in the absence of T-regulatory cell infiltrates. This study provides novel insights into the MOC immune landscape. Despite relatively low immune activity overall, immunotherapy could be explored for a subset of patients with MOC. Supported by NSW Ministry of Health and UNSW Sydney, through the NSW Health PhD Scholarship Program 2017-2022 Translational Cancer Research Network top-up scholarship 2021
Publisher: Elsevier BV
Date: 04-2018
DOI: 10.1038/MODPATHOL.2017.159
Abstract: A previous multicenter study of 67 cases of Stage I/II tubo-ovarian high-grade serous carcinoma with complete tubal s ling identified 7 cases in which there were only two disease sites, comprising tumor involving opposite adnexa with no extra-adnexal involvement. This study aimed to determine whether such low-stage extrauterine high-grade serous carcinomas with only two sites of involvement, located on opposite adnexa, have identical or different TP53 mutations in order to investigate their clonal relationship. DNA extracted from both sites of involvement was subjected to TP53 sequencing (n=6) or sequencing of one site and mutation confirmation by droplet digital PCR for the other site (n=1). Of the 7 cases analyzed, 1 case had unilateral serous tubal intraepithelial carcinoma with contralateral ovarian high-grade serous carcinoma, 3 had tubal high-grade serous carcinomas (±serous tubal intraepithelial carcinoma) with contralateral ovarian high-grade serous carcinoma, 2 had bilateral ovarian high-grade serous carcinomas with normal tubes, and 1 had bilateral fallopian tube high-grade serous carcinoma with normal ovaries. All 7 cases showed identical TP53 mutations in tumor from both disease sites. Therefore, these rare cases of high-grade serous carcinoma confined to opposite adnexa all show clonal identity between the two sites of involvement, suggesting unifocal origin and metastasis rather than multifocal origin. Our results suggest that serous tubal intraepithelial carcinoma or adnexal high-grade serous carcinoma can metastasize to the contralateral adnexa without peritoneal involvement. Given the clonal relationship between the two sites, such cases should be considered stage II, with stage I reserved for cases with unilateral and unifocal adnexal involvement. Furthermore, serous tubal intraepithelial carcinoma without invasion should be taken to constitute a disease site for staging purposes.
Publisher: Springer Science and Business Media LLC
Date: 09-01-2023
Publisher: Wiley
Date: 06-01-2017
DOI: 10.1002/CNCR.30496
Abstract: Classification of endometrial carcinomas (ECs) by morphologic features is irreproducible and imperfectly reflects tumor biology. The authors developed the Proactive Molecular Risk Classifier for Endometrial Cancer (ProMisE), a molecular classification system based on The Cancer Genome Atlas genomic subgroups, and sought to confirm both feasibility and prognostic ability in a new, large cohort of ECs. Immunohistochemistry (IHC) for the presence or absence of mismatch repair (MMR) proteins (to identify MMR deficiency [MMR-D]), sequencing for polymerase-ɛ (POLE) exonuclease domain mutations (POLE EDMs), and IHC for tumor protein 53 (p53) (wild type vs null/missense mutations p53 wt and p53 abn, respectively) were performed on 319 new EC s les. Subgroups were characterized and assessed relative to outcomes. The prognostic ability of ProMisE was compared with that of current risk-stratification systems (European Society of Medical Oncology [ESMO]). ProMisE decision-tree classification achieved categorization of all cases and identified 4 prognostic subgroups with distinct overall, disease-specific, and progression-free survival (P < .001). Tumors with POLE EDMs had the most favorable prognosis, and those with p53 abn the worst prognosis, and separation of the 2 middle survival curves (p53 wt and MMR-D) was observed. There were no significant differences in survival between the ESMO low-risk and intermediate-risk groups. ProMisE improved the ability to discriminate outcomes compared with ESMO risk stratification. There was substantial overlap (89%) between the p53 abn and high-risk ESMO subgroups but, otherwise, there were no predictable associations between molecular and ESMO risk groups. Molecular classification of ECs can be achieved using clinically applicable methods and provides independent prognostic information beyond established clinicopathologic risk factors available at diagnosis. Consistent, biologically relevant categorization enables stratification for clinical trials and/or targeted therapy, identification of women who are at increased risk of having Lynch syndrome, and may guide clinical management. Cancer 2017 :802-13. © 2016 American Cancer Society.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.C.6534651.V1
Abstract: AbstractBackground: Better understanding of prognostic factors in tubo-ovarian high-grade serous carcinoma (HGSC) is critical, as diagnosis confers an aggressive disease course. Variation in tumor DNA methylation shows promise predicting outcome, yet prior studies were largely platform-specific and unable to evaluate multiple molecular features. Methods: We analyzed genome-wide DNA methylation in 1,040 frozen HGSC, including 325 previously reported upon, seeking a multi-platform quantitative methylation signature that we evaluated in relation to clinical features, tumor characteristics, time to recurrence/death, extent of CD8 sup + /sup tumor-infiltrating lymphocytes (TIL), gene expression molecular subtypes, and gene expression of the ATP-binding cassette transporter TAP1. Results: Methylation signature was associated with shorter time to recurrence, independent of clinical factors ( i N /i = 715 new set, hazard ratio (HR), 1.65 95% confidence interval (CI), 1.10–2.46 i P /i = 0.015 i N /i = 325 published set HR, 2.87 95% CI, 2.17–3.81 i P /i = 2.2 × 10 sup −13 /sup ) and remained prognostic after adjustment for gene expression molecular subtype and TAP1 expression ( i N /i = 599 HR, 2.22 95% CI, 1.66–2.95 i P /i = 4.1 × 10 sup −8 /sup ). Methylation signature was inversely related to CD8 sup + /sup TIL levels ( i P /i = 2.4 × 10 sup −7 /sup ) and TAP1 expression ( i P /i = 0.0011) and was associated with gene expression molecular subtype ( i P /i = 5.9 × 10 sup −4 /sup ) in covariate-adjusted analysis. Conclusions: Multi-center analysis identified a novel quantitative tumor methylation signature of HGSC applicable to numerous commercially available platforms indicative of shorter time to recurrence/death, adjusting for other factors. Along with immune cell composition analysis, these results suggest a role for DNA methylation in the immunosuppressive microenvironment. Impact: This work aids in identification of targetable epigenome processes and stratification of patients for whom tailored treatment may be most beneficial. /
Publisher: American Society of Clinical Oncology (ASCO)
Date: 20-05-2018
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.C.6534651
Abstract: AbstractBackground: Better understanding of prognostic factors in tubo-ovarian high-grade serous carcinoma (HGSC) is critical, as diagnosis confers an aggressive disease course. Variation in tumor DNA methylation shows promise predicting outcome, yet prior studies were largely platform-specific and unable to evaluate multiple molecular features. Methods: We analyzed genome-wide DNA methylation in 1,040 frozen HGSC, including 325 previously reported upon, seeking a multi-platform quantitative methylation signature that we evaluated in relation to clinical features, tumor characteristics, time to recurrence/death, extent of CD8 sup + /sup tumor-infiltrating lymphocytes (TIL), gene expression molecular subtypes, and gene expression of the ATP-binding cassette transporter TAP1. Results: Methylation signature was associated with shorter time to recurrence, independent of clinical factors ( i N /i = 715 new set, hazard ratio (HR), 1.65 95% confidence interval (CI), 1.10–2.46 i P /i = 0.015 i N /i = 325 published set HR, 2.87 95% CI, 2.17–3.81 i P /i = 2.2 × 10 sup −13 /sup ) and remained prognostic after adjustment for gene expression molecular subtype and TAP1 expression ( i N /i = 599 HR, 2.22 95% CI, 1.66–2.95 i P /i = 4.1 × 10 sup −8 /sup ). Methylation signature was inversely related to CD8 sup + /sup TIL levels ( i P /i = 2.4 × 10 sup −7 /sup ) and TAP1 expression ( i P /i = 0.0011) and was associated with gene expression molecular subtype ( i P /i = 5.9 × 10 sup −4 /sup ) in covariate-adjusted analysis. Conclusions: Multi-center analysis identified a novel quantitative tumor methylation signature of HGSC applicable to numerous commercially available platforms indicative of shorter time to recurrence/death, adjusting for other factors. Along with immune cell composition analysis, these results suggest a role for DNA methylation in the immunosuppressive microenvironment. Impact: This work aids in identification of targetable epigenome processes and stratification of patients for whom tailored treatment may be most beneficial. /
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494843.V1
Abstract: Supplementary Table 6: Multivariate Modeling of Time to Recurrence/Death Among Studies with Gene Expression Data
Publisher: Springer Science and Business Media LLC
Date: 30-10-2014
DOI: 10.1038/BJC.2014.567
Publisher: Elsevier BV
Date: 12-2019
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494849.V1
Abstract: Supplementary Table 4: Multivariate Modeling of Methylation Signature Among Studies with Multiple Datatypes
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494861.V1
Abstract: Supplementary Table 1: Characteristics of Study Participants with High Grade Serous Tubo-Ovarian Carcinoma by Contributing Study
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22489535.V1
Abstract: Supplementary Figure from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes
Publisher: Elsevier BV
Date: 09-2022
DOI: 10.1016/J.FERTNSTERT.2022.05.030
Abstract: To investigate the heterogeneity of somatic cancer-driver mutations within patients and across endometriosis types. A single-center cohort, retrospective study. Tertiary specialist-care center at a university hospital. Patients with surgically and histologically confirmed endometriosis of at least 2 anatomically distinct types (ovarian, deep infiltrating, and superficial). None. Specimens were analyzed for the presence or absence of somatic cancer-driver mutations using targeted panel sequencing with orthogonal validation using droplet digital polymerase chain reaction and mutation-surrogate immunohistochemistry. It was found that 13 of 27 patients had informative somatic driver mutations in endometriosis lesions of these 13 patients, 9 had identical mutations across distinct lesions. Endometriomas showed a higher mutational complexity, with functionally redundant driver mutations in the same gene and within the same lesions. Our data are consistent with clonality across endometriosis lesions, regardless of subtype. Further, the finding of redundancy in mutations within the same gene and lesions is consistent with endometriosis representing an oligoclonal disease with dissemination likely to consist of multiple epithelial clones traveling together. This suggests that the current anatomically defined classification of endometriosis does not fully recognize the etiology of the disease. A novel classification should consider genomic and other molecular features to promote personalized endometriosis diagnosis and care.
Publisher: Wiley
Date: 21-09-2014
DOI: 10.1002/CJP2.109
Publisher: Elsevier BV
Date: 2021
Publisher: Cold Spring Harbor Laboratory
Date: 21-09-2021
DOI: 10.1101/2021.09.16.21262993
Abstract: ARID1A (BAF250a) is a component of the SWI/SNF chromatin modifying complex, plays an important tumor suppressor role, and is considered prognostic in several malignancies. However, in ovarian carcinomas there are contradictory reports on its relationship to outcome, immune response, and correlation with clinicopathological features. We assembled a series of 1623 endometriosis-associated ovarian carcinomas, including 1078 endometrioid (ENOC) and 545 clear cell (CCOC) ovarian carcinomas through combining resources of the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Canadian Ovarian Unified Experimental Resource (COEUR), local, and collaborative networks. Validated immunohistochemical surrogate assays for ARID1A mutations were applied to all s les. We investigated associations between ARID1A loss/mutation, clinical features, outcome, CD8+ tumor-infiltrating lymphocytes (CD8+ TIL), and DNA mismatch repair deficiency (MMRd). ARID1A loss was observed in 42% of CCOC and 25% of ENOC. We found no associations between ARID1A loss and outcomes, stage, age, or CD8+ TIL status in CCOC. Similarly, we found no association with outcome or stage in endometrioid cases. In ENOC, ARID1A loss was more prevalent in younger patients (p=0.012), and associated with MMRd (p .001), and presence of CD8+ TIL (p=0.008). Consistent with MMRd being causative of ARID1A mutations, in a subset of ENOC we also observed an association between ARID1A loss-of-function mutation as a result of small indels (p=0.011, vs. single nucleotide variants). In ENOC, the association between ARID1A loss, CD8+ TIL, and age, appears confounded by MMRd status. Although this observation does not explicitly rule out a role for ARID1A influence on CD8+ TIL infiltration in ENOC, given current knowledge regarding MMRd, it seems more likely that effects are dominated by the hypermutation phenotype. This large dataset with consistently applied biomarker assessment now provides a benchmark for the prevalence of ARID1A loss-of-function mutations in endometriosis-associated ovarian cancers and brings clarity to the prognostic significance.
Publisher: American Association for Cancer Research (AACR)
Date: 15-01-2016
DOI: 10.1158/1557-3265.OVCA15-B08
Abstract: While the genomics of high-grade serous carcinoma are well-studied in large international consortia, the less common subtypes have been neglected. We have sought to rectify this gap by analyzing international collections of low-grade serous and mucinous ovarian carcinomas and their putative benign and borderline precursors. Exome sequencing and copy number analysis of low-grade serous carcinomas (n=9) and serous borderline tumours (n=13) and targeted sequencing and copy number analysis in additional carcinomas (n=10) and borderline tumours (n=44) identified recurrent mutations in novel drivers such as EIF1AX and USP9X, as well as the known drivers KRAS, BRAF and NRAS. Copy number changes including 9p and 1p losses were significantly associated with progression from borderline to carcinoma. Exome and targeted sequencing analysis of mucinous carcinomas (GAMuT study) found a surprisingly high proportion (~50%) with TP53 mutations, and mutations in new drivers like RNF43 and ELF3. Despite similarities in early RAS/RAF pathway oncogenic drivers and CDKN2A disruption, the genetics of these two subtypes are otherwise distinct, suggesting differing etiologies and selective pressures. We also present here the first whole-genome sequencing analysis of a high-grade mucinous ovarian carcinoma collected from multiple sites at autopsy (CASCADE study). The patient, aged just 41 when diagnosed with Stage I mucinous ovarian carcinoma, had a 26-month progression-free interval, including normal CA125 and CA19-9 measurements at 21 months. The primary tumor was mostly borderline in appearance, with only a small focus of carcinoma. At autopsy, the carcinoma was widespread in the body, and whole-genome sequencing data was obtained from deposits in the omentum, iliac lymph node, para-aortic lymph node and upper diaphragm. These data were compared to the primary ovarian tumor and nine other sites s led at autopsy. Citation Format: Kylie L. Gorringe, Matthew Wakefield, Sally M. Hunter, Georgina L. Ryland, Dane Cheasley, Michael S. Anglesio, Michael Christie, Raghwa Sharma, Antill Yoland, Simone M. Rowley, Jason Li, Blake Gilks, Prue E. Allan, Andrew N. Stephens, Sumi Ananda, Jan Pyman, Martin Koebel, Jessica McAlpine, Charlie Gourley, David G. Huntsman, Anna deFazio, David DL Bowtell, Ian G. C bell, Clare Scott. Genomics analyses of less common epithelial ovarian cancer subtypes. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities Oct 17-20, 2015 Orlando, FL. Philadelphia (PA): AACR Clin Cancer Res 2016 (2 Suppl):Abstract nr B08.
Publisher: Oxford University Press (OUP)
Date: 14-07-2004
DOI: 10.1093/HMG/DDH215
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22489526.V1
Abstract: Supplementary Figure from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes
Publisher: Wiley
Date: 07-2018
DOI: 10.1002/CJP2.108
Publisher: American Association for Cancer Research (AACR)
Date: 04-0002
DOI: 10.1158/1078-0432.22489541.V1
Abstract: Supplementary Figure from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes
Publisher: BMJ Publishing Group Ltd
Date: 11-2019
Publisher: American Association for Cancer Research (AACR)
Date: 04-2011
DOI: 10.1158/1538-7445.AM2011-4289
Abstract: Ovarian cancer cell lines provide an important tool in exploring disease phenotypes and biology. Within the spectrum of ovarian epithelial cancers at least five histologically distinguishable unique diseases exist: high-grade serous, clear cell, endometrioid, mucinous, and low-grade serous. While sharing a common site of presentation, these ovarian cancer types exhibit distinct genomic signatures, clinical characteristics and treatment responses. Thus, the critical interpretation of the results of cell based experiments performed in in-vitro and in-vivo model systems of ovarian cancer first requires characterization of the disease subtype each model represents. Our group has recently used a minimal panel of nine immunohistochemical (IHC) markers, termed “COSP” (Calculator for Ovarian carcinoma Subtype Prediction), to predict each ovarian cancer type. Application of COSP has suggested that as many as 19% of primary ovarian cancer s les may be misclassified prior to an expert review. Commonly used cell lines are rarely classified into ovarian cancer types, confounding interpretation of results and potentially delaying transition of basic research to clinically relevant application. We now apply COSP for typing commonly used ovarian cancer cell lines, as well as in-house derived xenografts, and primary culture models. The COSP immuno-predictive tool is combined with molecular and mutational data to support each cell line's subtype prediction while primary tumour types are compared to their derivative cell lines. We now present an extensive panel of accurately classified ovarian cancer cell lines to facilitate disease specific analysis of the biology of ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research 2011 Apr 2-6 Orlando, FL. Philadelphia (PA): AACR Cancer Res 2011 (8 Suppl):Abstract nr 4289. doi:10.1158/1538-7445.AM2011-4289
Publisher: Public Library of Science (PLoS)
Date: 13-04-2011
Publisher: © 2020. Thieme. All rights reserved.
