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Cross-Cancer Genome-Wide Association Study of Endometrial Cancer and Epithelial Ovarian Cancer Identifies Genetic Risk Regions Associated with Risk of Both Cancers

2020; American Association for Cancer Research; Volume: 30; Issue: 1 Linguagem: Inglês

10.1158/1055-9965.epi-20-0739

1538-7755

Dylan M. Glubb, Deborah J. Thompson, Katja K.H. Aben, Ahmad Alsulimani, Frédéric Amant, Daniela Annibali, John Attia, Aurelio Barricarte, Matthias W. Beckmann, Andrew Berchuck, Marina Bermisheva, Marcus Q. Bernardini, Katharina Bischof, Line Bjørge, Clara Bodelón, Alison H. Brand, James D. Brenton, Louise A. Brinton, Fiona Bruinsma, Daniel D. Buchanan, Stefanie Burghaus, Ralf Bützow, