ORCID Profile
0000-0002-6615-2037
Current Organisations
CSIRO
,
University of Calgary
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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: 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: 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: 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: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488654
Abstract: Supplementary Figures S1-S13
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: Wiley
Date: 30-04-2015
DOI: 10.1002/PATH.4536
Abstract: High-grade serous carcinomas (HGSCs) account for approximately 70% of all epithelial ovarian cancers diagnosed. Using microarray gene expression profiling, we previously identified four molecular subtypes of HGSC: C1 (mesenchymal), C2 (immunoreactive), C4 (differentiated), and C5 (proliferative), which correlate with patient survival and have distinct biological features. Here, we describe molecular classification of HGSC based on a limited number of genes to allow cost-effective and high-throughput subtype analysis. We determined a minimal signature for accurate classification, including 39 differentially expressed and nine control genes from microarray experiments. Taqman-based (low-density arrays and Fluidigm), fluorescent oligonucleotides (Nanostring), and targeted RNA sequencing (Illumina) assays were then compared for their ability to correctly classify fresh and formalin-fixed, paraffin-embedded s les. All platforms achieved > 90% classification accuracy with RNA from fresh frozen s les. The Illumina and Nanostring assays were superior with fixed material. We found that the C1, C2, and C4 molecular subtypes were largely consistent across multiple surgical deposits from in idual chemo-naive patients. In contrast, we observed substantial subtype heterogeneity in patients whose primary ovarian s le was classified as C5. The development of an efficient molecular classifier of HGSC should enable further biological characterization of molecular subtypes and the development of targeted clinical trials.
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: CSIRO
Date: 2022
DOI: 10.25919/189F-D066
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: 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: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488645
Abstract: Supplementary Tables S1-S11
Publisher: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 31-08-2017
DOI: 10.1158/1055-9965.EPI-17-0367
Abstract: Background: Comorbidities can affect survival of ovarian cancer patients by influencing treatment efficacy. However, little evidence exists on the association between in idual concurrent comorbidities and prognosis in ovarian cancer patients. Methods: Among patients diagnosed with invasive ovarian carcinoma who participated in 23 studies included in the Ovarian Cancer Association Consortium, we explored associations between histories of endometriosis asthma depression osteoporosis and autoimmune, gallbladder, kidney, liver, and neurological diseases and overall and progression-free survival. Using Cox proportional hazards regression models adjusted for age at diagnosis, stage of disease, histology, and study site, we estimated pooled HRs and 95% confidence intervals to assess associations between each comorbidity and ovarian cancer outcomes. Results: None of the comorbidities were associated with ovarian cancer outcome in the overall s le nor in strata defined by histologic subtype, weight status, age at diagnosis, or stage of disease (local/regional vs. advanced). Conclusions: Histories of endometriosis asthma depression osteoporosis and autoimmune, gallbladder, kidney, liver, or neurologic diseases were not associated with ovarian cancer overall or progression-free survival. Impact: These previously diagnosed chronic diseases do not appear to affect ovarian cancer prognosis. Cancer Epidemiol Biomarkers Prev 26(9) 1470–3. ©2017 AACR.
