Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers
Dylan M. Glubb(QIMR Berghofer Medical Research Institute), Deborah J. Thompson(Cancer Research UK), Katja K.H. Aben(Radboud University Nijmegen), Ahmad Alsulimani(Roswell Park Comprehensive Cancer Center), Frédéric Amant(KU Leuven), Daniela Annibali(KU Leuven), John Attia(John Hunter Hospital), Aurelio Barricarte(Instituto de Salud Pública de Navarra), Matthias W. Beckmann(Comprehensive Cancer Center Erlangen), Andrew Berchuck(Duke University Hospital), Marina Bermisheva(Ufa Institute of Chemistry), Marcus Q. Bernardini(Princess Margaret Cancer Centre), Katharina Bischof(Haukeland University Hospital), Line Bjørge(Haukeland University Hospital), Clara Bodelón(Cancer Genetics (United States)), Alison H. Brand(The University of Sydney), James D. Brenton(University of Cambridge), Louise A. Brinton(Cancer Genetics (United States)), Fiona Bruinsma(Cancer Council Victoria), Daniel D. Buchanan(The Royal Melbourne Hospital), Stefanie Burghaus(Comprehensive Cancer Center Erlangen), Ralf Bützow(University of Helsinki), Hui Cai(Vanderbilt University), Michael E. Carney(University of Hawaiʻi at Mānoa), Stephen J. Chanock(Department of Health and Human Services), Chu Chen(Fred Hutch Cancer Center), Xiao Qing Chen(QIMR Berghofer Medical Research Institute), Zhihua Chen(Moffitt Cancer Center), Linda S. Cook(Alberta Health Services), Julie M. Cunningham(Mayo Clinic), Immaculata De Vivo(Brigham and Women's Hospital), Anna DeFazio(Westmead Hospital), Jennifer A. Doherty(Huntsman Cancer Institute), Thilo Dörk(Medizinische Hochschule Hannover), Andreas du Bois(Praxis für Humangenetik), Alison M. Dunning(Cancer Research UK), Matthias Dürst(Friedrich Schiller University Jena), Todd Edwards(Vanderbilt University Medical Center), Robert P. Edwards(University of Pittsburgh), Arif B. Ekici(Comprehensive Cancer Center Erlangen), Ailith Ewing(Cancer Research UK), Peter A. Fasching(University of California, Los Angeles), Sarah Ferguson(Princess Margaret Cancer Centre), James M. Flanagan(Ovarian Cancer Action), Florentia Fostira(National Centre of Scientific Research "Demokritos"), George Fountzilas(Aristotle University of Thessaloniki), Christine M. Friedenreich(Alberta Health Services), Bo Gao(Westmead Hospital), Mia M. Gaudet(American Cancer Society), Jan Gawełko(University of Rzeszów), Aleksandra Gentry‐Maharaj(MRC Clinical Trials Unit at UCL), Graham G. Giles(The University of Melbourne), Rosalind Glasspool(Beatson West of Scotland Cancer Centre), Marc T. Goodman(Cedars-Sinai Medical Center), Jacek Gronwald(Pomeranian Medical University), Holly R. Harris(University of Washington), Philipp Harter(Kliniken Essen-Mitte), Alexander Hein(Comprehensive Cancer Center Erlangen), Florian Heitz(Kliniken Essen-Mitte), Michelle A.T. Hildebrandt(The University of Texas MD Anderson Cancer Center), Peter Hillemanns(Medizinische Hochschule Hannover), Estrid Høgdall(Herlev Hospital), Claus Høgdall(University of Copenhagen), Elizabeth Holliday(John Hunter Hospital), David G. Huntsman(BC Cancer Agency), Tomasz Huzarski(International Hereditary Cancer Center), Anna Jakubowska(Pomeranian Medical University), Allan Jensen(Danish Cancer Society), Michael E. Jones(Cancer Research UK), Beth Y. Karlan(University of California, Los Angeles), Anthony N. Karnezis(University of California Davis Medical Center), Joseph L. Kelley(University of Pittsburgh), Э. К. Хуснутдинова(Bashkir State University), Jeffrey Killeen(Kapiolani Medical Center for Women and Children), Susanne K. Kjær(University of Copenhagen), Rüdiger Klapdor(Medizinische Hochschule Hannover), Martin Köbel(Foothills Medical Centre), Bożena Konopka(National Institute of Oncology), Irene Konstantopoulou(National Centre of Scientific Research "Demokritos"), Reidun Kristin Kopperud(Haukeland University Hospital), Madhuri Koti(Queen's University), Peter Kraft(Harvard University), Jolanta Kupryjańczyk(National Institute of Oncology), Diether Lambrechts(VIB-KU Leuven Center for Cancer Biology), Melissa