Date: 10-2020
Publisher: Wiley
Date: 14-10-2022
DOI: 10.1002/PATH.6006
Abstract: Clear cell ovarian carcinoma (CCOC) is the second most common subtype of epithelial ovarian carcinoma. Late‐stage CCOC is not responsive to gold‐standard chemotherapy and results in suboptimal outcomes for patients. In‐depth molecular insight is urgently needed to stratify the disease and drive therapeutic development. We conducted global proteomics for 192 cases of CCOC and compared these with other epithelial ovarian carcinoma subtypes. Our results showed distinct proteomic differences in CCOC compared with other epithelial ovarian cancer subtypes including alterations in lipid and purine metabolism pathways. Furthermore, we report potential clinically significant proteomic subgroups within CCOC, suggesting the biologic plausibility of stratified treatment for this cancer. Taken together, our results provide a comprehensive understanding of the CCOC proteomic landscape to facilitate future understanding and research of this disease. © 2022 The Pathological Society of Great Britain and Ireland.
Publisher: American Association for Cancer Research (AACR)
Date: 03-2017
Publisher: American Association for Cancer Research (AACR)
Date: 04-2011
DOI: 10.1158/1538-7445.AM2011-924
Abstract: Somatic mutations in PPP2R1A have been found at low frequencies in lung, breast cancer and melanoma and most recently through whole-exome sequencing in ovarian clear cell carcinoma. We examined whole-transcriptome sequencing data from ovarian clear cell carcinomas (OCCC) and identified a cluster of mutations in exon 5 of PPP2R1A. The protein phosphatase 2, regulatory subunit A, alpha (PPP2R1A, or PR65a) gene is the scaffolding subunit of the serine-threonine protein phosphatase 2A (PP2A) holoenzyme. PP2A is involved in growth and survival cellular pathways, and has been suggested to play a role as a tumor suppressor gene in some human cancers. The PP2A holoenzyme is made up of the A scaffolding subunit (isoforms α and β), the C catalytic subunit (isoforms α and β and multiple regulatory B subunits also with many isoforms. PPP2R1A is made up of 15 HEAT domains forming a horseshoe-like multi-helical structure that interacts with both the C and B subunits of PP2A. We have examined the frequency of PPP2R1A mutations across the spectrum of both ovarian and endometrial carcinomas. DNA from endometrial and ovarian subtypes was sequenced across exons 5 and 6 of PPP2R1A using PCR based Sanger sequencing, and somatic mutation status was verified by sequencing matched normal DNA. Targeted sequencing of PPP2R1A revealed somatic missense mutations in 36.7% (18 of 49) of endometrial high-grade serous primary tumors. This high frequency of mutations has not previously been reported and suggests a strong link to the pathology of this disease subtype. Mutations were also identified at a lower frequency of 4.9% (3 of 61) in endometrial endometrioid carcinomas, and ovarian primary tumors at 11.6% (5 of 43) in endometrioid, 4% (2 of 50) in clear cell, 0% (0 of 50) in high-grade serous and 0% (0 of 12) of low-grade serous carcinomas. These nucleotide missense mutations result in the modification of amino acid residues that are highly conserved within the intrarepeat helix of the HEAT domains of PPP2R1A. Previous mutation based biochemical studies have identified these amino acid residues as important in the interaction between the regulatory B subunit and PPP2R1A. This indicates a strong functional role of PPP2R1A in stabilization of the PP2A complex, and a probable role in cellular tumorgenesis. A closer survey of mutations found within PPP2R1A and the PP2A complex, as well as functional characterization of this pathway, may pave the way to defining biologically relevant pathways and targets within endometrial carcinomas, ultimately leading to improved patient-targeted therapies and survival. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research 2011 Apr 2-6 Orlando, FL. Philadelphia (PA): AACR Cancer Res 2011 (8 Suppl):Abstract nr 924. doi:10.1158/1538-7445.AM2011-924
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22489520.V1
Abstract: Supplementary Figure from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes
Publisher: American Association for Cancer Research (AACR)
Date: 13-07-2023
DOI: 10.1158/1078-0432.23676032
Abstract: Supplementary Tables S1-S5
Publisher: American Association for Cancer Research (AACR)
Date: 13-07-2023
DOI: 10.1158/1078-0432.23676035
Abstract: Supplementary Figures S1-S4
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22489553.V1
Abstract: Supplementary Data from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494867.V1
Abstract: Supplementary Figure 4: Correlations between Methylation at CpG Sites and TAP1 mRNA Expression
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22476891
Abstract: Package with all supplemental figures and tables
Publisher: Springer Science and Business Media LLC
Date: 22-02-2014
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22489547.V1
Abstract: Supplementary Figure from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes
Publisher: Elsevier BV
Date: 11-2020
Publisher: American Association for Cancer Research (AACR)
Date: 10-2014
DOI: 10.1158/1538-7445.AM2014-544
Abstract: Alternation in genes associated with microRNA (miRNA) biogenesis pathway may lead to miRNA dysregulation, and is implicated in a variety of human malignancies. Previously our group identified recurrent somatic “hotspot” mutations (E1705, D1709, D1810, E1813) in a critical miRNA-processing gene, DICER1, in rare sex cord-stromal tumors. During miRNA biogenesis, the two RNase III domains of DICER1 form an intramolecular dimer, which leads to the cleavage of the precursor miRNA (pre-miRNA) hairpin and generate mature 5p and 3p miRNAs from 5’ and 3’ arms of the precursor hairpin respectively. Studies have shown that the hotspot mutations in the RNase IIIb metal binding domain could impair DICER1's ability to generate mature 5p miRNAs, leading to global loss of 5p miRNAs. Recently, in collaboration with The Cancer Genome Atlas (TCGA), we identified DICER1 hotspot mutations in a small subset of endometrial cancer from TCGA cohort (6/248) as well as our own tumor bank (6/307), suggesting disruption of DICER1 is implicated in a common malignancy. We also found an additional recurrent mutation G1809R and demonstrated that it has similar detrimental effects on miRNA biogenesis as hotspot mutations through deep sequencing and realtime PCR. Using Illumina Miseq targeted resequencing and Sanger sequencing, we observed biallelic DICER1 mutations in RNase IIIb domain in some but not all cases. miRNA deep sequencing confirmed that 5p miRNAs are decreased in both cell line models and endometrial tumors with hotspot mutations. Bioinformatic analysis of RNA sequencing profiles from TCGA dataset predicted hotspot DICER1 mutations to have greater functional impact than non-hotspot DICER1 mutations on gene expression. The oncogenic properties of DICER1 hotspot mutations are currently under investigation. Citation Format: Jiamin Chen, Yemin Wang, Melissa McConechy, Michael Anglesio, Janine Senz, Winnie Yang, Jamie Rosner, Andy Chu, Grace Cheng, Gregg Morin, David Huntsman. Recurrent DICER1 hotspot mutations in endometrial cancer and their impact on microRNA biogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research 2014 Apr 5-9 San Diego, CA. Philadelphia (PA): AACR Cancer Res 2014 (19 Suppl):Abstract nr 544. doi:10.1158/1538-7445.AM2014-544
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494873.V1
Abstract: Supplementary Figure 2: No Association between Methylation Signature and Baseline Clinical Factors
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: Wiley
Date: 22-03-2023
DOI: 10.1002/CJP2.311
Abstract: Our objective was to test whether p53 expression status is associated with survival for women diagnosed with the most common ovarian carcinoma histotypes (high‐grade serous carcinoma [HGSC], endometrioid carcinoma [EC], and clear cell carcinoma [CCC]) using a large multi‐institutional cohort from the Ovarian Tumor Tissue Analysis (OTTA) consortium. p53 expression was assessed on 6,678 cases represented on tissue microarrays from 25 participating OTTA study sites using a previously validated immunohistochemical (IHC) assay as a surrogate for the presence and functional effect of TP53 mutations. Three abnormal expression patterns (overexpression, complete absence, and cytoplasmic) and the normal (wild type) pattern were recorded. Survival analyses were performed by histotype. The frequency of abnormal p53 expression was 93.4% (4,630/4,957) in HGSC compared to 11.9% (116/973) in EC and 11.5% (86/748) in CCC. In HGSC, there were no differences in overall survival across the abnormal p53 expression patterns. However, in EC and CCC, abnormal p53 expression was associated with an increased risk of death for women diagnosed with EC in multivariate analysis compared to normal p53 as the reference (hazard ratio [HR] = 2.18, 95% confidence interval [CI] 1.36–3.47, p = 0.0011) and with CCC (HR = 1.57, 95% CI 1.11–2.22, p = 0.012). Abnormal p53 was also associated with shorter overall survival in The International Federation of Gynecology and Obstetrics stage I/II EC and CCC. Our study provides further evidence that functional groups of TP53 mutations assessed by abnormal surrogate p53 IHC patterns are not associated with survival in HGSC. In contrast, we validate that abnormal p53 IHC is a strong independent prognostic marker for EC and demonstrate for the first time an independent prognostic association of abnormal p53 IHC with overall survival in patients with CCC.
Publisher: American Association for Cancer Research (AACR)
Date: 15-10-2020
DOI: 10.1158/1078-0432.CCR-20-0103
Abstract: Gene expression–based molecular subtypes of high-grade serous tubo-ovarian cancer (HGSOC), demonstrated across multiple studies, may provide improved stratification for molecularly targeted trials. However, evaluation of clinical utility has been hindered by nonstandardized methods, which are not applicable in a clinical setting. We sought to generate a clinical grade minimal gene set assay for classification of in idual tumor specimens into HGSOC subtypes and confirm previously reported subtype-associated features. Adopting two independent approaches, we derived and internally validated algorithms for subtype prediction using published gene expression data from 1,650 tumors. We applied resulting models to NanoString data on 3,829 HGSOCs from the Ovarian Tumor Tissue Analysis consortium. We further developed, confirmed, and validated a reduced, minimal gene set predictor, with methods suitable for a single-patient setting. Gene expression data were used to derive the predictor of high-grade serous ovarian carcinoma molecular subtype (PrOTYPE) assay. We established a de facto standard as a consensus of two parallel approaches. PrOTYPE subtypes are significantly associated with age, stage, residual disease, tumor-infiltrating lymphocytes, and outcome. The locked-down clinical grade PrOTYPE test includes a model with 55 genes that predicted gene expression subtype with & % accuracy that was maintained in all analytic and biological validations. We validated the PrOTYPE assay following the Institute of Medicine guidelines for the development of omics-based tests. This fully defined and locked-down clinical grade assay will enable trial design with molecular subtype stratification and allow for objective assessment of the predictive value of HGSOC molecular subtypes in precision medicine applications. See related commentary by McMullen et al., p. 5271
Publisher: Informa UK Limited
Date: 2006
Publisher: BMJ
Date: 06-2016
DOI: 10.1097/IGC.0000000000000698
Abstract: Atypical endometriosis (AE) is thought to be a precursor lesion to the ovarian cancer subtypes associated with endometriosis, namely, endometrioid and clear cell carcinomas. ARID1A encodes a nuclear protein (BAF250a) governing chromatin remodeling, and mutations in ARID1A have been found in 30% to 50% of clear cell and endometrioid ovarian cancers. As BAF250a expression loss by immunohistochemistry (IHC) has been documented in the endometriosis precursor lesions closely associated with these ovarian cancers subtypes, our goal was to further study the association between BAF250a expression in cases of AE with and without an associated cancer. Three separate databases were screened for suspected cases of AE. Based on a detailed review of the pathology reports, we selected cases likely to contain AE for slide review. After slide review, tissue blocks were recalled to perform IHC for BAF250a in the associated cancer, AE, or typical endometriosis when present. There were 35 cases of endometriosis-associated cancer and 8 cases of AE not associated with cancer. Atypical endometriosis was found on pathology review in 23 endometriosis-associated cancer cases (66%). In the 35 cancer cases, BAF250a IHC showed loss of expression in 14 cases. Atypical endometriosis was present in 10 of these cases, 6 of which showed BAF250a loss (60%). BAF250a loss was not observed in the 8 cases of AE not associated with cancer or in the contiguous AE of 13 cases, whereby BAF250a expression was retained in the associated cancer. BAF250a loss in AE is consistently associated with the development of BAF250a-negative endometriosis-associated cancers and appears to be an early event in most of these cases. This research provides additional evidence that in the absence of cancer, BAF250a expression should be evaluated as a biomarker of cancer risk in patients diagnosed with AE.
Publisher: American Association for Cancer Research (AACR)
Date: 15-04-2019
DOI: 10.1158/1078-0432.CCR-18-3241
Abstract: Tumors with high mutation load are thought to engender stronger immune responses, which in turn promote prolonged patient survival. To investigate this, we assessed tumor-infiltrating lymphocytes (TILs) and immunosuppressive factors across the 4 molecular subtypes of endometrial cancer, which have characteristic mutation rates ranging from low to ultra-high. A total of 460 endometrial cancers were stratified by ProMisE (Proactive Molecular Risk Classifier in Endometrial cancer) into 4 molecular subtypes: mismatch repair-deficient (MMRd), POLE mutant (POLE), p53 abnormal (p53abn), and p53 wild-type (p53wt). Immune markers (CD3, CD8, CD79a, CD138, PD-1, PD-L1, FoxP3, IDO-1) were quantified by multiplex IHC and tested for associations with ProMisE subtype, survival, and other clinicopathologic parameters. Two major TIL patterns were observed. TILhigh tumors harbored dense T- and B-lineage infiltrates and multiple immunosuppressive features and were common in molecular subtypes associated with high mutation load (MMRd and POLE) however, equally strong responses were seen in significant numbers of p53abn and p53wt tumors, which have characteristically low mutation loads. TILlow tumors were generally devoid of immunologic features and were more prevalent in p53abn and p53wt endometrial cancers, yet were also seen in MMRd and POLE subtypes. In multivariable models involving ProMisE subtype, T-cell markers, and TIL clusters, only ProMisE showed independent prognostic significance. Immune response correlates with endometrial cancer molecular subtype but does not carry independent prognostic significance. Profound variation in immune response is seen across and within endometrial cancer molecular subtypes, suggesting that assessment of immune response rather than molecular subtype may better predict response to immunotherapy. See related commentary by Mullen and Mutch, p. 2366
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.C.6532782
Abstract: AbstractPurpose: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. Experimental Design: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC ( i n /i = 333), mucinous borderline ovarian tumors (MBOT, i n /i = 151), and upper GI ( i n /i = 65) and lower GI tumors ( i n /i = 55). Results: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77 95% confidence interval (CI), 1.04–7.41, i P /i = 0.042]. Increased expression of i THBS2 /i and i TAGLN /i was associated with shorter OS in MOC patients (HR, 1.25 95% CI, 1.04–1.51, i P /i = 0.016) and (HR, 1.21 95% CI, 1.01–1.45, i P /i = 0.043), respectively. i ERBB2 /i (HER2) lification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). Conclusions: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of i THBS2 /i and i TAGLN /i in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC s les clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies. /
Publisher: Elsevier BV
Date: 12-2022
Publisher: Springer Science and Business Media LLC
Date: 18-06-2020
DOI: 10.1038/S41416-020-0900-0
Abstract: PTEN loss is a putative driver in histotypes of ovarian cancer (high-grade serous (HGSOC), endometrioid (ENOC), clear cell (CCOC), mucinous (MOC), low-grade serous (LGSOC)). We aimed to characterise PTEN expression as a biomarker in epithelial ovarian cancer in a large population-based study. Tumours from 5400 patients from a multicentre observational, prospective cohort study of the Ovarian Tumour Tissue Analysis Consortium were used to evaluate associations between immunohistochemical PTEN patterns and overall survival time, age, stage, grade, residual tumour, CD8+ tumour-infiltrating lymphocytes (TIL) counts, expression of oestrogen receptor (ER), progesterone receptor (PR) and androgen receptor (AR) by means of Cox proportional hazard models and generalised Cochran–Mantel–Haenszel tests. Downregulation of cytoplasmic PTEN expression was most frequent in ENOC (most frequently in younger patients p value = 0.0001) and CCOC and was associated with longer overall survival in HGSOC (hazard ratio: 0.78, 95% CI: 0.65–0.94, p value = 0.022). PTEN expression was associated with ER, PR and AR expression ( p values: 0.0008, 0.062 and 0.0002, respectively) in HGSOC and with lower CD8 counts in CCOC ( p value 0.0001). Heterogeneous expression of PTEN was more prevalent in advanced HGSOC ( p value = 0.019) and associated with higher CD8 counts ( p value = 0.0016). PTEN loss is a frequent driver in ovarian carcinoma associating distinctly with expression of hormonal receptors and CD8+ TIL counts in HGSOC and CCOC histotypes.