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: Springer Science and Business Media LLC
Date: 12-05-2021
Publisher: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.C.6532782.V1
Abstract: AbstractPurpose: Advanced-stage mucinous ovarian carcinoma (MOC) has poor chemotherapy response and prognosis and lacks biomarkers to aid stage I adjuvant treatment. Differentiating primary MOC from gastrointestinal (GI) metastases to the ovary is also challenging due to phenotypic similarities. Clinicopathologic and gene-expression data were analyzed to identify prognostic and diagnostic features. Experimental Design: Discovery analyses selected 19 genes with prognostic/diagnostic potential. Validation was performed through the Ovarian Tumor Tissue Analysis consortium and GI cancer biobanks comprising 604 patients with MOC ( i n /i = 333), mucinous borderline ovarian tumors (MBOT, i n /i = 151), and upper GI ( i n /i = 65) and lower GI tumors ( i n /i = 55). Results: Infiltrative pattern of invasion was associated with decreased overall survival (OS) within 2 years from diagnosis, compared with expansile pattern in stage I MOC [hazard ratio (HR), 2.77 95% confidence interval (CI), 1.04–7.41, i P /i = 0.042]. Increased expression of i THBS2 /i and i TAGLN /i was associated with shorter OS in MOC patients (HR, 1.25 95% CI, 1.04–1.51, i P /i = 0.016) and (HR, 1.21 95% CI, 1.01–1.45, i P /i = 0.043), respectively. i ERBB2 /i (HER2) lification or high mRNA expression was evident in 64 of 243 (26%) of MOCs, but only 8 of 243 (3%) were also infiltrative (4/39, 10%) or stage III/IV (4/31, 13%). Conclusions: An infiltrative growth pattern infers poor prognosis within 2 years from diagnosis and may help select stage I patients for adjuvant therapy. High expression of i THBS2 /i and i TAGLN /i in MOC confers an adverse prognosis and is upregulated in the infiltrative subtype, which warrants further investigation. Anti-HER2 therapy should be investigated in a subset of patients. MOC s les clustered with upper GI, yet markers to differentiate these entities remain elusive, suggesting similar underlying biology and shared treatment strategies. /
Publisher: American Association for Cancer Research (AACR)
Date: 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: 27-03-2017
DOI: 10.1038/NG.3826
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: 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: 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: 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: 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: 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: American Association for Cancer Research (AACR)
Date: 09-2023
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.C.6527802.V1
Abstract: AbstractPurpose: Although ovarian clear cell carcinomas (OCCC) are commonly resistant to platinum-based chemotherapy, good clinical outcomes are observed in a subset of patients. The explanation for this is unknown but may be due to misclassification of high-grade serous ovarian cancer (HGSOC) as OCCC or mixed histology. Experimental Design: To discover potential biomarkers of survival benefit following platinum-based chemotherapy, we ascertained a cohort of 68 Japanese and Australian patients in whom progression-free survival (PFS) and overall survival (OS) could be assessed. We performed IHC reclassification of tumors, and targeted sequencing and immunohistochemistry of known driver genes. Exome sequencing was performed in 10 patients who had either unusually long survival ( i N /i = 5) or had a very short time to progression ( i N /i = 5). Results: The majority of mixed OCCC ( i N /i = 6, 85.7%) and a small proportion of pure OCCC ( i N /i = 3, 4.9%) were reclassified as likely HGSOC. However, the PFS and OS of patients with misclassified s les were similar to that of patients with pathologically validated OCCC. Absent HNF1B expression was significantly correlated with longer PFS and OS ( i P /i = 0.0194 and 0.0395, respectively). Mutations in i ARID1A, PIK3CA, PPP2R1A /i , and i TP53 /i were frequent, but did not explain length of PFS and OS. An exploratory exome analysis of patients with favorable and unfavorable outcomes did not identify novel outcome-associated driver mutations. Conclusions: Survival benefit following chemotherapy in OCCC was not associated with pathological misclassification of tumor histotype. HNF1B loss may help identify the subset of patients with OCCC with a more favorable outcome. /
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: 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: American Association for Cancer Research (AACR)
Date: 04-2023
DOI: 10.1158/1078-0432.22488654.V1
Abstract: Supplementary Figures S1-S13
Publisher: Impact Journals, LLC
Date: 08-09-2015
Publisher: CSIRO
Date: 2020
Publisher: American Association for Cancer Research (AACR)
Date: 13-07-2023
DOI: 10.1158/1078-0432.23676032.V1
Abstract: Supplementary Tables S1-S5
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: 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: 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: 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: 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: 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: 10-2018
Publisher: Elsevier BV
Date: 12-2019
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: Springer Science and Business Media LLC
Date: 03-01-2017
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: 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: 07-2019
DOI: 10.1158/1078-0432.CCR-18-3691
Abstract: Although ovarian clear cell carcinomas (OCCC) are commonly resistant to platinum-based chemotherapy, good clinical outcomes are observed in a subset of patients. The explanation for this is unknown but may be due to misclassification of high-grade serous ovarian cancer (HGSOC) as OCCC or mixed histology. To discover potential biomarkers of survival benefit following platinum-based chemotherapy, we ascertained a cohort of 68 Japanese and Australian patients in whom progression-free survival (PFS) and overall survival (OS) could be assessed. We performed IHC reclassification of tumors, and targeted sequencing and immunohistochemistry of known driver genes. Exome sequencing was performed in 10 patients who had either unusually long survival (N = 5) or had a very short time to progression (N = 5). The majority of mixed OCCC (N = 6, 85.7%) and a small proportion of pure OCCC (N = 3, 4.9%) were reclassified as likely HGSOC. However, the PFS and OS of patients with misclassified s les were similar to that of patients with pathologically validated OCCC. Absent HNF1B expression was significantly correlated with longer PFS and OS (P = 0.0194 and 0.0395, respectively). Mutations in ARID1A, PIK3CA, PPP2R1A, and TP53 were frequent, but did not explain length of PFS and OS. An exploratory exome analysis of patients with favorable and unfavorable outcomes did not identify novel outcome-associated driver mutations. Survival benefit following chemotherapy in OCCC was not associated with pathological misclassification of tumor histotype. HNF1B loss may help identify the subset of patients with OCCC with a more favorable outcome.
