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Grant Details

Grant Number: 5R01CA248288-02 Interpret this number
Primary Investigator: Goode, Ellen
Organization: Mayo Clinic Rochester
Project Title: Relating Molecular Subgroups of Endometriosis-Associated Ovarian Cancers to Survival and Risk
Fiscal Year: 2022


Abstract

PROJECT SUMMARY/ABSTRACT Ovarian cancer (OC) is the eleventh most common cancer and fifth deadliest among U.S. women. The low incidence, high fatality and molecularly broad range of tumor histotypes make OC challenging to study and to treat. Consequently, survival rates have scarcely changed over the past 35 years, largely because precision therapy lags behind most other cancers. Endometrioid (ENOC) and clear cell (CCOC) account for ~25% of all invasive OC. They are a heterogeneous and understudied group of tumors that are closely associated with endometriosis, but show few similarities to the more common high grade serous OC. ENOC or CCOC have variable or poor response to standard platinum-based chemotherapy. CCOC, in particular, is more likely to be platinum resistant at early stage and resistant to second line chemotherapy at advanced stage, resulting in worse survival than HGSOC. We hypothesize that molecular tumor subtypes exist for ENOC and CCOC that reflect differences in biological processes and risk factors and that might inform new treatment strategies. Our preliminary results using genomics analyses of 185 ENOC and 115 CCOC supports this hypothesis by showing that associations with survival and risk factors such as smoking and body mass index differ according to the tumor’s molecular profile, with some subgroups showing rapidly fatal outcome. In the current proposal, we intend to delve deeper into the genomic profile of ~1,100 ENOC and CCOC tumors to identify key molecular features of the tumor subtypes. Our approach uses a consortium effort that combines existing data from well-conducted epidemiologic studies of risk factors with corresponding clinical information among investigators with a strong history of collaboration. We will first characterize molecular subtypes, separately for ENOC and CCOC, by integrating sequencing and array data from gene expression, mutations and methylated regions from a training set (483 ENOC, 292 CCOC) using statistical clustering. Next, we will assess replication of the molecular subtypes in an independent test set (207 ENOC, 125 CCOC). To assess subtype-specific associations in the total sample (689 ENOC, 417 CCOC), we will relate molecular subtypes of ENOC and CCOC separately to risk factors and to survival. Impact: Less common OC such as ENOC or CCOC are often overshadowed by investigations of more common cancers, yet our data show that ENOC and CCOC can also be rapidly fatal in certain patient subsets or show more favorable outcome in others, directly impacting patients’ lives. Finding patterns with other cancers by using integrated analysis of ENOC and CCOC subtypes has high potential to inform new avenues for targeted therapy and to enhance understanding of ENOC and CCOC cancer biology. Future replication of our findings using an independent 1,400 ENOC/CCOC tumors from our unique consortia resources can lead to needed gains in biological, epidemiologic and therapeutic insights for these patients.



Publications

The proteome of clear cell ovarian carcinoma.
Authors: Ji J.X. , Cochrane D.R. , Negri G.L. , Colborne S. , Spencer Miko S.E. , Hoang L.N. , Farnell D. , Tessier-Cloutier B. , Huvila J. , Thompson E. , et al. .
Source: The Journal of pathology, 2022 Dec; 258(4), p. 325-338.
EPub date: 2022-10-14.
PMID: 36031730
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Molecular Subclasses of Clear Cell Ovarian Carcinoma and Their Impact on Disease Behavior and Outcomes.
Authors: Bolton K.L. , Chen D. , Corona de la Fuente R. , Fu Z. , Murali R. , Köbel M. , Tazi Y. , Cunningham J.M. , Chan I.C.C. , Wiley B.J. , et al. .
Source: Clinical cancer research : an official journal of the American Association for Cancer Research, 2022-11-14; 28(22), p. 4947-4956.
PMID: 35816189
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Into the future: A pilot study combining imaging with molecular profiling to predict resectability in ovarian cancer.
Authors: Kumar A. , Wang C. , Sheedy S.P. , McCauley B.M. , Winham S.J. , Ramus S.J. , Anglesio M.S. , Kim B. , Torres D. , Keeney G.L. , et al. .
Source: Gynecologic oncology, 2022 Sep; 166(3), p. 508-514.
EPub date: 2022-08-02.
PMID: 35931468
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Germline BRCA variants, lifestyle and ovarian cancer survival.
Authors: Gersekowski K. , Delahunty R. , Alsop K. , Goode E.L. , Cunningham J.M. , Winham S.J. , Pharoah P. , Song H. , Jordan S. , Fereday S. , et al. .
Source: Gynecologic oncology, 2022 Jun; 165(3), p. 437-445.
EPub date: 2022-04-07.
PMID: 35400525
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Correction: Polygenic risk modeling for prediction of epithelial ovarian cancer risk.
Authors: Dareng E.O. , Tyrer J.P. , Barnes D.R. , Jones M.R. , Yang X. , Aben K.K.H. , Adank M.A. , Agata S. , Andrulis I.L. , Anton-Culver H. , et al. .
Source: European journal of human genetics : EJHG, 2022 May; 30(5), p. 630-631.
PMID: 35314806
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CA-125 Levels Are Predictive of Survival in Low-Grade Serous Ovarian Cancer-A Multicenter Analysis.
Authors: Wohlmuth C. , Djedovic V. , Kjaer S.K. , Jensen A. , Glasspool R. , Roxburgh P. , DeFazio A. , Johnatty S.E. , Webb P.M. , Modugno F. , et al. .
Source: Cancers, 2022-04-13; 14(8), .
EPub date: 2022-04-13.
PMID: 35454861
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Validated biomarker assays confirm that ARID1A loss is confounded with MMR deficiency, CD8+ TIL infiltration, and provides no independent prognostic value in endometriosis-associated ovarian carcinomas.
Authors: Heinze K. , Nazeran T.M. , Lee S. , Krämer P. , Cairns E.S. , Chiu D.S. , Leung S.C. , Kang E.Y. , Meagher N.S. , Kennedy C.J. , et al. .
Source: The Journal of pathology, 2022 Apr; 256(4), p. 388-401.
EPub date: 2022-02-07.
PMID: 34897700
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MCM3 is a novel proliferation marker associated with longer survival for patients with tubo-ovarian high-grade serous carcinoma.
Authors: Kang E.Y. , Millstein J. , Popovic G. , Meagher N.S. , Bolithon A. , Talhouk A. , Chiu D.S. , Anglesio M.S. , Leung B. , Tang K. , et al. .
Source: Virchows Archiv : an international journal of pathology, 2022 Apr; 480(4), p. 855-871.
EPub date: 2021-11-15.
PMID: 34782936
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Polygenic risk modeling for prediction of epithelial ovarian cancer risk.
Authors: Dareng E.O. , Tyrer J.P. , Barnes D.R. , Jones M.R. , Yang X. , Aben K.K.H. , Adank M.A. , Agata S. , Andrulis I.L. , Anton-Culver H. , et al. .
Source: European journal of human genetics : EJHG, 2022 Mar; 30(3), p. 349-362.
EPub date: 2022-01-14.
PMID: 35027648
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High Prediagnosis Inflammation-Related Risk Score Associated with Decreased Ovarian Cancer Survival.
Authors: Brieger K.K. , Phung M.T. , Mukherjee B. , Bakulski K.M. , Anton-Culver H. , Bandera E.V. , Bowtell D.D.L. , Cramer D.W. , DeFazio A. , Doherty J.A. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2022 Feb; 31(2), p. 443-452.