Publisher: Elsevier BV
Date: 08-2015
Publisher: American Association for Cancer Research (AACR)
Date: 15-01-2016
DOI: 10.1158/1557-3265.OVCA15-PR07
Abstract: Background: Almost half of ovarian endometrioid histotype carcinomas present with concurrent endometrial carcinoma or pre-cancerous lesions. These “synchronous” ovarian and endometrial (SEO) tumors, when organ-confined and low-grade, consistently behave as two independent primary tumors, rather than a tumor-metastasis pair typical of advanced-stage carcinoma. Our study aims to investigate the ancestral relationship between ovarian and endometrial components of SEOs. Methods: We identified a cohort of SEOs and performed targeted, with the Illumina Truseq Custom Amplicon assay, and exome-level, with Nugen Ovation Library System and Agilent SureSelect XT2 capture, library construction followed by massively parallel sequencing on illumina MiSeq or HiSeq. Results: Despite complexities introduced as a result of s ling formalin fixed and paraffin embedded archival specimens we were able to confirm shared identical mutations, and thus a clonal relationship, between ovarian and endometrial tumors in all but one case. Discussion: In simultaneous presentation of cancer of the endometrium and ovary from our series we observed strong evidence of a primary tumor and metastasis relationship. However, the clinical behavior of this series, and SEOs in general, defies the basic tenant of cancer metastasis as a dire prognosis. Curiously similar anomalies, where there is advanced stage yet favorable outcome, occur in other organ systems. We therefore suggest a generalizable process “pseudo-metastasis” through which cells can spread to microenvironment-compatible and physically accessible sites. This restricted metastatic process can occur in cells that lack the full complement of cancer-associated transformation hallmarks required for tissue invasion and hematogenous or lymphatic metastasis. This phenomenon may be an important early step in dissemination of apparent multi-focal benign lesions, pre-malignant lesions, and low-grade carcinomas. This abstract is also presented as Poster B07. Citation Format: Michael S. Anglesio, Yi Kan Wang, Madlen Maassen, Hugo M. Horlings, Ali Bashashati, Blake Gilks, Stefan Kommoss, David G. Huntsman. Synchronous ovarian and endometrial carcinomas: The case for pseudo-metastasis. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: Exploiting Vulnerabilities Oct 17-20, 2015 Orlando, FL. Philadelphia (PA): AACR Clin Cancer Res 2016 (2 Suppl):Abstract nr PR07.
Publisher: BMJ Publishing Group Ltd
Date: 12-2022
Publisher: American Association for Cancer Research (AACR)
Date: 11-07-2022
DOI: 10.1158/1078-0432.CCR-21-3817
Abstract: To identify molecular subclasses of clear cell ovarian carcinoma (CCOC) and assess their impact on clinical presentation and outcomes. We profiled 421 primary CCOCs that passed quality control using a targeted deep sequencing panel of 163 putative CCOC driver genes and whole transcriptome sequencing of 211 of these tumors. Molecularly defined subgroups were identified and tested for association with clinical characteristics and overall survival. We detected a putative somatic driver mutation in at least one candidate gene in 95% (401/421) of CCOC tumors including ARID1A (in 49% of tumors), PIK3CA (49%), TERT (20%), and TP53 (16%). Clustering of cancer driver mutations and RNA expression converged upon two distinct subclasses of CCOC. The first was dominated by ARID1A-mutated tumors with enriched expression of canonical CCOC genes and markers of platinum resistance the second was largely comprised of tumors with TP53 mutations and enriched for the expression of genes involved in extracellular matrix organization and mesenchymal differentiation. Compared with the ARID1A-mutated group, women with TP53-mutated tumors were more likely to have advanced-stage disease, no antecedent history of endometriosis, and poorer survival, driven by their advanced stage at presentation. In women with ARID1A-mutated tumors, there was a trend toward a lower rate of response to first-line platinum-based therapy. Our study suggests that CCOC consists of two distinct molecular subclasses with distinct clinical presentation and outcomes, with potential relevance to both traditional and experimental therapy responsiveness. See related commentary by Lheureux, p. 4838
Publisher: Wiley
Date: 28-03-2023
DOI: 10.1002/CJP2.317
Abstract: The clinical phenotype of somatic mutations in endometriosis is unknown. The objective was to determine whether somatic KRAS mutations were associated with greater disease burden in endometriosis (i.e. more severe subtypes and higher stage). This prospective longitudinal cohort study included 122 subjects undergoing endometriosis surgery at a tertiary referral center between 2013 and 2017, with 5–9 years of follow‐up. Somatic activating KRAS codon 12 mutations were detected in endometriosis lesions using droplet digital PCR. KRAS mutation status for each subject was coded as present ( KRAS mutation in at least one endometriosis s le in a subject) or absent. Standardized clinical phenotyping for each subject was carried out via linkage to a prospective registry. Primary outcome was anatomic disease burden, based on distribution of subtypes (deep infiltrating endometriosis, ovarian endometrioma, and superficial peritoneal endometriosis) and surgical staging (Stages I–IV). Secondary outcomes were markers of surgical difficulty, demographics, pain scores, and risk of re‐operation. KRAS mutation presence was higher in subjects with deep infiltrating endometriosis or endometrioma lesions only (57.9% 11/19) and subjects with mixed subtypes (60.6% 40/66), compared with those with superficial endometriosis only (35.1% 13/37) ( p = 0.04). KRAS mutation was present in 27.6% (8/29) of Stage I cases, in comparison to 65.0% (13/20) of Stage II, 63.0% (17/27) of Stage III, and 58.1% (25/43) of Stage IV cases ( p = 0.02). KRAS mutation was also associated with greater surgical difficulty (ureterolysis) (relative risk [RR] = 1.47, 95% CI: 1.02–2.11) and non‐Caucasian ethnicity (RR = 0.64, 95% CI: 0.47–0.89). Pain severities did not differ based on KRAS mutation status, at either baseline or follow‐up. Re‐operation rates were low overall, occurring in 17.2% with KRAS mutation compared with 10.3% without (RR = 1.66, 95% CI: 0.66–4.21). In conclusion, KRAS mutations were associated with greater anatomic severity of endometriosis, resulting in increased surgical difficulty. Somatic cancer‐driver mutations may inform a future molecular classification of endometriosis.
Publisher: American Association for Cancer Research (AACR)
Date: 10-2013
DOI: 10.1158/1078-0432.OVCA13-B14
Abstract: Background: Ovarian cancer is a series of distinct diseases typically identified by their histopathological appearance as high-grade serous (HGSC 70% of cases), low-grade serous (LGSC 5%), endometrioid (ENOCa, 8%), clear cell (CCC, 12%), and mucinous (MC 5%) carcinomas. Each type has defining molecular events, gene rotein expression patterns, genetic risk factors, sites of origin, and responses to treatment. Gold standard treatment is surgery followed by platinum-taxane chemotherapy despite mounting evidence suggesting CCCs, MCs, and LGSCs are largely platinum-taxane resistant. If outcomes are to be improved, it is critical to adopt a type specific strategy. Retrospective review studies have suggested histotype may be misdiagnosed or omitted in up to 30% of cases. However, pathological diagnosis of histotypes has been greatly refined in recent years and the use of biomarkers as aides is becoming more widespread. Nonetheless a rapid and fully objective classifier of histotypes will undoubtedly improve diagnostic accuracy, especially in the case of pre-surgical biopsies where small amounts of material present a challenge. Methods: Over 1000 ovarian carcinoma s les underwent expert gynecopathological review to establish a gold standard diagnosis for the 5 major carcinoma types. RNA was extracted from FFPE tissues and levels of a pre-selected set of & genes were quantified using the NanoString GX system. Cohort was split with ~1/3 set aside for independent validation. Several statistical models were tested to generate a prediction algorithm for histological type including PAM, Random Forest, Lasso, Recursive Partitioning, and Discriminant Analysis. Feature selection methods and prediction error were examined using cross-validation in the train /test series prior to validation in the independent set. Results: Preliminary analysis suggests classification of the 5 major histotypes is possible using NanoString derived RNA expression levels. Accuracy appears to be equivalent to interobserver variation amongst expert gynecopathologist. Conclusions: The NanoString GX platform provides a stable and reproducible platform on which a robust single s le histological type classifier can be established. Our algorithm combined with the NanoString platform provides a rapid, and cost-effective option that does not require modification to current pathology lab tissue processing protocols. Diagnostic prediction require little material and is applicable to pre- and post- surgical specimens where an objective measure is desired to confirm diagnosis or aide in especially challenging cases. Citation Format: Michael S. Anglesio, Aline Talhouk, Steve E. Kalloger, Gholamreza Haffari, Robertson Mackenzie, Martin Cheung, Janine Senz, Christine Chow, Sherman Lau, Maria Intermaggio, Susan J. Ramus, Andreas du Bois, Jacobus Pfisterer, Jessica N. McAlpine, Friedrich Kommoss, Blake Gilks, Stefan Kommoss, David G. Huntsman. Rapid RNA-based histotyping of ovarian carcinomas. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic Sep 18-21, 2013 Miami, FL. Philadelphia (PA): AACR Clin Cancer Res 2013 (19 Suppl):Abstract nr B14.
Publisher: American Association for Cancer Research (AACR)
Date: 14-04-2011
DOI: 10.1158/1078-0432.CCR-10-3314
Abstract: Purpose: Ovarian clear cell adenocarcinoma (OCCA) is an uncommon histotype that is generally refractory to platinum-based chemotherapy. We analyze here the most comprehensive gene expression and copy number data sets, to date, to identify potential therapeutic targets of OCCA. Experimental Design: Gene expression and DNA copy number were carried out using primary human OCCA tumor s les, and findings were confirmed by immunohistochemistry on tissue microarrays. Circulating interleukin (IL) 6 levels were measured in serum from patients with OCCA or high-grade serous cancers and related to progression-free and overall survival. Two patients were treated with sunitinib, and their therapeutic responses were measured clinically and by positron emission tomography. Results: We find specific overexpression of the IL6-STAT3-HIF (interleukin 6-signal transducer and activator of transcription 3-hypoxia induced factor) pathway in OCCA tumors compared with high-grade serous cancers. Expression of PTHLH and high levels of circulating IL6 in OCCA patients may explain the frequent occurrence of hypercalcemia of malignancy and thromboembolic events in OCCA. We describe lification of several receptor tyrosine kinases, most notably MET, suggesting other potential therapeutic targets. We report sustained clinical and functional imaging responses in two OCCA patients with chemotherapy-resistant disease who were treated with sunitinib, thus showing significant parallels with renal clear cell cancer. Conclusions: Our findings highlight important therapeutic targets in OCCA, suggest that more extensive clinical trials with sunitinib in OCCA are warranted, and provide significant impetus to the growing realization that OCCA is molecularly and clinically distinct to other forms of ovarian cancer. Clin Cancer Res 17(8) 2538–48. ©2011 AACR.
Publisher: Wiley
Date: 22-09-2017
DOI: 10.1111/HIS.13327
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494843
Abstract: Supplementary Table 6: Multivariate Modeling of Time to Recurrence/Death Among Studies with Gene Expression Data
Publisher: Cold Spring Harbor Laboratory
Date: 26-02-2019
DOI: 10.1101/561050
Abstract: The presence of somatic driver mutations in endometriosis has previously been believed to represent early events in transformation, however our group and others have described such mutations in roughly one-third of cases of deep infiltrating or iatrogenic endometriosis. These forms of endometriosis rarely progress to malignancy. Recent studies have also shown somatic driver mutations in normal skin, blood, peritoneal washings, and esophageal epithelium. Such findings prompt speculation on whether such mutations exist in the eutopic endometrium – the likely tissue of origin of endometriosis. In the current study we investigated the presence of somatic driver mutations in histologically normal endometrium from women lacking evidence of gynecologic malignancy or endometrial hyperplasia. Twenty-five women who underwent hysterectomies and 85 women who underwent endometrial biopsies were included in this study. Formalin-fixed, paraffin-embedded tissue specimens were analyzed by means of targeted sequencing followed by orthogonal validation with droplet digital PCR. PTEN and ARID1A immunohistochemistry (IHC) was also performed as surrogates for inactivating mutations in the respective genes. Overall, we observed somatic driver-like events in over 50% of histologically normal endometrial s les analyzed, which included hotspot mutations in KRAS , PIK3CA , and FGFR2 as well as PTEN-loss by IHC. Analysis of anterior and posterior s lings collected from women who underwent hysterectomies is consistent with the presence of somatic driver mutations within clonal pockets spread throughout the uterus. The prevalence of such oncogenic mutations also increased with age (OR: 1.05 (95% CI: 1.00 – 1.10), p = 0.035). These findings have implications on our understanding of aging and so-called “normal tissues”, thereby necessitating caution in the utilization of mutation-based early detection tools for endometrial or other cancers.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494849
Abstract: Supplementary Table 4: Multivariate Modeling of Methylation Signature Among Studies with Multiple Datatypes
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488651
Abstract: Supplementary Methods
Publisher: Cold Spring Harbor Laboratory
Date: 19-04-2021
DOI: 10.1101/2021.04.12.21255355
Abstract: Endometriosis symptoms are heterogeneous with controversy on whether it constitutes a single disease or multiple distinct types. Our previous work found recurrent somatic cancer-driver alterations in endometriosis however, these have not been found ubiquitously. A handful of cases spread across studies also suggest mutations might be shared (clonal) between lesions of the same type. As current classification systems correlate poorly with symptoms or outcomes, somatic genomics may improve the current system. Here, we investigate heterogeneity of somatic cancer-driver mutations within patients and across endometriosis types. We examined anatomically distinct types of endometriosis (ovarian, deep infiltrating, and superficial endometriosis) in 27 in idual patients all of whom had at least two types of endometriosis. Specimens were analyzed using high-sensitivity targeted sequencing with orthogonal validation from droplet digital PCR and mutation-surrogate immunohistochemistry. Results found 13/27 patients had informative somatic driver mutation in endometriosis, 9/13 had identical mutations across distinct lesions. Endometriomas tended to have a higher mutational complexity, with functionally redundant driver mutations in same gene and within the same lesions. Our data are consistent with clonality across endometriosis lesions regardless of subtype. Further the finding of redundancy in mutations with the same gene and lesions is also consistent with endometriosis representing an oligoclonal disease with dissemination likely to consist of multiple epithelial clones travelling together. This suggests the current anatomically defined classification of endometriosis does not fully recognize the etiology of the disease. A novel classification should take into account genomic and other molecular features. These findings could further contribute to development of a more personalized endometriosis diagnosis and care.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488654
Abstract: Supplementary Figures S1-S13
Publisher: Public Library of Science (PLoS)
Date: 20-04-2016
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
DOI: 10.1158/1078-0432.C.6740546
Abstract: AbstractPurpose: Endometrioid ovarian carcinoma (ENOC) is the second most-common type of ovarian carcinoma, comprising 10%–20% of cases. Recently, the study of ENOC has benefitted from comparisons to endometrial carcinomas including defining ENOC with four prognostic molecular subtypes. Each subtype suggests differential mechanisms of progression, although tumor-initiating events remain elusive. There is evidence that the ovarian microenvironment may be critical to early lesion establishment and progression. However, while immune infiltrates have been well studied in high-grade serous ovarian carcinoma, studies in ENOC are limited. Experimental Design: We report on 210 ENOC, with clinical follow-up and molecular subtype annotation. Using multiplex IHC and immunofluorescence, we examine the prevalence of T-cell lineage, B-cell lineage, macrophages, and populations with programmed cell death protein 1 or programmed death-ligand 1 across subtypes of ENOC. Results: Immune cell infiltrates in tumor epithelium and stroma showed higher densities in ENOC subtypes with known high mutation burden ( i POLE /i mut and MMRd). While molecular subtypes were prognostically significant, immune infiltrates were not (overall survival i P /i 0.2). Analysis by molecular subtype revealed that immune cell density was prognostically significant in only the i no specific molecular profile /i (NSMP) subtype, where immune infiltrates lacking B cells (TIL sub B minus /sub ) had inferior outcome (disease-specific survival: HR, 4.0 95% confidence interval, 1.1–14.7 i P /i 0.05). Similar to endometrial carcinomas, molecular subtype stratification was generally superior to immune response in predicting outcomes. Conclusions: Subtype stratification is critical for better understanding of ENOC, in particular the distribution and prognostic significance of immune cell infiltrates. The role of B cells in the immune response within NSMP tumors warrants further study. /
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494846
Abstract: Supplementary Table 5: Modeling of Time to Recurrence/Death Among Studies with Gene Expression Data, excluding data from Previously Published Participants
Publisher: Massachusetts Medical Society
Date: 14-10-2010
Publisher: American Association for Cancer Research (AACR)
Date: 30-11-2011
DOI: 10.1158/1078-0432.CCR-11-2080
Abstract: Purpose: Serous ovarian carcinomas are the predominant epithelial ovarian cancer subtype and it has been widely believed that some or all of these may arise from precursors derived from the ovarian surface epithelium or fimbriae, although direct molecular evidence for this is limited. This study aimed to conduct copy number (CN) analysis using a series of benign and borderline serous ovarian tumors to identify underlying genomic changes that may be indicative of early events in tumorigenesis. Experimental Design: High resolution CN analysis was conducted on DNA from the epithelial and fibroblast components of a cohort of benign (N = 39) and borderline (N = 24) serous tumors using the Affymetrix OncoScan assay and SNP6.0 arrays. Results: CN aberrations were detected in the epithelium of only 2.9% (1 of 35) of serous cystadenomas and cystadenofibromas. In contrast, CN aberrations were detected in the epithelium of 67% (16 of 24) of the serous borderline tumors (SBT). Unexpectedly, CN aberrations were detected in the fibroblasts of 33% (13 of 39) of the benign serous tumors and in 15% (3 of 20) of the SBTs. Of the 16 cases with CN aberrations in the fibroblasts, 12 of these carried a gain of chromosome 12. Conclusions: Chromosome 12 trisomy has been previously identified in pure fibromas, supporting the concept that a significant proportion of benign serous tumors are in fact primary fibromas with an associated cystic mass. This is the first high resolution genomic analysis of benign serous ovarian tumors and has shown not only that the majority of benign serous tumors have no genetic evidence of epithelial neoplasia but that a significant proportion may be more accurately classified as primary fibromas. Clin Cancer Res 17(23) 7273–82. ©2011 AACR.