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: 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: 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: 10.1158/1078-0432.22489535.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: 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: 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: 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: Wiley
Date: 21-09-2014
DOI: 10.1002/CJP2.109
Publisher: Elsevier BV
Date: 2021
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: 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: 10.1158/1078-0432.22489526.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: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22471188
Abstract: Supplementary Tables
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: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22471185
Abstract: Supplementary Figures
Publisher: Elsevier BV
Date: 03-2020
Publisher: Elsevier BV
Date: 03-2018
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: 31-03-2023
DOI: 10.1158/1078-0432.22471188.V1
Abstract: Supplementary Tables
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: 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: American Association for Cancer Research (AACR)
Date: 10-2013
DOI: 10.1158/1055-9965.EPI-13-0391
Abstract: Background: Ovarian carcinoma is composed of five major histologic types, which associate with outcome and predict therapeutic response. Our aim was to evaluate histologic type assessments across the centers participating in the Ovarian Tumor Tissue Analysis (OTTA) consortium using an immunohistochemical (IHC) prediction model. Methods: Tissue microarrays (TMA) and clinical data were available for 524 pathologically confirmed ovarian carcinomas. Centralized IHC was conducted for ARID1A, CDKN2A, DKK1, HNF1B, MDM2, PGR, TP53, TFF3, VIM, and WT1, and three histologic type assessments were compared: the original pathologic type, an IHC-based calculated type (termed TB_COSPv2), and a WT1-assisted TMA core review. Results: The concordance between TB_COSPv2 type and original type was 73%. Applying WT1-assisted core review, the remaining 27% discordant cases sub ided into unclassifiable (6%), TB_COSPv2 error (6%), and original type error (15%). The largest discordant subgroup was classified as endometrioid carcinoma by original type and as high-grade serous carcinoma (HGSC) by TB_COSPv2. When TB_COSPv2 classification was used, the difference in overall survival of endometrioid carcinoma compared with HGSC became significant [RR 0.60 95% confidence interval (CI), 0.37–0.93 P = 0.021], consistent with previous reports. In addition, 71 cases with unclear original type could be histologically classified by TB_COSPv2. Conclusions: Research cohorts, particularly those across different centers within consortia, show significant variability in original histologic type diagnosis. Our IHC-based reclassification produced more homogeneous types with respect to outcome than original type. Impact: Biomarker-based classification of ovarian carcinomas is feasible, improves comparability of results across research studies, and can reclassify cases which lack reliable original pathology. Cancer Epidemiol Biomarkers Prev 22(10) 1677–86. ©2013 AACR.
Publisher: American Association for Cancer Research (AACR)
Date: 2021
DOI: 10.1158/1055-9965.EPI-20-0739
Abstract: Accumulating evidence suggests a relationship between endometrial cancer and ovarian cancer. Independent genome-wide association studies (GWAS) for endometrial cancer and ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. We aimed to identify joint endometrial and ovarian cancer risk loci by performing a meta-analysis of GWAS summary statistics from these two cancers. Using LDScore regression, we explored the genetic correlation between endometrial cancer and ovarian cancer. To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e., inverse-variance meta-analysis, colocalization, and M-values) and performed analyses stratified by subtype. Candidate target genes were then prioritized using functional genomic data. Genetic correlation analysis revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 × 10−5). We found seven loci associated with risk for both cancers (PBonferroni & 2.4 × 10−9). In addition, four novel subgenome-wide regions at 7p22.2, 7q22.1, 9p12, and 11q13.3 were identified (P & 5 × 10−7). Promoter-associated HiChIP chromatin loops from immortalized endometrium and ovarian cell lines and expression quantitative trait loci data highlighted candidate target genes for further investigation. Using cross-cancer GWAS meta-analysis, we have identified several joint endometrial and ovarian cancer risk loci and candidate target genes for future functional analysis. Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger s le sets are required to confirm our findings.