C. Larson(Mayo Clinic), Loı̈c Le Marchand(Cancer Center of Hawaii), Shashikant Lele(Gynecologic Oncology Group), Jenny Lester(University of California, Los Angeles), Andrew J. Li(Cedars-Sinai Medical Center), Dong Liang(Texas Southern University), Clemens Liebrich(Fraunhofer Project Centre Wolfsburg), Loren Lipworth(Vanderbilt University Medical Center), Jolanta Lissowska(The Maria Sklodowska-Curie National Research Institute of Oncology), Lingeng Lu(Yale University), Karen H. Lu(The University of Texas MD Anderson Cancer Center), Alessandra Macciotta(Kliniken Essen-Mitte), Amalia Mattiello(Federico II University Hospital), Taymaa May(Princess Margaret Cancer Centre), Jessica N. McAlpine(Vancouver General Hospital), Valerie McGuire(Stanford Health Care), Iain A. McNeish(Ovarian Cancer Action), Usha Menon(MRC Clinical Trials Unit at UCL), Francesmary Modugno(University of Pittsburgh), Kirsten B. Moysich(Roswell Park Comprehensive Cancer Center), Heli Nevanlinna(University of Helsinki), Kunle Odunsi(Gynecologic Oncology Group), Håkan Olsson(Lund University), Sandra Oršulić(Cedars-Sinai Medical Center), Ana Osório(Spanish National Cancer Research Centre), Domenico Palli(Prevention Institute), Tjoung‐Won Park‐Simon(Medizinische Hochschule Hannover), Celeste Leigh Pearce(University of Southern California), Tanja Pejović(Oregon Health & Science University), Jennifer B. Permuth(Moffitt Cancer Center), Agnieszka Podgórska(National Institute of Oncology), Susan J. Ramus(Cancer Institute of New South Wales), Timothy R. Rebbeck(Massachusetts Department of Public Health), Marjorie J. Riggan(Duke University Hospital), Harvey A. Risch(Yale University), Joseph H. Rothstein(Icahn School of Medicine at Mount Sinai), Ingo B. Runnebaum(Friedrich Schiller University Jena), Rodney J. Scott(John Hunter Hospital), Thomas A. Sellers(Moffitt Cancer Center), Janine Senz(University of British Columbia), Veronica Wendy Setiawan(University of Southern California), Nadeem Siddiqui(Glasgow Royal Infirmary), Weiva Sieh(Icahn School of Medicine at Mount Sinai), Beata Śpiewankiewicz(Radom College), Rebecca Sutphen(University of South Florida), Anthony J. Swerdlow(Breast Cancer Now), Lukasz M. Szafron(The Maria Sklodowska-Curie National Research Institute of Oncology), Soo‐Hwang Teo(University of Malaya), Pamela J. Thompson(Cedars-Sinai Medical Center), Liv Cecilie Vestrheim Thomsen(Haukeland University Hospital), Linda Titus(Dartmouth College), Alicia Tone(Princess Margaret Cancer Centre), Rosario Tumino(Humboldt-Universität zu Berlin), Constance Turman(Harvard University), Adriaan Vanderstichele(VIB-KU Leuven Center for Cancer Biology), Digna Velez Edwards(Vanderbilt University Medical Center), Ignace Vergote(VIB-KU Leuven Center for Cancer Biology), Robert A. Vierkant(Mayo Clinic), Zhaoming Wang(Cancer Genetics (United States)), Shan Wang‐Gohrke(University Hospital Ulm), Penelope M. Webb(QIMR Berghofer Medical Research Institute), for the OPAL Study Group(University of Washington), for the AOCS Group(Stanford Health Care), Emily White(Mayo Clinic), Alice S. Whittemore(The University of Texas MD Anderson Cancer Center), Stacey J. Winham(University of Southern California), Xifeng Wu(The University of Texas MD Anderson Cancer Center), Anna H. Wu(University of Southern California), Drakoulis Yannoukakos(National Centre of Scientific Research "Demokritos"), Amanda B. Spurdle(QIMR Berghofer Medical Research Institute), Tracy A. O’Mara(QIMR Berghofer Medical Research Institute)
Cited by 23Open Access
Abstract
Abstract Background: 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. Methods: 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. Results: 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. Conclusions: 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. Impact: Our research highlights the shared genetic relationship between endometrial cancer and ovarian cancer. Further studies in larger sample sets are required to confirm our findings.
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