Publisher: Springer Science and Business Media LLC
Date: 10-08-2014
DOI: 10.1038/S41467-019-11862-X
Abstract: Mucinous ovarian carcinoma (MOC) is a unique subtype of ovarian cancer with an uncertain etiology, including whether it genuinely arises at the ovary or is metastatic disease from other organs. In addition, the molecular drivers of invasive progression, high-grade and metastatic disease are poorly defined. We perform genetic analysis of MOC across all histological grades, including benign and borderline mucinous ovarian tumors, and compare these to tumors from other potential extra-ovarian sites of origin. Here we show that MOC is distinct from tumors from other sites and supports a progressive model of evolution from borderline precursors to high-grade invasive MOC. Key drivers of progression identified are TP53 mutation and copy number aberrations, including a notable licon on 9p13. High copy number aberration burden is associated with worse prognosis in MOC. Our data conclusively demonstrate that MOC arise from benign and borderline precursors at the ovary and are not extra-ovarian metastases.
Publisher: Massachusetts Medical Society
Date: 11-05-2017
Publisher: Elsevier BV
Date: 06-2018
DOI: 10.1016/J.CELL.2018.03.073
Abstract: High-grade serous ovarian cancer (HGSC) exhibits extensive malignant clonal ersity with widespread but non-random patterns of disease dissemination. We investigated whether local immune microenvironment factors shape tumor progression properties at the interface of tumor-infiltrating lymphocytes (TILs) and cancer cells. Through multi-region study of 212 s les from 38 patients with whole-genome sequencing, immunohistochemistry, histologic image analysis, gene expression profiling, and T and B cell receptor sequencing, we identified three immunologic subtypes across s les and extensive within-patient ersity. Epithelial CD8+ TILs negatively associated with malignant ersity, reflecting immunological pruning of tumor clones inferred by neoantigen depletion, HLA I loss of heterozygosity, and spatial tracking between T cell and tumor clones. In addition, combinatorial prognostic effects of mutational processes and immune properties were observed, illuminating how specific genomic aberration types associate with immune response and impact survival. We conclude that within-patient spatial immune microenvironment variation shapes intraperitoneal malignant spread, provoking new evolutionary perspectives on HGSC clonal dispersion.
Publisher: Cold Spring Harbor Laboratory
Date: 24-08-2020
DOI: 10.1101/2020.08.21.20178830
Abstract: In this study, we aimed to test whether prognostic biomarkers can achieve a clinically relevant stratification of patients with stage I ovarian clear cell carcinoma (OCCC) and to survey the expression of 10 selected actionable targets (theragnostic biomarkers) in stage II to IV cases. From the population-based Alberta Ovarian Tumor Type study, 160 s les of OCCC were evaluated by immunohistochemistry and/or silver-enhanced in-situ hybridization for the status of 5 prognostic (p53, p16, IGF2BP3, CCNE1, FOLR1) and 10 theragnostic biomarkers (ALK, BRAF, ERBB2, ER, MET, MMR, PR, ROS1, NTRK1-3, VEGFR2). Kaplan-Meier survival analyses were performed. Cases with abnormal p53 or combined p16/IFG2BP3 abnormal expression identified a small subset of patients (6/54 cases) with stage I OCCC with an aggressive course (5-year ovarian cancer specific survival of 33.3%, compared to 91.5% in the other stage I cases). Among theragnostic targets, ERBB2 lification was present in 11/158 (7%) of OCCC, while MET was ubiquitously expressed in OCCC similar to a variety of normal control tissues. ER/PR showed a low prevalence of expression. No abnormal expression was detected for any of the other targets. We propose a combination of 3 biomarkers (p53, p16, IGF2BP3) to predict prognosis and the potential need for adjuvant therapy for patients with stage I OCCC. This finding requires replication in larger cohorts. Additionally, OCCC could be tested for ERBB2 lification for inclusion in gynecological basket trials targeting this alteration.
Publisher: Elsevier BV
Date: 09-2022
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488645
Abstract: Supplementary Tables S1-S11
Publisher: © 2020. Thieme. All rights reserved.
Date: 10-2020
Publisher: © 2020. Thieme. All rights reserved.
Date: 10-2020
Publisher: American Association for Cancer Research (AACR)
Date: 15-08-2015
DOI: 10.1158/1557-3265.OVCASYMP14-AS18
Abstract: Introduction: Clear Cell ovarian carcinomas (CCC) represent 10% of ovarian carcinomas, with outcomes for high-stage significantly worse than high-grade serous form. The complete mutational landscape, the molecular basis of the transformation of endometriosis, the putative precursor, and patterns of clonal evolution in CCC are not well understood. Methods: Whole genome sequencing and gene expression profiling was done to uncover somatic alterations and measure effects on transcriptional networks. Targeted deep sequencing of primary tumors, metastases and endometriosis was also performed and statistical modeling approaches were used to validate mutations, quantify clonal ersity, and trace patterns of selection. Results: Mutations in ARID1A (11/19) and PIK3CA (8/19) were by far the most frequent aberrations seen. Three other SWI/SNF components also showed somatic alteration: two in non-ARID1A mutant cases and a truncating mutation of ARID1B in an ARID1A-null case. Amongst 24 significant “candidate drivers” impacting expression, five “cancer genes” have been previously described: PIK3CA, ARID1A, CTNNB1, TP53, and PPP2R1A. We observed no association between PIK3CA or ARID1A status with disease stage, genomic instability, or mutation load. Deep sequencing data suggested multiple clones in every case. In cases with matching precursor lesions, we observed multiple mutations in at least one such lesion. In precursor lesions where tumor-matched somatic mutations were observed, ARID1A and PIK3CA mutations were also always present, if observed in the matched tumor. Conclusions: ARID1A and PIK3CA mutations appear as early and histo-type defining events in CCC. Pattern of endometriosis transformation can be associated with somatic mutations in all cases, including histologically “Atypical” and non-atypical endometriosis. Finally, patterns of mutational conservation across the series of precursor lesions may present an opportunity for early screening of endometriosis tissues as an indicator of transformation potential. Citation Format: Michael S Anglesio, Ali Bashashati, Yikan Wang, Gavin Ha, Janine Senz, Winnie Yang, Steve E Kalloger, Leah M Prentice, Satoshi Yanagida, Clara Salamanca, Galina Soukhatcheva, Anthony Kazernis, Hector Chang, Anne-Marie Mes-Mason, Aikou Okamoto, Marco A Marra, Blake Gilks, Sohrab P Shah, David G Huntsman. The somatic mutational landscape of endometriosis associated ovarian cancers and precursor lesions [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium Sep 8-9, 2014 Seattle, WA. Philadelphia (PA): AACR Clin Cancer Res 2015 (16 Suppl):Abstract nr AS18.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494864
Abstract: Supplementary Methods 1: The original 60 CpG loci defining methylation-based subtypes, and the approximation method for methylation signature
Publisher: Springer Science and Business Media LLC
Date: 02-01-2020
DOI: 10.1007/S00428-019-02728-0
Abstract: Acid ceramidase (ASAH1) is a key player in sphingolipid metabolism and signaling. It has prognostic value for several cancers, but histotype-specific analyses of ovarian cancer are not yet available. We used three retrospective TMA cohorts encompassing a total of 1106 ovarian cancers with follow-up data for immunohistochemical analysis of acid ceramidase (ASAH1) expression. Patients with sub-optimal debulking and persistent residual tumor after surgery introduced bias in the prognostic analysis and were excluded from further studies. Overall, we detected an association of ASAH1 expression with better prognosis in ovarian cancer patients. ASAH1 expression differed between histological ovarian cancer histotypes with most frequent expression in endometrioid and clear cell ovarian cancer, which are both associated with good prognosis. Stratified subgroup analyses within these histotypes did not reveal significant survival differences, but the power of the analysis may be limited by smaller s le sizes. In contrast to breast cancer, we found only a modest concordance between estrogen receptor status and ASAH1 expression within the endometrioid ovarian cancer histotype. In an exploratory analysis of estrogen receptor negative endometrioid ovarian cancer, ASAH1 expression was associated with significantly better overall survival (P = 0.007). Acid ceramidase is most frequently expressed in endometrioid and clear cell histotypes and could add independent prognostic value to estrogen receptor in endometrioid ovarian cancer. Modulating sphingolipid metabolism may lead to novel therapeutic intervention strategies for this disease.
Publisher: American Association for Cancer Research (AACR)
Date: 10-2013
DOI: 10.1158/1078-0432.OVCA13-A13
Abstract: Borderline ovarian tumors fill an unusual niche between completely benign tumors and frank malignancies. These tumors tend to follow a relatively benign clinical course however, they can recur as low grade serous carcinoma. Tumor features such as invasive implants and micropapillary growth pattern have been proposed to separate serous borderline tumors (SBTs) with invasive-like behaviour from SBTs with benign behaviour. It is currently unknown whether these features are associated with specific molecular events and whether molecular profiling of borderline tumors could offer a significant improvement of predicting likelihood of recurrence and progression. This study aimed to perform genome-wide high-resolution molecular analysis of a large cohort of serous borderline ovarian tumors (n=57), employing copy number analysis and mutation screening, and compared these to a cohort of low grade serous carcinomas (n=19). Clinical features such as tumor stage and laterality were found to correlate with the identity of the underlying oncogenic driver mutation, as were the presence or absence of genomic copy number aberrations and the presence of specific copy number aberrations in the SBT cohort. Comparison of genomic aberrations in SBTs to low grade serous carcinomas (LGSCs) identified loss of heterozygosity events that were very significantly enriched in carcinomas. In conclusion, we have identified correlations between the specific oncogenic mutation a tumor carries and tumor characteristics such as level of genomic aberration and spread beyond the ovary. These findings are consistent with previous reports that specific oncogenic mutations may have a better prognosis in low grade serous tumors. Identifiable correlations between molecular events and tumor characteristics suggest it will be possible to use patient-specific tumor characteristics to better define a suitable level of treatment and follow-up. This is an important consideration as although patients have a very good short term prognosis, over an extended period recurrence and progression of SBTs to LGSCs is not insignificant and later stage LGSCs are relatively chemoresistant. Citation Format: Sally M. Hunter, Kylie L. Gorringe, Michael S. Anglesio, Raghwa Sharma, Yoke-Eng Chiew, Phillip Moss, Andrew Stephens, C Blake Gilks, Group Australian Ovarian Cancer Study, David Hunstman, Anna deFazio, Ian C bell. Molecular profiling of low grade serous ovarian tumors. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic Sep 18-21, 2013 Miami, FL. Philadelphia (PA): AACR Clin Cancer Res 2013 (19 Suppl):Abstract nr A13.
Publisher: Springer Science and Business Media LLC
Date: 03-03-2021
DOI: 10.1007/S00432-021-03558-X
Abstract: Sphingosine-kinase-1 (SPHK1) is a key enzyme of sphingolipid metabolism which is involved in ovarian cancer pathogenesis, progression and mechanisms of drug resistance. It is overexpressed in a variety of cancer subtypes. We investigated SPHK1 expression as a prognostic factor in epithelial ovarian cancer patients. Expression analysis of SPHK1 was performed on formalin-fixed paraffin-embedded tissue from 1005 ovarian cancer patients with different histological subtypes using immunohistochemistry. Staining intensity of positive tumor cells was assessed semi-quantitatively, and results were correlated with clinicopathological characteristics and survival. In our ovarian cancer collective, high levels of SPHK1 expression correlated significantly with complete surgical tumor resection ( p = 0.002) and lower FIGO stage ( p = 0.04). Progression-free and overall survival were further significantly longer in patients with high-grade serous ovarian cancer and overexpression of SPHK1 ( p = 0.002 and p = 0.006, respectively). Our data identify high levels of SPHK1 expression as a potential favorable prognostic marker in ovarian cancer patients.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494861
Abstract: Supplementary Table 1: Characteristics of Study Participants with High Grade Serous Tubo-Ovarian Carcinoma by Contributing Study
Publisher: American Association for Cancer Research (AACR)
Date: 10-2013
DOI: 10.1158/1078-0432.OVCA13-A18
Abstract: Background: Mucinous ovarian carcinomas (MC) and mucinous borderline ovarian tumours (MBOT) are associated with ERBB2 lification and KRAS activating mutations. These events occur in a near-mutually exclusive pattern, and KRAS mutations are more prevalent in MBOTs than MC's whereas ERBB2 lification is more frequently seen in MCs. Frequencies of mutations in other oncogenes and tumour suppressor genes in MC are not well established though TP53, BRAF, NRAS, and CDKN2A mutations have all been reported. As these carcinomas are commonly chemo-resistant a definitive molecular categorization of this subtype is needed as treatment options are explored. Methods: We undertook review of pathology reports and after exclusion of potential gastric, appendiceal or pancreatic involvement over 100 mucinous ovarian tumours were identified. HPV testing was undertaken to exclude rare metastasis from endocervical primary site. All specimens were assayed for p53 expression via TMA and subject to sequencing of common cancer gene hotspots using Ion-Torrent or Illumina MiSeq. Previously derived data on ERBB2 status was combined in our analysis and, where available, s les showing heterogeneity of ERBB2 lification and any other Ras-pathway activating mutation were microdissected with components evaluated independently for concurrent hotspot mutations. Results: All s les were consistent with mucinous tumours of ovarian origin and none were HPV positive. We detected mutations in KRAS, BRAF, CDKN2A, TP53, PTEN, PIK3CA as well as presumed somatic/detrimental, variants in APC that have not previously been reported in mucinous tumours. Despite some s les having enriched tumour content, lower than expected allelic frequencies of KRAS activating mutations suggested intra-tumoural heterogeneity. This was consistent with results observed previously with rare ERBB2 lification coinciding KRAS mutations. Conclusions: The prevalence of Ras-pathway mutations, especially amongst borderline lesions, suggests these mutations are critical for tumour onset. However varying allelic frequencies of KRAS mutations suggest progression to carcinoma is strongly influenced by other molecular features. Citation Format: Michael S. Anglesio, Robertson Mackenzie, Stefan Kommoss, Boris J. Winterhoff, Benjamin Kipp, Jaoquin Garcia, Jesse S. Voss, Kevin Halling, Sarah Kerr, Janine Senz, Winnie Yang, Magnus von Knebel Doeberitz, Elena-Sophie Prigge, Miriam Reuschenbach, Anna V. Tinker, Blake Gilks, Jamie N. Bakkum-Gamez, David G. Huntsman, Jessica N. McAlpine. Defining ovarian mucinous tumors: Cancer genes and heterogeneity. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic Sep 18-21, 2013 Miami, FL. Philadelphia (PA): AACR Clin Cancer Res 2013 (19 Suppl):Abstract nr A18.
Publisher: © 2020. Thieme. All rights reserved.