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: 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: Ovid Technologies (Wolters Kluwer Health)
Date: 09-2016
DOI: 10.1097/PGP.0000000000000274
Abstract: There are 5 major histotypes of ovarian carcinomas. Diagnostic typing criteria have evolved over time, and past cohorts may be misclassified by current standards. Our objective was to reclassify the recently assembled Canadian Ovarian Experimental Unified Resource and the Alberta Ovarian Tumor Type cohorts using immunohistochemical (IHC) biomarkers and to develop an IHC algorithm for ovarian carcinoma histotyping. A total of 1626 ovarian carcinoma s les from the Canadian Ovarian Experimental Unified Resource and the Alberta Ovarian Tumor Type were subjected to a reclassification by comparing the original with the predicted histotype. Histotype prediction was derived from a nominal logistic regression modeling using a previously reclassified cohort (N=784) with the binary input of 8 IHC markers. Cases with discordant original or predicted histotypes were subjected to arbitration. After reclassification, 1762 cases from all cohorts were subjected to prediction models (χ 2 Automatic Interaction Detection, recursive partitioning, and nominal logistic regression) with a variable IHC marker input. The histologic type was confirmed in 1521/1626 (93.5%) cases of the Canadian Ovarian Experimental Unified Resource and the Alberta Ovarian Tumor Type cohorts. The highest misclassification occurred in the endometrioid type, where most of the changes involved reclassification from endometrioid to high-grade serous carcinoma, which was additionally supported by mutational data and outcome. Using the reclassified histotype as the endpoint, a 4-marker prediction model correctly classified 88%, a 6-marker 91%, and an 8-marker 93% of the 1762 cases. This study provides statistically validated, inexpensive IHC algorithms, which have versatile applications in research, clinical practice, and clinical trials.
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: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22471179
Abstract: Supplementary methods
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: Springer Science and Business Media LLC
Date: 29-06-2022
DOI: 10.1038/S41698-022-00288-2
Abstract: Hormone receptor expression is a characteristic of low-grade serous ovarian carcinoma (LGSOC). Studies investigating estrogen receptor (ER) and progesterone receptor (PR) expression levels suggest its prognostic and predictive significance, although their associations with key molecular aberrations are not well understood. As such, we sought to describe the specific genomic profiles associated with different ER/PR expression patterns and survival outcomes in a cohort of patients with advanced disease. The study comprised fifty-five advanced-staged (III/IV) LGSOCs from the Canadian Ovarian Experimental Unified Resource (COEUR) for which targeted mutation sequencing, copy-number aberration, clinical and follow-up data were available. ER, PR, and p16 expression were assessed by immunohistochemistry. Tumors were ided into low and high ER/PR expression groups based on Allred scoring. Copy number analysis revealed that PR-low tumors (Allred score ) had a higher fraction of the genome altered by copy number changes compared to PR-high tumors ( p = 0.001), with cancer genes affected within specific loci linked to altered peptidyl-tyrosine kinase, MAP-kinase, and PI3-kinase signaling. Cox regression analysis showed that ER-high ( p = 0.02), PR-high ( p = 0.03), stage III disease ( p = 0.02), low residual disease burden ( p = 0.01) and normal p16 expression ( p .001) were all significantly associated with improved overall survival. This study provides evidence that genomic aberrations are linked to ER/PR expression in primary LGSOC.
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: 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: 31-03-2023
DOI: 10.1158/1078-0432.22471185.V1
Abstract: Supplementary Figures
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: 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: 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: 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: 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: American Association for Cancer Research (AACR)
Date: 14-08-2017
DOI: 10.1158/0008-5472.CAN-16-2224
Abstract: Low-grade serous ovarian carcinomas (LGSC) are associated with a poor response to chemotherapy and are molecularly characterized by RAS pathway activation. Using exome and whole genome sequencing, we identified recurrent mutations in the protein translational regulator EIF1AX and in NF1, USP9X, KRAS, BRAF, and NRAS. RAS pathway mutations were mutually exclusive however, we found significant co-occurrence of mutations in NRAS and EIF1AX. Missense EIF1AX mutations were clustered at the N-terminus of the protein in a region associated with its role in ensuring translational initiation fidelity. Coexpression of mutant NRAS and EIF1AX proteins promoted proliferation and clonogenic survival in LGSC cells, providing the first ex le of co-occurring, growth-promoting mutational events in ovarian cancer. Cancer Res 77(16) 4268–78. ©2017 AACR.