EPub date: 2021-11-17.
PMID: 34789471
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Computational tumor stroma reaction evaluation led to novel prognosis-associated fibrosis and molecular signature discoveries in high-grade serous ovarian carcinoma.
Authors: Jiang J. , Tekin B. , Yuan L. , Armasu S. , Winham S.J. , Goode E.L. , Liu H. , Huang Y. , Guo R. , Wang C. .
Source: Frontiers in medicine, 2022; 9, p. 994467.
EPub date: 2022-09-07.
PMID: 36160147
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DNA Methylation Profiles of Ovarian Clear Cell Carcinoma.
Authors: Cunningham J.M. , Winham S.J. , Wang C. , Weiglt B. , Fu Z. , Armasu S.M. , McCauley B.M. , Brand A.H. , Chiew Y.E. , Elishaev E. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2022 Jan; 31(1), p. 132-141.
EPub date: 2021-10-25.
PMID: 34697060
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Identification of a Locus Near ULK1 Associated With Progression-Free Survival in Ovarian Cancer.
Authors: Quinn M.C.J. , McCue K. , Shi W. , Johnatty S.E. , Beesley J. , Civitarese A. , O'Mara T.A. , Glubb D.M. , Tyrer J.P. , Armasu S.M. , et al. .
Source: Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology, 2021 Sep; 30(9), p. 1669-1680.
EPub date: 2021-06-23.
PMID: 34162658
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Pleiotropy-guided transcriptome imputation from normal and tumor tissues identifies candidate susceptibility genes for breast and ovarian cancer.
Authors: Kar S.P. , Considine D.P.C. , Tyrer J.P. , Plummer J.T. , Chen S. , Dezem F.S. , Barbeira A.N. , Rajagopal P.S. , Rosenow W.T. , Moreno F. , et al. .
Source: HGG advances, 2021-07-08; 2(3), .
EPub date: 2021-06-16.
PMID: 34317694
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Frequent POLE-driven hypermutation in ovarian endometrioid cancer revealed by mutational signatures in RNA sequencing.
Authors: Davila J.I. , Chanana P. , Sarangi V. , Fogarty Z.C. , Weroha S.J. , Guo R. , Goode E.L. , Huang Y. , Wang C. .
Source: BMC medical genomics, 2021-06-22; 14(1), p. 165.
EPub date: 2021-06-22.
PMID: 34158040
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Gene-based mediation analysis in epigenetic studies.
Authors: Fang R. , Yang H. , Gao Y. , Cao H. , Goode E.L. , Cui Y. .
Source: Briefings in bioinformatics, 2021-05-20; 22(3), .
PMID: 32608480
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Population-based targeted sequencing of 54 candidate genes identifies PALB2 as a susceptibility gene for high-grade serous ovarian cancer.
Authors: Song H. , Dicks E.M. , Tyrer J. , Intermaggio M. , Chenevix-Trench G. , Bowtell D.D. , Traficante N. , Group A. , Brenton J. , Goranova T. , et al. .
Source: Journal of medical genetics, 2021 May; 58(5), p. 305-313.
EPub date: 2020-06-16.
PMID: 32546565
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Circulating CD14+ HLA-DRlo/- monocytic cells as a biomarker for epithelial ovarian cancer progression.
Authors: Stenzel A.E. , Abrams S.I. , Joseph J.M. , Goode E.L. , Tario J.D. , Wallace P.K. , Kaur D. , Adamson A.K. , Buas M.F. , Lugade A.A. , et al. .
Source: American journal of reproductive immunology (New York, N.Y. : 1989), 2021 Mar; 85(3), p. e13343.
EPub date: 2020-09-21.
PMID: 32905653
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Expanding Our Understanding of Ovarian Cancer Risk: The Role of Incomplete Pregnancies.
Authors: Lee A.W. , Rosenzweig S. , Wiensch A. , Australian Ovarian Cancer Study Group , Ramus S.J. , Menon U. , Gentry-Maharaj A. , Ziogas A. , Anton-Culver H. , Whittemore A.S. , et al. .
Source: Journal of the National Cancer Institute, 2021-03-01; 113(3), p. 301-308.
PMID: 32766851
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Generating real-world evidence from unstructured clinical notes to examine clinical utility of genetic tests: use case in BRCAness.
Authors: Zhao Y. , Weroha S.J. , Goode E.L. , Liu H. , Wang C. .
Source: BMC medical informatics and decision making, 2021-01-06; 21(1), p. 3.
EPub date: 2021-01-06.
PMID: 33407429
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