Date: 10-2020
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22489520
Abstract: Supplementary Figure from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes
Publisher: Wiley
Date: 02-09-2013
DOI: 10.1111/HIS.12219
Abstract: The recent recognition that ovarian carcinoma is composed of five distinct disease entities has served to increase the value of accurate histotyping. Reliable identification of histotypes is essential for the success of studies testing novel therapies, as well as for biomarker discovery research. The aim of this study was to examine the utility of a nine-marker immunohistochemical (IHC) panel, designated the Calculator for Ovarian Subtype Prediction (COSP), to reliably reproduce the consensus diagnosis of two expert gynaecological pathologists. A total of 423 cases from the AGO-OVAR11 trial were evaluated using the COSP IHC panel, and compared to original diagnoses from >100 local contributing pathologists and independent expert gynaecopathology review. The overall concordance between COSP and expert review was 89% in cases where a local pathologist's diagnosis was confirmed by COSP, the expert gynaecopathologist also agreed in 97.5% of cases. The incorporation of COSP into a high-throughput diagnostic review algorithm will decrease the need for expert review by identifying a small number of difficult cases that truly require expert review. This modification will serve to increase the efficiency of the diagnostic review process, which will probably serve to reduce operational costs and expedite translational studies on ovarian carcinoma.
Publisher: Wiley
Date: 23-03-2015
DOI: 10.1002/PATH.4516
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22489523
Abstract: Supplementary Figure from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494867
Abstract: Supplementary Figure 4: Correlations between Methylation at CpG Sites and TAP1 mRNA Expression
Publisher: Morressier
Date: 11-09-2016
Publisher: Wiley
Date: 26-12-2022
DOI: 10.1002/CNCR.34582
Abstract: Cyclin E1 (CCNE1) is a potential predictive marker and therapeutic target in tubo‐ovarian high‐grade serous carcinoma (HGSC). Smaller studies have revealed unfavorable associations for CCNE1 lification and CCNE1 overexpression with survival, but to date no large‐scale, histotype‐specific validation has been performed. The hypothesis was that high‐level lification of CCNE1 and CCNE1 overexpression, as well as a combination of the two, are linked to shorter overall survival in HGSC. Within the Ovarian Tumor Tissue Analysis consortium, lification status and protein level in 3029 HGSC cases and mRNA expression in 2419 s les were investigated. High‐level lification ( copies by chromogenic in situ hybridization) was found in 8.6% of HGSC and overexpression ( % with at least 5% demonstrating strong intensity by immunohistochemistry) was found in 22.4%. CCNE1 high‐level lification and overexpression both were linked to shorter overall survival in multivariate survival analysis adjusted for age and stage, with hazard stratification by study (hazard ratio [HR], 1.26 95% CI, 1.08‐1.47, p = .034, and HR, 1.18 95% CI, 1.05‐1.32, p = .015, respectively). This was also true for cases with combined high‐level lification/overexpression (HR, 1.26 95% CI, 1.09‐1.47, p = .033). CCNE1 mRNA expression was not associated with overall survival (HR, 1.00 per 1‐SD increase 95% CI, 0.94‐1.06 p = .58). CCNE1 high‐level lification is mutually exclusive with the presence of germline BRCA1/2 pathogenic variants and shows an inverse association to RB1 loss. This study provides large‐scale validation that CCNE1 high‐level lification is associated with shorter survival, supporting its utility as a prognostic biomarker in HGSC.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2011
DOI: 10.1158/1538-7445.AM2011-LB-271
Abstract: Ovarian cancer is a very significant health burden and the fifth leading cause of cancer death in women. At the time of diagnosis, women often have advanced disease and as a consequence their prognosis is extremely poor. Our understanding of the progression of ovarian cancer through precursor stages and the molecular genetic events underlying these changes is currently limited. Although a number of candidate precursor lesions have been identified it remains to confirm the true contribution of these precursor lesions to the onset of ovarian cancer. Epithelial tumors account for 70–80% of all ovarian tumors and the serous subtype accounts for approximately 53% of ovarian epithelial tumors. Serous cystadenomas and cystadenofibromas are common ovarian lesions, accounting for 25% of all benign ovarian tumors and 58% of the ovarian serous tumors. Although there is little definitive molecular or histopathological evidence, ovarian serous cystadenomas and cystadenofibromas have been presumed by many to be the precursor lesions to serous borderline tumors and low grade serous carcinomas. Using the ultra high-resolution Affymetrix SNP6.0 microarray (& .8M probes) and the high-resolution Molecular Inversion Probe (MIP) assay (& k probes) we performed copy number (CN) and loss of heterozygosity analysis on 14 ovarian serous cystadenomas and 20 ovarian serous cystadenofibromas. Each tumour was microdissected to allow analysis of tumour epithelium and adjacent stroma with matching lymphocyte DNA for each case. CN alterations were only detected in the epithelial component in 2 of 34 cases (5.9%) but surprisingly alterations were seen in 35% of the stromal components (2/14 cystadenomas and 10/20 cystadenofibromas). Notably, 9/12 of these cases carried a chromosome 12 gain, which has been previously identified as characteristic of the fibroma-thecoma group of ovarian stromal tumors. One of 34 cases (2.9%) was biphasic with CN alterations in both the epithelium and stroma. The lack of identifiable CN alterations or KRAS and BRAF mutations in the epithelium of the vast majority of the ovarian serous cystadenomas and cystadenofibromas supports the notion that these lesions have limited neoplastic potential. These findings are consistent with the predictions of Seidman and Mehrotra (2005) that the majority of benign ovarian serous tumors are potentially cystically dilated glandular inclusions and misclassified fibromas with epithelial inclusions. This would considerably deflate the frequency of the serous subtype within ovarian epithelial tumors and alter the significance of the other epithelial subtypes, with compelling implications for studies of serous ovarian “precursor” lesions. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research 2011 Apr 2-6 Orlando, FL. Philadelphia (PA): AACR Cancer Res 2011 (8 Suppl):Abstract nr LB-271. doi:10.1158/1538-7445.AM2011-LB-271
Publisher: Wiley
Date: 07-02-2022
DOI: 10.1002/PATH.5849
Abstract: ARID1A (BAF250a) is a component of the SWI/SNF chromatin modifying complex, plays an important tumour suppressor role, and is considered prognostic in several malignancies. However, in ovarian carcinomas there are contradictory reports on its relationship to outcome, immune response, and correlation with clinicopathological features. We assembled a series of 1623 endometriosis‐associated ovarian carcinomas, including 1078 endometrioid (ENOC) and 545 clear cell (CCOC) ovarian carcinomas, through combining resources of the Ovarian Tumor Tissue Analysis (OTTA) Consortium, the Canadian Ovarian Unified Experimental Resource (COEUR), local, and collaborative networks. Validated immunohistochemical surrogate assays for ARID1A mutations were applied to all s les. We investigated associations between ARID1A loss/mutation, clinical features, outcome, CD8 + tumour‐infiltrating lymphocytes (CD8 + TILs), and DNA mismatch repair deficiency (MMRd). ARID1A loss was observed in 42% of CCOCs and 25% of ENOCs. We found no associations between ARID1A loss and outcomes, stage, age, or CD8 + TIL status in CCOC. Similarly, we found no association with outcome or stage in endometrioid cases. In ENOC, ARID1A loss was more prevalent in younger patients ( p = 0.012) and was associated with MMRd ( p 0.001) and the presence of CD8 + TILs ( p = 0.008). Consistent with MMRd being causative of ARID1A mutations, in a subset of ENOCs we also observed an association with ARID1A loss‐of‐function mutation as a result of small indels ( p = 0.035, versus single nucleotide variants). In ENOC, the association with ARID1A loss, CD8 + TILs, and age appears confounded by MMRd status. Although this observation does not explicitly rule out a role for ARID1A influence on CD8 + TIL infiltration in ENOC, given current knowledge regarding MMRd, it seems more likely that effects are dominated by the hypermutation phenotype. This large dataset with consistently applied biomarker assessment now provides a benchmark for the prevalence of ARID1A loss‐of‐function mutations in endometriosis‐associated ovarian cancers and brings clarity to the prognostic significance. © 2021 The Pathological Society of Great Britain and Ireland.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22489526
Abstract: Supplementary Figure from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22489517
Abstract: Supplementary Figure from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes
Publisher: American Association for Cancer Research (AACR)
Date: 28-02-2017
DOI: 10.1158/1541-7786.MCR-16-0132
Abstract: Clear cell ovarian carcinoma (CCOC) is an aggressive form of epithelial ovarian cancer that exhibits low response rates to systemic therapy and poor patient outcomes. Multiple studies in CCOC have revealed expression profiles consistent with increased hypoxia, and our previous data suggest that hypoxia is correlated with increased autophagy in CCOC. Hypoxia-induced autophagy is a key factor promoting tumor cell survival and resistance to therapy. Recent clinical trials with the molecular-targeted receptor tyrosine kinase (RTK) inhibitor sunitinib have demonstrated limited activity. Here, it was evaluated whether the hypoxia–autophagy axis could be modulated to overcome resistance to sunitinib. Importantly, a significant increase in autophagic activity was found with a concomitant loss in cell viability in CCOC cells treated with sunitinib. Pharmacologic inhibition of autophagy with the lysosomotropic analog Lys05 inhibited autophagy and enhanced sunitinib-mediated suppression of cell viability. These results were confirmed by siRNA targeting the autophagy-related gene Atg5. In CCOC tumor xenografts, Lys05 potentiated the antitumor activity of sunitinib compared with either treatment alone. These data reveal that CCOC tumors have an autophagic dependency and are an ideal tumor histotype for autophagy inhibition as a strategy to overcome resistance to RTK inhibitors like sunitinib. Implications: This study shows that autophagy inhibition enhances sunitinib-mediated cell death in a preclinical model of CCOC. Mol Cancer Res 15(3) 250–8. ©2017 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494852
Abstract: Supplementary Table 3: Differential Methylation Analysis for Mayo Training and Testing Sets for all QC-passed CpG loci from 450k
Publisher: Wiley
Date: 12-11-2012
DOI: 10.1002/PATH.4090
Abstract: Clear cell ovarian cancer histotypes exhibit metabolic features associated with resistance to hypoxia and glucose deprivation-induced cell death. This metabolic characteristic suggests that clear cell ovarian cancers activate survival mechanisms not typical of other epithelial ovarian cancers. Here we demonstrate that microtubule-associated protein 1 light chain 3A (LC3A), a marker of autophagy, is related to hypoxia and poor prognosis in clear cell ovarian cancer. In 485 ovarian tumours, we found that LC3A was significantly associated with poor progression-free (p = 0.0232), disease-specific (p = 0.0011) and overall patient survival (p = 0.0013) in clear cell ovarian cancer patients, but not in other subtypes examined. LC3A was an independent prognostic marker of reduced disease-specific [hazard ratio (HR): 2.55 (95% CI 1.21-5.37) p = 0.014] and overall survival [HR: 1.95 (95% CI 1.00-3.77) p = 0.049] in patients with clear cell ovarian carcinoma. We also found a strong link between autophagy and hypoxia as LC3A staining revealed a significant positive association with the hypoxia-related proteins carbonic anhydrase-IX and HIF-1α. The functional link between hypoxia and autophagy was demonstrated using clear cell and high-grade serous cell lines that were subjected to hypoxia or hypoxia + glucose deprivation. Clear cell carcinoma lines displayed greater autophagy induction and were subsequently more sensitive to inhibition of autophagy under hypoxia compared to the high-grade serous lines. Together, our findings indicate that hypoxia-induced autophagy may be crucial to the clinical pathology of clear cell ovarian cancer and is a potential explanation for histological subtype differences in patient disease progression and outcomes.
Publisher: American Association for Cancer Research (AACR)
Date: 10-2013
DOI: 10.1158/1078-0432.OVCA13-A27
Abstract: Our understanding of ovarian cancer is complicated by disease heterogeneity. There are five major histological types, each with alterations in different pathways and distinct clinical outcomes. Even within these histological types there is clinical and molecular heterogeneity. The Ovarian Tumor Tissue Analysis (OTTA) consortium was established to validate prognostic markers for ovarian cancer in a large population of patients to allow stratification by histological type and molecular subtype. OTTA is currently a collaboration among 38 studies and has tissue microarrays (TMAs) from over 8,000 tumors available for immunohistochemical (IHC) analysis. In addition formalin fixed paraffin embedded (FFPE) tissue on slides or cores are available from the majority of OTTA studies for DNA and RNA analysis. Approximatley 60% of the cases are part of the Ovarian Cancer Association Consortium (OCAC) and have genotype data on over 200,000 single nucleotide polymorphisms and extensive epidemiological data. We recently performed IHC analysis of 12 markers using centralised staining and scoring to reduce heterogeneity and improve power to validate biomarkers. We showed that estrogen receptor and progesterone receptor were prognostic markers for endometrioid and high-grade serous carcinomas by performing the first robust subtype-specific analyses of these biomarkers in nearly 3000 patients. In contrast, FOLR1 expression was not associated with survival in 1507 high-grade serous carcinomas. We have shown that FFPE material from OTTA is suitable for RNA expression analysis on high through-put platforms such as the NanoString GX system. Expression analysis of 50 candidate genes in 244 high grade serous ovarian cancer cases has validated prognostic markers identified by The Cancer Genome Atlas (TCGA) project and investigated a series of novel candidate genes. IHC and RNA expression profiling from formalin fixed paraffin embedded (FFPE) tumor tissue is being used to better subclassify the ovarian tumors for further analysis. We would welcome groups with collections of ovarian tumor s les and corrsponding clinical data to join OTTA and participate in ongoing collaborative projects. Citation Format: Susan J. Ramus, Martin Köbel, Weiva Sieh, Michael S. Anglesio, Joshua Millstein, David D. Bowtell, James D. Brenton, Estrid Høgdall, Paul DP Pharoah, Ellen L. Goode, David G. Huntsman. The ovarian tumor tissue analysis (OTTA) consortium. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic Sep 18-21, 2013 Miami, FL. Philadelphia (PA): AACR Clin Cancer Res 2013 (19 Suppl):Abstract nr A27.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6529509.V1
Abstract: AbstractPurpose: Endometrioid ovarian carcinoma (ENOC) is generally associated with a more favorable prognosis compared with other ovarian carcinomas. Nonetheless, current patient treatment continues to follow a “one-size-fits-all” approach. Even though tumor staging offers stratification, personalized treatments remain elusive. As ENOC shares many clinical and molecular features with its endometrial counterpart, we sought to investigate The Cancer Genome Atlas–inspired endometrial carcinoma (EC) molecular subtyping in a cohort of ENOC. Experimental Design: IHC and mutation biomarkers were used to segregate 511 ENOC tumors into four EC-inspired molecular subtypes: low-risk i POLE /i mutant (POLEmut), moderate-risk mismatch repair deficient (MMRd), high-risk p53 abnormal (p53abn), and moderate-risk with no specific molecular profile (NSMP). Survival analysis with established clinicopathologic and subtype-specific features was performed. Results: A total of 3.5% of cases were POLEmut, 13.7% MMRd, 9.6% p53abn, and 73.2% NSMP, each showing distinct outcomes ( i P /i 0.001) and survival similar to observations in EC. Median OS was 18.1 years in NSMP, 12.3 years in MMRd, 4.7 years in p53abn, and not reached for POLEmut cases. Subtypes were independent of stage, grade, and residual disease in multivariate analysis. Conclusions: EC-inspired molecular classification provides independent prognostic information in ENOC. Our findings support investigating molecular subtype–specific management recommendations for patients with ENOC for ex le, subtypes may provide guidance when fertility-sparing treatment is desired. Similarities between ENOC and EC suggest that patients with ENOC may benefit from management strategies applied to EC and the opportunity to study those in umbrella trials. /
Publisher: Public Library of Science (PLoS)
Date: 04-09-2013
Publisher: American Association for Cancer Research (AACR)
Date: 14-12-2014
DOI: 10.1158/1078-0432.CCR-14-1292
Abstract: Purpose: Low-grade serous ovarian carcinomas (LGSC) are Ras pathway-mutated, TP53 wild-type, and frequently associated with borderline tumors. Patients with LGSCs respond poorly to platinum-based chemotherapy and may benefit from pathway-targeted agents. High-grade serous carcinomas (HGSC) are TP53-mutated and are thought to be rarely associated with borderline tumors. We sought to determine whether borderline histology associated with grade 2 or 3 carcinoma was an indicator of Ras mutation, and we explored the molecular relationship between coexisting invasive and borderline histologies. Experimental Design: We reviewed & ,200 patients and identified 102 serous carcinomas with adjacent borderline regions for analyses, including candidate mutation screening, copy number, and gene expression profiling. Results: We found a similar frequency of low, moderate, and high-grade carcinomas with coexisting borderline histology. BRAF/KRAS alterations were common in LGSC however, we also found recurrent NRAS mutations. Whereas borderline tumors harbored BRAF/KRAS mutations, NRAS mutations were restricted to carcinomas, representing the first ex le of a Ras oncogene with an obligatory association with invasive serous cancer. Coexisting borderline and invasive components showed nearly identical genomic profiles. Grade 2 cases with coexisting borderline included tumors with molecular features of LGSC, whereas others were typical of HGSC. However, all grade 3 carcinomas with coexisting borderline histology were molecularly indistinguishable from typical HGSC. Conclusion: Our findings suggest that NRAS is an oncogenic driver in serous ovarian tumors. We demonstrate that borderline histology is an unreliable predictor of Ras pathway aberration and underscore an important role for molecular classification in identifying patients that may benefit from targeted agents. Clin Cancer Res 20(24) 6618–30. ©2014 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 13-07-2023