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: 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: 31-03-2023
DOI: 10.1158/1078-0432.C.6527802
Abstract: AbstractPurpose: Although ovarian clear cell carcinomas (OCCC) are commonly resistant to platinum-based chemotherapy, good clinical outcomes are observed in a subset of patients. The explanation for this is unknown but may be due to misclassification of high-grade serous ovarian cancer (HGSOC) as OCCC or mixed histology. Experimental Design: To discover potential biomarkers of survival benefit following platinum-based chemotherapy, we ascertained a cohort of 68 Japanese and Australian patients in whom progression-free survival (PFS) and overall survival (OS) could be assessed. We performed IHC reclassification of tumors, and targeted sequencing and immunohistochemistry of known driver genes. Exome sequencing was performed in 10 patients who had either unusually long survival ( i N /i = 5) or had a very short time to progression ( i N /i = 5). Results: The majority of mixed OCCC ( i N /i = 6, 85.7%) and a small proportion of pure OCCC ( i N /i = 3, 4.9%) were reclassified as likely HGSOC. However, the PFS and OS of patients with misclassified s les were similar to that of patients with pathologically validated OCCC. Absent HNF1B expression was significantly correlated with longer PFS and OS ( i P /i = 0.0194 and 0.0395, respectively). Mutations in i ARID1A, PIK3CA, PPP2R1A /i , and i TP53 /i were frequent, but did not explain length of PFS and OS. An exploratory exome analysis of patients with favorable and unfavorable outcomes did not identify novel outcome-associated driver mutations. Conclusions: Survival benefit following chemotherapy in OCCC was not associated with pathological misclassification of tumor histotype. HNF1B loss may help identify the subset of patients with OCCC with a more favorable outcome. /
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: American Medical Association (AMA)
Date: 14-12-2017
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: 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: American Association for Cancer Research (AACR)
Date: 07-2010
DOI: 10.1158/1055-9965.EPI-09-1317
Abstract: Background: We previously reported the risks of ovarian carcinoma for common polymorphisms in one-carbon transfer genes. We sought to replicate associations for DPYD rs1801265, DNMT3A rs13420827, MTHFD1 rs1950902, MTHFS rs17284990, and TYMS rs495139 with risk of ovarian carcinoma overall and to use the large s le of assembled cases to investigate associations by histologic type. Methods: Associations were evaluated in the Ovarian Cancer Association Consortium, including 16 studies of 5,593 epithelial ovarian carcinoma cases and 9,962 controls of white non-Hispanic origin. Odds ratios (OR) and 95% confidence intervals (CI) were adjusted for age and study site. Results: The five polymorphisms were not associated with ovarian carcinoma overall (Ptrend & 0.13) however, associations for the minor allele at TYMS rs495139 were observed for carcinomas of mucinous type (OR, 1.19 95% CI, 1.03-1.39 P = 0.02), clear cell type (OR, 0.86 95% CI, 0.75-0.99 P = 0.04), and endometrioid type (OR, 0.90 95% CI, 0.81-0.99 P = 0.04 Pheterogeneity = 0.001). Restriction to low-grade mucinous carcinomas further strengthened the association for the mucinous type (OR, 1.32 95% CI, 1.07-1.62 P = 0.01). TYMS rs495139 was not associated with serous type (OR, 1.06 95% CI, 1.00-1.13 P = 0.05). Conclusions: TYMS rs495139 may be associated with a differential risk of ovarian carcinoma types, indicating the importance of accurate histopathologic classification. Impact: Biomarkers that distinguish ovarian carcinoma types are few, and TYMS rs495139 may provide a novel clue to type etiology. Cancer Epidemiol Biomarkers Prev 19(7) 1822–30. ©2010 AACR.
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: 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: 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.
Publisher: American Association for Cancer Research (AACR)
Date: 31-03-2023
DOI: 10.1158/1078-0432.22471179.V1
Abstract: Supplementary methods
No related grants have been discovered for Martin Köbel.