DOI: 10.1158/1078-0432.23676032.V1
Abstract: Supplementary Tables S1-S5
Publisher: BMJ Publishing Group Ltd
Date: 11-2020
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 12-2017
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6529509
Abstract: AbstractPurpose: Endometrioid ovarian carcinoma (ENOC) is generally associated with a more favorable prognosis compared with other ovarian carcinomas. Nonetheless, current patient treatment continues to follow a “one-size-fits-all” approach. Even though tumor staging offers stratification, personalized treatments remain elusive. As ENOC shares many clinical and molecular features with its endometrial counterpart, we sought to investigate The Cancer Genome Atlas–inspired endometrial carcinoma (EC) molecular subtyping in a cohort of ENOC. Experimental Design: IHC and mutation biomarkers were used to segregate 511 ENOC tumors into four EC-inspired molecular subtypes: low-risk i POLE /i mutant (POLEmut), moderate-risk mismatch repair deficient (MMRd), high-risk p53 abnormal (p53abn), and moderate-risk with no specific molecular profile (NSMP). Survival analysis with established clinicopathologic and subtype-specific features was performed. Results: A total of 3.5% of cases were POLEmut, 13.7% MMRd, 9.6% p53abn, and 73.2% NSMP, each showing distinct outcomes ( i P /i 0.001) and survival similar to observations in EC. Median OS was 18.1 years in NSMP, 12.3 years in MMRd, 4.7 years in p53abn, and not reached for POLEmut cases. Subtypes were independent of stage, grade, and residual disease in multivariate analysis. Conclusions: EC-inspired molecular classification provides independent prognostic information in ENOC. Our findings support investigating molecular subtype–specific management recommendations for patients with ENOC for ex le, subtypes may provide guidance when fertility-sparing treatment is desired. Similarities between ENOC and EC suggest that patients with ENOC may benefit from management strategies applied to EC and the opportunity to study those in umbrella trials. /
Publisher: Wiley
Date: 15-01-2019
DOI: 10.1111/HIS.13772
Abstract: Ovarian endometrioid carcinoma (EC) generally has a good prognosis. Adjuvant chemotherapy can be spared in low-stage disease, but prognostic biomarkers are needed to refine the treatment threshold. Wnt/β-catenin signalling is commonly altered in EC. We examined immunohistochemical expression of nuclear β-catenin and CDX2 as prognostic biomarkers for EC both are mediators of the Wnt pathway. We evaluated two ovarian EC cohorts, discovery set (n = 183) and validation set (n = 174), with ovarian cancer-specific survival (OCSS) as the primary end-point. In univariable analysis, nuclear β-catenin expression was significantly associated with longer OCSS in the discovery set [hazard ratio (HR) = 0.36, 95% confidence interval (CI) = 0.16-0.74, P = 0.004] and the validation set (HR = 0.35, 95% CI = 0.11-0.89, P = 0.006). Similar significant associations were observed with CDX2 expression in the discovery set (HR = 0.25, 95% CI = 0.11-0.50, P < 0.001) and validation set (HR = 0.27, 95% CI = 0.07-0.75, P = 0.020). In multivariable analysis, combined positivity of both markers was significantly associated with longer OCSS in the discovery set (HR = 0.20, 95% CI = 0.06-0.49, P < 0.001) and in the validation set (HR = 0.33 95% CI = 0.07-0.1.06, P = 0.047). In a stratified analysis for stage IC/II EC, combined positivity identified a subset of patients with a significantly longer OCSS in the discovery cohort but only a non-significant trend in the validation cohort. Nuclear β-catenin and CDX2 expression in idually or in combination are validated prognostic markers for ovarian EC. However, their full potential to stratify low risk patients at adjuvant threshold awaits further multimarker study.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494858
Abstract: Supplementary Table 2: CpGs That Defined Previously Reported Methylation Subtypes Using a Semi-Supervised Clustering Approach
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22489532.V1
Abstract: Supplementary Figure from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes
Publisher: BMJ
Date: 09-2015
DOI: 10.1097/IGC.0000000000000492
Abstract: Polymerase epsilon (POLE) is a DNA polymerase with a proofreading (exonuclease) domain, responsible for the recognition and excision of mispaired bases, thereby allowing high-fidelity DNA replication to occur. The Cancer Genome Atlas research network recently identified an ultramutated group of endometrial carcinomas, characterized by mutations in POLE, and exceptionally high substitution mutation rates. These POLE mutated endometrial tumors were almost exclusively of the endometrioid histotype. The prevalence and patterns of POLE mutated tumors in endometrioid carcinomas of the ovary, however, have not been studied in detail. In this study, we investigate the frequency of POLE exonuclease domain mutations in a series of 89 ovarian endometrioid carcinomas. We found POLE mutations in 4 of 89 (4.5%) cases, occurring in 3 of 23 (13%) International Federation of Gynecology and Obstetrics (FIGO) grade 1, 1 of 43 (2%) FIGO grade 2, and 0 of 23 (0%) FIGO grade 3 tumors. All mutations were somatic missense point mutations, occurring at the commonly reported hotspots, P286R and V411L. All 3 POLE-mutated FIGO grade 1 tumors displayed prototypical histology, and the POLE-mutated FIGO grade 2 tumor displayed morphologic heterogeneity with focally high-grade features. All 4 patients with POLE-mutated tumors followed an uneventful clinical course with no disease recurrence however, this finding was not statistically significant ( P = 0.59). The low rate of POLE mutations in ovarian endometrioid carcinoma and their predominance within the low FIGO grade tumors are in contrast to the findings in the endometrium.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22489529.V1
Abstract: Supplementary Figure from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes
Publisher: American Association for Cancer Research (AACR)
Date: 10-2019
DOI: 10.1158/1078-0432.CCR-18-3720
Abstract: Ovarian cancer is a heterogeneous disease that can be ided into multiple subtypes with variable etiology, pathogenesis, and prognosis. We analyzed DNA methylation profiling data to identify biologic subgroups of ovarian cancer and study their relationship with histologic subtypes, copy number variation, RNA expression data, and outcomes. A total of 162 paraffin-embedded ovarian epithelial tumor tissues, including the five major epithelial ovarian tumor subtypes (high- and low-grade serous, endometrioid, mucinous, and clear cell) and tumors of low malignant potential were selected from two different sources: The Polish Ovarian Cancer study, and the Surveillance, Epidemiology, and End Results Residual Tissue Repository (SEER RTR). Analyses were restricted to Caucasian women. Methylation profiling was conducted using the Illumina 450K methylation array. For 45 tumors array copy number data were available. NanoString gene expression data for 39 genes were available for 61 high-grade serous carcinomas (HGSC). Consensus nonnegative matrix factorization clustering of the 1,000 most variable CpG sites showed four major clusters among all epithelial ovarian cancers. We observed statistically significant differences in survival (log-rank test, P = 9.1 × 10−7) and genomic instability across these clusters. Within HGSC, clustering showed three subgroups with survival differences (log-rank test, P = 0.002). Comparing models with and without methylation subgroups in addition to previously identified gene expression subtypes suggested that the methylation subgroups added significant survival information (P = 0.007). DNA methylation profiling of ovarian cancer identified novel molecular subgroups that had significant survival difference and provided insights into the molecular underpinnings of ovarian cancer. See related commentary by Ishak et al., p. 5729
Publisher: MDPI AG
Date: 18-12-2020
Abstract: Anti-PD1/PDL1 therapy has proven efficacious against many cancers but only reached modest objective response rates against recurrent ovarian cancer. A deeper understanding of the tumor microenvironment (TME) may reveal other immunosuppressive mechanisms that warrant investigation as immunotherapeutic targets for this challenging disease. Matched primary and recurrent tumors from patients with high-grade serous ovarian carcinoma (HGSC) were analyzed by multicolor immunohistochemistry/immunofluorescence for the presence of T cells, B cells, macrophages, and for the expression of immunosuppressive and HLA molecules. Cancer- and immune-related gene expression was assessed by NanoString analysis. Recurrent tumors showed increased infiltration by immune cells, displayed higher expression of PDL1, IDO, and HLA molecules, and contained more stromal tissue. NanoString analysis demonstrated increased expression of gene signatures related to chemokines and T cell functions in recurrent tumors. The ovarian tumors showed high gene expression of LAG3 and HAVCR2 (TIM3) and enhanced levels of TIGIT and CTLA4 in recurrent tumors compared to primary tumors. The majority of HGSC developed into a more inflamed phenotype during progression from primary to recurrent disease, including indications of adaptive immune resistance. This suggests that recurrent tumors may be particularly sensitive to inhibition of adaptive immune resistance mechanisms.
Publisher: American Association for Cancer Research (AACR)
Date: 15-07-2016
DOI: 10.1158/1538-7445.AM2016-LB-324
Abstract: Background: Ovarian carcinoma is comprised of distinct histological subtypes with different etiology, molecular, genomic and clinical attributes. Patterns of genomic ersity and different treatment responses differentiate each ovarian cancer histotype. The relative patterns of both mutational, copy number and structural variation have not been studied with relation to each disease phenotype. We hypothesized that global genomic architectures will stratify ovarian cancer patients and reveal different treatment response groups. Methods: Whole genome sequencing was performed on 133 ovarian tumors, including 123 carcinomas (59 high-grade serous (HGSC), 35 clear cell (CCOC), 29 endometrioid (ENOC)) and 10 granulosa cell tumours (GCT). Profiles of copy number aberrations, loss of heterozygosity (LOH), mutations (SNVs and INDELs) and structural variations were assessed. Mutational characteristics including mutation signatures derived from tri-nucleotide substitution patterns together with genomic structural characteristics, such as the relative proportion of rearrangement types, reflective of specific DNA repair processes were calculated for each patient. Results: Integrative clustering of the 133 patients according to their mutation and structural signatures resulted in seven distinct subgroups of patients. LOH and the homologous recombination deficiency mutation signature mainly distinguished HGSC cases from non-serous histotypes. HGSC cases were further clustered into two main subgroups. One subgroup (n = 23, 39%) showed a high prevalence of foldback inversions with homology size & bp, while the other group (n = 25, 42%) was enriched in tandem duplications and deletions, and associated with microhomology (& bp). Survival analysis revealed that the foldback inversion group associated with poor overall and progression-free survival (logrank p-value = 0.016 and 0.015). CCOC cases were characterized by tandem duplications (Median = 39%, p-value & .001). The mutation signatures further identified two main subgroups of CCOC one (n = 10, 29%) showing prevalence of kataegis events typically associated with an APOBEC mutational signature, and the other (n = 17, 49%) characterized by an age-related signature. Enrichment of a mis-match repair defect signature identified a microsatellite instable subgroup of ENOC (n = 8). A signature related to breast cancers uniquely identified GCT cases. Conclusion: Our results suggest that mutational and chromosomal structural variant signatures (rearrangement and copy number profiles) constitute new and defining features of ovarian carcinoma that relate to different DNA repair mechanisms. Our results provide insight into ergent etiologies within histotypes and suggest a novel structure on which to base treatment. Citation Format: Yikan Wang, Ali Bashashati, Michael S. Anglesio, Dawn Cochrane, Diljot Grewal, Hugo Horlings, Anthony Karnezis, Anne-Marie Mes-Masson, Aikou Okamoto, Satoshi Yanagida, Nozomu Yanaihara, Misato Saito, Blake Gilks, Jessica McAlpine, Samuel Aparicio, David Huntsman, Sohrab Shah. Genomic consequences of aberrant DNA repair stratify ovarian cancer histotypes. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research 2016 Apr 16-20 New Orleans, LA. Philadelphia (PA): AACR Cancer Res 2016 (14 Suppl):Abstract nr LB-324.
Publisher: Wiley
Date: 17-12-2012
DOI: 10.1002/PATH.4088
Abstract: Mucinous ovarian carcinomas (MCs) typically do not respond to current conventional therapy. We have previously demonstrated lification of HER2 in 6 of 33 (18.2%) mucinous ovarian carcinomas (MCs) and presented anecdotal evidence of response with HER2-targeted treatment in a small series of women with recurrent HER2- lified (HER2+) MC. Here, we explore HER2 lification and KRAS mutation status in an independent cohort of 189 MCs and 199 mucinous borderline ovarian tumours (MBOTs) and their association to clinicopathological features. HER2 status was assessed by immunohistochemistry (IHC), FISH, and CISH, and interpreted per ASCO/CAP guidelines, with intratumoural heterogeneity assessment on full sections, where available. KRAS mutation testing was performed with Sanger sequencing. Stage and grade were associated with recurrence on both univariate and multivariate analysis (p < 0.001). Assessment of HER2 status revealed overexpression/ lification of HER2 in 29/154 (18.8%) MCs and 11/176 (6.2%) MBOTs. There was excellent agreement between IHC, FISH, and CISH assessment of HER2 status (perfect concordance of HER2 0 or 1+ IHC with non- lified status, and 3+ IHC with lified status). KRAS mutations were seen in 31/71 (43.6%) MCs and 26/33 (78.8%) MBOTs, and were near mutually exclusive of HER2 lification. In the 189 MC cases, a total of 54 recurrences and 59 deaths (53 of progressive disease) were observed. Within MCs, either HER2 lification/overexpression or KRAS mutation was associated with decreased likelihood of disease recurrence (p = 0.019) or death (p = 0.0041) when compared to cases with neither feature. Intratumoural heterogeneity was noted in 26% of HER2-overexpressing cases. These data support the stratification of MCs for the testing of new treatments, with HER2-targeted therapy as a viable option for HER2+ advanced or recurrent disease. Further research is required to delineate the molecular and clinical features of the ∼34% of MC cases with neither HER2 lification nor KRAS mutations.
Publisher: Elsevier BV
Date: 10-2018
Publisher: Elsevier BV
Date: 09-2020
Publisher: Oxford University Press (OUP)
Date: 14-11-2018
Abstract: Does incisional endometriosis (IE) harbor somatic cancer-driver mutations? We found that approximately one-quarter of IE cases harbor somatic-cancer mutations, which commonly affect components of the MAPK/RAS or PI3K-Akt-mTor signaling pathways. Despite the classification of endometriosis as a benign gynecological disease, it shares key features with cancers such as resistance to apoptosis and stimulation of angiogenesis and is well-established as the precursor of clear cell and endometrioid ovarian carcinomas. Our group has recently shown that deep infiltrating endometriosis (DE), a form of endometriosis that rarely undergoes malignant transformation, harbors recurrent somatic mutations. In a retrospective study comparing iatrogenically induced and endogenously occurring forms of endometriosis unlikely to progress to cancer, we examined endometriosis specimens from 40 women with IE and 36 women with DE. Specimens were collected between 2004 and 2017 from five hospital sites in either Canada, Germany or the Netherlands. IE and DE cohorts were age-matched and all women presented with histologically typical endometriosis without known history of malignancy. Archival tissue specimens containing endometriotic lesions were macrodissected and/or laser-capture microdissected to enrich endometriotic stroma and epithelium and a hypersensitive cancer hotspot sequencing panel was used to assess for presence of somatic mutations. Mutations were subsequently validated using droplet digital PCR. PTEN and ARID1A immunohistochemistry (IHC) were performed as surrogates for somatic events resulting in functional loss of respective proteins. Overall, we detected somatic cancer-driver events in 11 of 40 (27.5%) IE cases and 13 of 36 (36.1%) DE cases, including hotspot mutations in KRAS, ERBB2, PIK3CA and CTNNB1. Heterogeneous PTEN loss occurred at similar rates in IE and DE (7/40 vs 5/36, respectively), whereas ARID1A loss only occurred in a single case of DE. While rates of detectable somatic cancer-driver events between IE and DE are not statistically significant (P 0.05), KRAS activating mutations were more prevalent in DE. Detection of somatic cancer-driver events were limited to hotspots analyzed in our panel-based sequencing assay and loss of protein expression by IHC from archival tissue. Whole genome or exome sequencing, or epigenetic analysis may uncover additional somatic alterations. Moreover, because of the descriptive nature of this study, the functional roles of identified mutations within the context of endometriosis remain unclear and causality cannot be established. The alterations we report may be important in driving the growth and survival of endometriosis in ectopic regions of the body. Given the frequency of mutation in surgically displaced endometrium (IE), examination of similar somatic events in eutopic endometrium, as well as clinically annotated cases of other forms of endometriosis, in particular endometriomas that are most commonly linked to malignancy, is warranted. This study was funded by a Canadian Cancer Society Impact Grant [701603, PI Huntsman], Canadian Institutes of Health Research Transitional Open Operating Grant [MOP-142273, PI Yong], the Canadian Institutes of Health Research Foundation Grant [FDN-154290, PI Huntsman], the Canadian Institutes of Health Research Project Grant [PJT-156084, PIs Yong and Anglesio], and the Janet D. Cottrelle Foundation through the BC Cancer Foundation [PI Huntsman]. D.G. Huntsman is a co-founder and shareholder of Contextual Genomics Inc., a for profit company that provides clinical reporting to assist in cancer patient treatment. R. Aguirre-Hernandez, J. Khattra and L.M. Prentice have a patent MOLECULAR QUALITY ASSURANCE METHODS FOR USE IN SEQUENCING pending and are current (or former) employees of Contextual Genomics Inc. The remaining authors have no competing interests to declare. Not applicable.
Publisher: Elsevier BV
Date: 06-2013
DOI: 10.1038/MODPATHOL.2012.226
Abstract: A single, recurrent somatic point mutation (402C→G) in FOXL2 has been described in almost all adult-type granulosa cell tumors but not other ovarian neoplasms. Histopathological features of adult-type granulosa cell tumors can be mimicked by a variety of other tumors, making diagnosis of adult-type granulosa cell tumor challenging. It has been suggested that molecular testing for FOXL2 mutation might be a useful tool in the diagnosis of adult-type granulosa cell tumors. The aim of this study was to demonstrate how testing for the FOXL2 mutation can be used in a gynecological pathology consultation service and to establish clear procedural guidelines for FOXL2 testing. Immunohistochemistry for FOXL2 was done using an anti-FOXL2 polyclonal antiserum. If immunohistochemistry was positive, FOXL2 mutation status was subsequently analyzed using a TaqMan assay. A dilution experiment was done to assess the sensitivity and minimum tumor cellularity requirements for our TaqMan assay. Twenty problematic cases were assessed, where the differential diagnosis after the initial investigations included adult-type granulosa cell tumors. Differential diagnoses included: thecoma, Sertoli-Leydig cell tumor, juvenile granulosa cell tumor, endometrial stromal sarcoma and others. In all cases, FOXL2 immunohistochemistry was positive and in six s les the FOXL2 mutation was detected, thus confirming a diagnosis of adult-type granulosa cell tumor. The TaqMan assay was able to reliably detect the FOXL2 mutation with input DNA in the range of 2.5-20 ng, and with a minimum of 25% tumor cell nuclei. The analysis of the FOXL2 mutational status in clinical s les is a useful diagnostic tool in situations where the differential diagnosis is between adult-type granulosa cell tumor and other ovarian tumors. The TaqMan assay requires a minimum of 2.5 ng DNA, with optimal assay performance for 5 to 10 ng DNA input. Laser capture or needle-macrodissection should be undertaken to enrich s les with tumor cell content below 25%.
Publisher: Oxford University Press (OUP)
Date: 06-2015
DOI: 10.1093/JNCI/DJV428
Abstract: Many women with ovarian endometrioid carcinoma present with concurrent endometrial carcinoma. Organ-confined and low-grade synchronous endometrial and ovarian tumors (SEOs) clinically behave as independent primary tumors rather than a single advanced-stage carcinoma. We used 18 SEOs to investigate the ancestral relationship between the endometrial and ovarian components. Based on both targeted and exome sequencing, 17 of 18 patient cases of simultaneous cancer of the endometrium and ovary from our series showed evidence of a clonal relationship, ie, primary tumor and metastasis. Eleven patient cases fulfilled clinicopathological criteria that would lead to classification as independent endometrial and ovarian primary carcinomas, including being of FIGO stage T1a/1A, with organ-restricted growth and without surface involvement 10 of 11 of these cases showed evidence of clonality. Our observations suggest that the disseminating cells amongst SEOs are restricted to physically accessible and microenvironment-compatible sites yet remain indolent, without the capacity for further dissemination.
Publisher: American Association for Cancer Research (AACR)
Date: 11-2008
DOI: 10.1158/1541-7786.MCR-08-0193
Abstract: Approximately, 10% to 15% of serous ovarian tumors fall into the category designated as tumors of low malignant potential (LMP). Like their invasive counterparts, LMP tumors may be associated with extraovarian disease, for ex le, in the peritoneal cavity and regional lymph nodes. However, unlike typical invasive carcinomas, patients generally have a favorable prognosis. The mutational profile also differs markedly from that seen in most serous carcinomas. Typically, LMP tumors are associated with KRAS and BRAF mutations. Interrogation of expression profiles in serous LMP tumors suggested overall redundancy of RAS-MAPK pathway mutations and a distinct mechanism of oncogenesis compared with high-grade ovarian carcinomas. Our findings indicate that activating mutation of the RAS-MAPK pathway in serous LMP may be present in & % of cases compared with ∼12.5% in serous ovarian carcinomas. In addition to mutations of KRAS (18%) and BRAF (48%) mutations, ERBB2 mutations (6%), but not EGFR, are prevalent among serous LMP tumors. Based on the expression profile signature observed throughout our serous LMP cohort, we propose that RAS-MAPK pathway activation is a requirement of serous LMP tumor development and that other activators of this pathway are yet to be defined. Importantly, as few nonsurgical options exist for treatment of recurrent LMP tumors, therapeutic targeting of this pathway may prove beneficial, especially in younger patients where maintaining fertility is important. (Mol Cancer Res 2008 (11):1678–90)
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22489541
Abstract: Supplementary Figure from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22489544
Abstract: Supplementary Figure from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22476891.V1
Abstract: Package with all supplemental figures and tables
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22489547
Abstract: Supplementary Figure from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22489538
Abstract: Supplementary Figure from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494846.V1
Abstract: Supplementary Table 5: Modeling of Time to Recurrence/Death Among Studies with Gene Expression Data, excluding data from Previously Published Participants
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: Ovid Technologies (Wolters Kluwer Health)
Date: 24-03-2021
DOI: 10.1097/PGP.0000000000000780
Abstract: In this study, we aimed to test whether prognostic biomarkers can achieve a clinically relevant stratification of patients with stage I ovarian clear cell carcinoma (OCCC) and to survey the expression of 10 selected actionable targets (theranostic biomarkers) in stage II to IV cases. From the population-based Alberta Ovarian Tumor Type study, 160 s les of OCCC were evaluated by immunohistochemistry and/or silver-enhanced in situ hybridization for the status of 5 prognostic (p53, p16, IGF2BP3, CCNE1, FOLR1) and 10 theranostic biomarkers (ALK, BRAF V600E, ERBB2, ER, MET, MMR, PR, ROS1, NTRK1-3, VEGFR2). Kaplan-Meier survival analyses were performed. Cases with abnormal p53 or combined p16/IFG2BP3 abnormal expression identified a small subset of patients (6/54 cases) with stage I OCCC with an aggressive course (5-yr ovarian cancer-specific survival of 33.3%, compared with 91.5% in the other stage I cases). Among theranostic targets, ERBB2 lification was present in 11/158 (7%) of OCCC, while MET was ubiquitously expressed in OCCC similar to a variety of normal control tissues. ER/PR showed a low prevalence of expression. No abnormal expression was detected for any of the other targets. We propose a combination of 3 biomarkers (p53, p16, IGF2BP3) to predict prognosis and the potential need for adjuvant therapy for patients with stage I OCCC. This finding requires replication in larger cohorts. In addition, OCCC could be tested for ERBB2 lification for inclusion in gynecological basket trials targeting this alteration.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494852.V1
Abstract: Supplementary Table 3: Differential Methylation Analysis for Mayo Training and Testing Sets for all QC-passed CpG loci from 450k
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: 15-08-2015
DOI: 10.1158/1557-3265.OVCASYMP14-POSTER-BIOL-1349
Abstract: DICER1, an endoribonuclease required for microRNA (miRNA) biogenesis, is essential for embryogenesis and development of many organs including ovary. Germline truncating mutations in DICER1 are seen in families with the pleuropulmonary blastoma-family tumour and dysplasia syndrome. These in iduals have a propensity to develop ovarian Sertoli-Leydig cell tumors (SLCTs), a rare class of sex-cord stromal cell tumors that occur in young female. We have recently identified hotspot somatic mutations in RNase IIIb domain (simplified as ‘hotspot mutations’ thereafter) of DICER1 in half of SLCTs. These hotspot mutations impaired IIIb cleavage activity of DICER1 in in vitro cleavage assay and caused a global abolishment of 5p-miRNAs and a partial reduction of 3p-miRNAs in mouse embryonic stems cells expressing ectopic mutant DICER1. However, whether the miRNA biogenesis defect occurs in tumor s les and how DICER1 hotspot mutations promote tumorigenesis are largely unknown. By reviewing the histological features of ovarian SLCTs, we observed a strong correlation between DICER1 hotspot mutation and ovairain SLCTs with retiform pattern, which is often malignant with worse prognosis. Using Illumina small RNA sequencing technology and Exiqon miRNA realtime qPCR, we reported that the global expression of 5p-miRNAs was dramatically reduced in ovarian SLCTs carrying DICER1 hotspot mutations compared to their counterparts without DICER1 hotspot mutation. Although the 3p-miRNAs were largely unaffected, a subset of 3p-miRNAs was significantly increased in ovarian SLCTs with DICER1 hotspot mutations. To address the impact of DICER1 mutation on cell fate, we examined the gene expression profile in SLCTs using Illumina DASL whole transcriptome analysis followed by validation with Nanostring nCounter system. The miRNA production defect was associated with deregulation of genes governing cell fate determination in ovary, such as CYP19A1 (aromatase), FOXL2, FST, FGF9 and FGFR2, and genes that are targets of let-7, such as HMGA2, DICER1, ARID3A and CDC25A. Accordingly, knockin of DICER1 hotspot mutation in SVOG3e cells (immortalized human granulosa cells) led to altered miRNA biogenesis and deregulated expression of genes crucial for ovarian gonadal genesis and cellular transformation. SVOG3e Cells expressing DICER1 hotspot mutation grew faster than those with wildtype DICER1, which was at least partially due to loss of let-7 expression because inhibition of let-7 function by a miRNA sponge also accelerated cell growth. Furthermore, we also showed that loss of function of RNase IIIa domain of DICER1 had similar effect on cell proliferation as wildtype DICER1. Taken together, our data revealed that the hotspot somatic mutations of DICER1 in RNase IIIb domain cause systemic loss of 5p-miRNAs and selective upregulation of some 3p-miRNAs to drive pseudo-differentiation of testicular elements in ovary and cause oncogenic transformation. Thus, our current study sheds lights on the oncogenic potential of DICER1 hotspot mutations in tumor development and sets the stage for developing effective treatment method for malignant ovarian SLCTs. Citation Format: Yemin Wang, Jiamin Chen, Winnie Yang, Janine Senz, Michael S. Anglesio, Blake Gilks, Gregg B. Morin, David G. Huntsman. The oncogenic role of DICER1 RNase IIIb domain mutations in ovarian sertoli-leydig cell tumors [abstract]. In: Proceedings of the 10th Biennial Ovarian Cancer Research Symposium Sep 8-9, 2014 Seattle, WA. Philadelphia (PA): AACR Clin Cancer Res 2015 (16 Suppl):Abstract nr POSTER-BIOL-1349.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494858.V1
Abstract: Supplementary Table 2: CpGs That Defined Previously Reported Methylation Subtypes Using a Semi-Supervised Clustering Approach
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22489544.V1
Abstract: Supplementary Figure from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494876
Abstract: Supplementary Figure 1: Methylation Signature Approximation
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494870
Abstract: Supplementary Figure 3: Immune Analysis
Publisher: Public Library of Science (PLoS)
Date: 23-12-2013
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494873
Abstract: Supplementary Figure 2: No Association between Methylation Signature and Baseline Clinical Factors
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22489550.V1
Abstract: Supplementary Data from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22489532
Abstract: Supplementary Figure from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22489538.V1
Abstract: Supplementary Figure from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 07-2018
DOI: 10.1097/PGP.0000000000000429
Abstract: The latest FIGO and TNM (eighth edition) staging systems for ovarian, tubal, and peritoneal neoplasms require primary site assignment as tubal/ovarian eritoneal, but provide no guidance or criteria. Fewer than 10% of extrauterine high-grade serous carcinoma (HGSC) cases present at low stage (stage I/II). Low-stage cases offer a unique opportunity to understand the pattern of disease early in its evolution prior to wide dissemination and provide valuable evidence for guiding specimen handling and tumor staging. This study aimed to examine disease distribution in low-stage tubo-ovarian HGSC. Anonymized pathology reports of 152 stage I/II extrauterine HGSCs from 6 teaching hospitals were analyzed: group 1 (n=67) comprised cases with complete tubal examination by Sectioning and Extensively Examining the FIMbriated end of the tube (SEE-FIM) and group 2 (n=85) consisted of cases without documentation of both tubes being fully examined by the SEE-FIM or a SEE-FIM-like protocol. The stage, site attern of involvement, site/size of largest tumor focus and laterality of tubal and ovarian involvement were recorded. Tubal mucosal involvement was present in 95% of optimally examined cases and many factors influenced detection of tubal disease. Bilateral involvement, suggestive of metastasis, was significantly more frequent in the ovaries (35%) than the tubes (9%) ( P .0001, Fisher exact test). No case showed a complete absence of tubal/ovarian involvement, questioning the biological existence of primary peritoneal HGSC. Disease distribution in low-stage cases supports a tubal origin for most HGSCs. Detailed tubal s ling upstages some apparent stage I cases through detection of microscopic tubal involvement.
Publisher: Springer Science and Business Media LLC
Date: 12-08-2007
DOI: 10.1038/NM1621
Abstract: Transformation and cancer growth are regulated by the coordinate actions of oncogenes and tumor suppressors. Here, we show that the novel E3 ubiquitin ligase HACE1 is frequently downregulated in human tumors and maps to a region of chromosome 6q21 implicated in multiple human cancers. Genetic inactivation of HACE1 in mice results in the development of spontaneous, late-onset cancer. A second hit from either environmental triggers or genetic heterozygosity of another tumor suppressor, p53, markedly increased tumor incidence in a Hace1-deficient background. Re-expression of HACE1 in human tumor cells directly abrogates in vitro and in vivo tumor growth, whereas downregulation of HACE1 via siRNA allows non-tumorigenic human cells to form tumors in vivo. Mechanistically, the tumor-suppressor function of HACE1 is dependent on its E3 ligase activity and HACE1 controls adhesion-dependent growth and cell cycle progression during cell stress through degradation of cyclin D1. Thus, HACE1 is a candidate chromosome 6q21 tumor-suppressor gene involved in multiple cancers.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22489535
Abstract: Supplementary Figure from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22489517.V1
Abstract: Supplementary Figure from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes
Publisher: Wiley
Date: 07-03-2011
DOI: 10.1002/PATH.2848
Abstract: PPP2R1A mutations have recently been described in 3/42 (7%) of clear cell carcinomas of the ovary. PPP2R1A encodes the α-isoform of the scaffolding subunit of the serine/threonine protein phosphatase 2A (PP2A) holoenzyme. This putative tumour suppressor complex is involved in growth and survival pathways. Through targeted sequencing of PPP2R1A, we identified somatic missense mutations in 40.8% (20/49) of high-grade serous endometrial tumours, and 5.0% (3/60) of endometrial endometrioid carcinomas. Mutations were also identified in ovarian tumours at lower frequencies: 12.2% (5/41) of endometrioid and 4.1% (2/49) of clear cell carcinomas. No mutations were found in 50 high-grade and 12 low-grade serous carcinomas. Amino acid residues affected by these mutations are highly conserved across species and are involved in direct interactions with regulatory B-subunits of the PP2A holoenzyme. PPP2R1A mutations in endometrial high-grade serous carcinomas are a frequent and potentially targetable feature of this disease. The finding of frequent PPP2R1A mutations in high-grade serous carcinoma of the endometrium but not in high-grade serous carcinoma of the ovary provides clear genetic evidence that these are distinct diseases.
Publisher: Springer Science and Business Media LLC
Date: 02-11-2022
DOI: 10.1038/S41416-022-02014-Y
Abstract: Recently, we showed a % difference in 5-year survival for patients with tubo-ovarian high-grade serous carcinoma (HGSC) when stratified by a 101-gene mRNA expression prognostic signature. Given the varied patient outcomes, this study aimed to translate prognostic mRNA markers into protein expression assays by immunohistochemistry and validate their survival association in HGSC. Two prognostic genes, FOXJ1 and GMNN , were selected based on high-quality antibodies, correlation with protein expression and variation in immunohistochemical scores in a preliminary cohort ( n = 134 and n = 80, respectively). Six thousand four hundred and thirty-four (FOXJ1) and 5470 (GMNN) formalin-fixed, paraffin-embedded ovarian neoplasms (4634 and 4185 HGSC, respectively) represented on tissue microarrays from the Ovarian Tumor Tissue Analysis consortium underwent immunohistochemical staining and scoring, then univariate and multivariate survival analysis. Consistent with mRNA, FOXJ1 protein expression exhibited a linear, increasing association with improved overall survival in HGSC patients. Women with % expression had the most favourable outcomes (HR = 0.78, 95% CI 0.67–0.91, p 0.0001). GMNN protein expression was not significantly associated with overall HSGC patient survival. However, HGSCs with % GMNN expression showed a trend for better outcomes, though this was not significant. We provide foundational evidence for the prognostic value of FOXJ1 in HGSC, validating the prior mRNA-based prognostic association by immunohistochemistry.
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22489529
Abstract: Supplementary Figure from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488645.V1
Abstract: Supplementary Tables S1-S11
Publisher: Wiley
Date: 22-07-2019
DOI: 10.1002/PATH.5314
Abstract: The advent of next generation sequencing has vastly improved the resolution of mutation detection, thereby both increasing the resolution of the analysis of cancer tissues and shining light on the existence of somatic driver mutations in normal tissues, even in the absence of cancer. Studies have described somatic driver mutations in normal skin, blood, peritoneal washings, and esophageal epithelium. Such findings prompt speculation on whether such mutations exist in other tissues, such as the eutopic endometrium in particular, due to the highly regenerative nature of the endometrium and the recent observation of recurrent somatic driver mutations in deep infiltrating and iatrogenic endometriosis (tissues believed to be derived from the eutopic endometrium) by our group and others. In the current study we investigated the presence of somatic driver mutations in histologically normal endometrium from women lacking evidence of gynecologic malignancy or endometrial hyperplasia. Twenty-five women who underwent hysterectomies and 85 women who underwent endometrial biopsies were included in this study. Formalin-fixed, paraffin-embedded tissue specimens were analyzed by means of targeted sequencing followed by orthogonal validation with droplet digital PCR. PTEN and ARID1A immunohistochemistry (IHC) was also performed as surrogates for inactivating mutations in the respective genes. Overall, we observed somatic driver-like events in over 50% of normal endometrial s les analyzed, including hotspot mutations in KRAS, PIK3CA, and FGFR2 as well as PTEN-loss by IHC. Analysis of anterior and posterior s lings collected from women who underwent hysterectomies was consistent with the presence of somatic driver mutations within clonal pockets spread throughout the uterus. The prevalence of such oncogenic mutations also increased with age (OR: 1.05 [95% CI: 1.00-1.10], p = 0.035). These findings have implications on our understanding of aging and so-called 'normal tissues', thereby necessitating caution in the utilization of mutation-based early detection tools for endometrial or other cancers. © 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
Publisher: American Association for Cancer Research (AACR)
Date: 06-2015
DOI: 10.1158/1535-7163.MCT-15-0039
Abstract: Identification of genomic alterations defining ovarian carcinoma subtypes may aid the stratification of patients to receive targeted therapies. We characterized high-grade serous ovarian carcinoma (HGSC) for the association of lified and overexpressed genes with clinical outcome using gene expression data from 499 HGSC patients in the Ovarian Tumor Tissue Analysis cohort for 11 copy number lified genes: ATP13A4, BMP8B, CACNA1C, CCNE1, DYRK1B, GAB2, PAK4, RAD21, TPX2, ZFP36, and URI. The Australian Ovarian Cancer Study and The Cancer Genome Atlas datasets were also used to assess the correlation between gene expression, patient survival, and tumor classification. In a multivariate analysis, high GAB2 expression was associated with improved overall and progression-free survival (P = 0.03 and 0.02), whereas high BMP8B and ATP13A4 were associated with improved progression-free survival (P = 0.004 and P = 0.02). GAB2 overexpression and copy number gain were enriched in the AOCS C4 subgroup. High GAB2 expression correlated with enhanced sensitivity in vitro to the dual PI3K/mTOR inhibitor PF-04691502 and could be used as a genomic marker for identifying patients who will respond to treatments inhibiting PI3K signaling. Mol Cancer Ther 14(6) 1495–503. ©2015 AACR.
Publisher: Elsevier BV
Date: 09-2009
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22489523.V1
Abstract: Supplementary Figure from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes
Publisher: Wiley
Date: 06-11-2013
DOI: 10.1111/HIS.12253
Abstract: The diagnosis of adult-type granulosa cell tumours of the ovary (aGCT) is based on histomorphology aided by immunohistochemical staining for sex cord markers. Recently a single, recurrent somatic point mutation (402C→G) in FOXL2 was described in aGCT. We have investigated the impact of FOXL2 mutation testing in a large cohort of aGCT diagnosed previously by conventional histology and immunohistochemistry. Formalin-fixed, paraffin-embedded tissue cores from a cohort of 52 aGCT diagnosed previously by expert gynaecopathologists were analysed immunohistologically. FOXL2 mutation status was determined by Sanger sequencing and high-sensitivity TaqMan allelic discrimination assay. Histomorphology was reassessed by two expert gynaecopathologists. FOXL2 mutation analyses could be performed successfully in 46 cases, 40 of which were positive for the c.402C>G mutation, confirming a diagnosis of aGCT. In the six cases negative for the c.402C>G mutation, one case was confirmed on review as FOXL2 wild-type aGCT, whereas in the remaining five cases diagnoses other than aGCT were made. In cases where a diagnosis of aGCT is a consideration and unequivocal diagnosis is not possible based on morphology and routine immunostains, FOXL2 mutation testing can help to confirm the diagnosis. It is particularly relevant for accurate subclassification within the group of sex cord-stromal tumours.
Publisher: BMJ Publishing Group Ltd
Date: 11-2021
Publisher: Wiley
Date: 14-07-2009
DOI: 10.1002/GCC.20694
Abstract: Ovarian cancer is characterized by complex genetic alterations, including copy number loss and copy number-neutral loss of heterozygosity (LOH). These alterations are assumed to represent the "second hit" of the underlying tumor suppressor gene (TSG), however, relative to the number of LOH hotspots reported, few ovarian TSGs have been identified. We conducted a high-resolution LOH analysis using SNP arrays (500K and SNP6.0) of 106 primary ovarian tumors of various histological subtypes together with matching normal DNA. LOH was detected in at least 35% of s les on chromosomes 17, 19p, 22q, Xp, 13q, 8p, 6q, 4q, 5q, 1p, 16q, and 9q with a median minimal region of overlap of only 300 kb. Subtype-specific differences in LOH frequency were noted, particularly for mucinous cases. We also identified 192 somatic homozygous deletions (HDs). Recurrent HDs targeted known TSGs such as CDKN2A (eight s les), RB1 (five s les), and PTEN (three s les). Additional recurrent HDs targeted 16 candidate TSGs near minimal regions of LOH on chromosomes 17, 13, 8p, 5q, and X. Given the importance of HDs in inactivating known genes, these candidates are highly likely to be ovarian TSGs. Our data suggest that the poor success of previous LOH studies was due to the inability of previous technology to resolve complex genomic alterations and distinguish true LOH from allelic imbalance. This study shows that recurrent regions of LOH and HD frequently align with known TSGs suggesting that LOH analysis remains a valid approach to discovering new candidates.
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: Elsevier BV
Date: 05-2011
DOI: 10.1016/J.YGYNO.2011.01.005
Abstract: Recent literature has highlighted histological types of ovarian carcinoma as distinct diseases, each with unique clinical and molecular features. Historically, the diagnosis of ovarian clear cell carcinoma (CCC) has been of concern to both patients and physicians due to reports that CCC is associated with a worse prognosis than the more common serous type of ovarian carcinoma (HGSC). This review discusses the unique features of ovarian CCC. In June of 2010, a group of researchers and clinicians convened in Vancouver to review and discuss the clinical, pathological, molecular, and treatment-related features of CCC. CCC is the second most common type of ovarian epithelial cancer, representing 5-25% of ovarian carcinomas. It is characterised by its association with endometriosis, and frequent mutations of ARID1A and PIK3CA. Low-stage CCC appears to have a better outcome than stage matched HGSC, while the opposite is true for high-stage disease, suggesting that the current standard treatments applied to HGSC are ineffective for CCC. Ovarian CCC is highly distinct from HGSC, and a clearer understanding of the basic biology of this disease is needed. Alternative therapies should be explored: irradiation and targeting disease-specific molecular markers should be examined in greater detail. Finally, novel approaches to clinical trial design are needed due to the smaller numbers of patients affected.
Publisher: American Association for Cancer Research (AACR)
Date: 10-2014
DOI: 10.1158/1538-7445.AM2014-LB-312
Abstract: Clear Cell ovarian carcinomas (CCC) represent ∼10% of ovarian carcinomas, with outcomes for high-stage cases significantly worse than the more common high-grade serous form. Response to standard chemotherapies are poor and efforts to improve treatment strategies are confounded by studies grouping ovarian histologies together, as well as a general lack of molecular background data on CCC. CCC frequently occurs in a background of endometriosis. The complete mutational landscape, the molecular basis of the transformation of endometriosis and patterns of clonal evolution in CCC are not understood. We performed whole genome sequencing and gene expression profiling on 19 CCC to uncover candidate somatic alterations (mutations and, copy number aberrations) and measure their effect on transcriptional networks as candidates for driver mutations. We then performed targeted deep sequencing on the primary tumor s les, metastases and, from a subset of cases, adjacent or distant typical and atypical endometriosis. We used statistical modeling approaches to validate mutations, quantify the degree of clonal ersity and trace patterns of selection through oncogenic transformation. Mutations in ARID1A and PIK3CA were by far the most frequent aberrations seen in the cohort (ARID1A: 10/19 cases PIK3CA: 8/19 cases). The majority of ARID1A mutant cases exhibited bi-allelic loss of function. Two non-ARID1A mutant cases showed alterations in other SWI/SNF complex components. Amongst the 24 most significant candidate drivers impacting expression, five genes (PIK3CA, CTNNB1, TP53, PPP2R1A and KRAS) were known drivers. No association between PIK3CA or ARID1A status with disease stage, genomic instability, or mutation load was observed. Analysis of deep sequencing data suggested the presence of multiple clones in every case. For each case with matching precursor lesions, we observed multiple mutations in at least one such lesion. Cases with ARID1A and PIK3CA mutations always showed evidence of these mutations in their precursor lesions. The proportion of mutations from the primary tumor that were also present in precursor lesions varied widely across the cohort from approximately 10% to nearly 100%. Our data support both ARID1A and PIK3CA mutations as early events in CCC. The pattern of endometriosis transformation could be associated with somatic mutations in all cases. This suggests that candidate tumor-initiating mutations and global- or in idually- targetable features should be a focus to improve management of this disease. Finally, we suggest that patterns of mutational conservation across the series of precursor lesions presents an opportunity for early screening of endometriosis tissues as an indicator of transformation potential. Citation Format: Ali Bashashati, Michael Anglesio, Yikan Wang, Gavin Ha, Janine Senz, Winnie Yang, Steve Kalloger, Leah Prentice, Satoshi Yanagida, Clara Salamanca, Galina Soukhatcheva, Anthony Karnezis, Hector Chang, Martin Hirst, Anne-Marie Mes-Mason, Aikou Okamoto, Marco Marra, Blake Gilks, Sohrab Shah, David Huntsman. The somatic mutational landscape of ovarian clear cell carcinoma and its precursor lesions. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research 2014 Apr 5-9 San Diego, CA. Philadelphia (PA): AACR Cancer Res 2014 (19 Suppl):Abstract nr LB-312. doi:10.1158/1538-7445.AM2014-LB-312
Publisher: Springer Science and Business Media LLC
Date: 15-11-2021
Publisher: Elsevier BV
Date: 08-2013
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2015
Publisher: Elsevier BV
Date: 03-2021
Publisher: American Association for Cancer Research (AACR)
Date: 14-08-2016
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22489550
Abstract: Supplementary Data from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes
Publisher: American Association for Cancer Research (AACR)
Date: 24-10-2023
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22489553
Abstract: Supplementary Data from Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494864.V1
Abstract: Supplementary Methods 1: The original 60 CpG loci defining methylation-based subtypes, and the approximation method for methylation signature
Publisher: Springer Science and Business Media LLC
Date: 19-01-2021
DOI: 10.1007/S43032-020-00451-9
Abstract: In this review, we provide a survey and appraisal of research into somatic genomic events in endometriosis. Methodologies have evolved from conventional cytogenetics to next-generation sequencing, with findings ranging from chromosome imbalances to recurrent somatic cancer driver mutations. Somatic cancer driver mutations have been described in a range of endometriosis lesions, dominated by recurrent mutations in KRAS and PIK3CA as well as loss of PTEN and BAF250a (ARID1A). These somatic events appear to be largely restricted to the endometriosis glandular epithelium. Somatic mutations, particularly PTEN loss, have also been observed in eutopic (uterine) endometrium, although at lower mutant allele frequencies compared with ectopic lesions. Systematic studies of the potential clinical phenotype of these somatic genomic events have yet to be performed. Thus, we propose a framework to investigate the potential clinical phenotype associated with somatic genomic events in endometriosis. Technical requirements include pathology review of histological endometriosis, microdissection for tissue enrichment, orthogonal validation of whole genome/exome sequencing, and a germline s le for confirmation of somatic origin. Clinical requirements include annotation of surgical findings patient demographics cross-sectional and prospective data on pain and fertility consideration of s ling multiple lesions in each patient, mutant allele frequency, and somatic events in the eutopic endometrium and confirmation of any associations with mechanistic studies. Given the multifactorial nature of endometriosis-associated symptoms, it is likely that somatic events have small (or at most, moderate) effect sizes, and thus careful consideration will have to be given to future study design.
Publisher: Ecancer Global Foundation
Date: 25-01-2018
Publisher: Wiley
Date: 06-07-2015
DOI: 10.1002/PATH.4569
Abstract: DICER1 plays a critical role in microRNA (miRNA) biogenesis. Recurrent somatic 'hotspot' mutations at the four metal-binding sites within the RNase IIIb domain of DICER1 were identified in ovarian sex cord-stromal tumours and have since been described in other paediatric tumours. In this study, we screened the RNase IIIb domain of DICER1 in 290 endometrial tumours and identified six cases with hotspot mutations, including two cases affected by an atypical G1809R mutation directly adjacent to a metal-binding site. Using Illumina and Sanger targeted resequencing, we observed and validated biallelic DICER1 mutations in several cases with hotspot mutations. Through in vitro DICER1 cleavage assays, small RNA deep sequencing and real-time PCR, we demonstrated that mutations adding a positively charged side chain to residue 1809 have similar detrimental effects on 5p miRNA production to mutations at the metal-binding sites. As expected, 5p miRNAs were globally reduced in tumours and cell lines with hotspot mutations. Pathway analysis of gene expression profiles indicated that genes de-repressed due to loss of 5p miRNAs are strongly associated with pathways regulating the cell cycle. Using a Dicer1-null mouse cell line model, we found that expression of DICER1 hotspot mutants promoted cell proliferation, whereas wild-type (WT) DICER1 inhibited cell proliferation. Furthermore, targets of let-7 family miRNAs are enriched among the up-regulated genes, suggesting that loss of let-7 may be impacting downstream pathways. Our results reveal that DICER1 hotspot mutations are implicated in common malignancies and may constitute a unique oncogenic pathway.
Publisher: American Association for Cancer Research (AACR)
Date: 03-04-2023
DOI: 10.1158/1055-9965.22494870.V1
Abstract: Supplementary Figure 3: Immune Analysis
Publisher: BMJ Publishing Group Ltd
Date: 11-2019
Publisher: Georg Thieme Verlag
Date: 10-2022
Publisher: American Association for Cancer Research (AACR)
Date: 15-10-2020
DOI: 10.1158/1078-0432.CCR-20-1268
Abstract: Endometrioid ovarian carcinoma (ENOC) is generally associated with a more favorable prognosis compared with other ovarian carcinomas. Nonetheless, current patient treatment continues to follow a “one-size-fits-all” approach. Even though tumor staging offers stratification, personalized treatments remain elusive. As ENOC shares many clinical and molecular features with its endometrial counterpart, we sought to investigate The Cancer Genome Atlas–inspired endometrial carcinoma (EC) molecular subtyping in a cohort of ENOC. IHC and mutation biomarkers were used to segregate 511 ENOC tumors into four EC-inspired molecular subtypes: low-risk POLE mutant (POLEmut), moderate-risk mismatch repair deficient (MMRd), high-risk p53 abnormal (p53abn), and moderate-risk with no specific molecular profile (NSMP). Survival analysis with established clinicopathologic and subtype-specific features was performed. A total of 3.5% of cases were POLEmut, 13.7% MMRd, 9.6% p53abn, and 73.2% NSMP, each showing distinct outcomes (P & 0.001) and survival similar to observations in EC. Median OS was 18.1 years in NSMP, 12.3 years in MMRd, 4.7 years in p53abn, and not reached for POLEmut cases. Subtypes were independent of stage, grade, and residual disease in multivariate analysis. EC-inspired molecular classification provides independent prognostic information in ENOC. Our findings support investigating molecular subtype–specific management recommendations for patients with ENOC for ex le, subtypes may provide guidance when fertility-sparing treatment is desired. Similarities between ENOC and EC suggest that patients with ENOC may benefit from management strategies applied to EC and the opportunity to study those in umbrella trials.
No related grants have been discovered for Michael Anglesio.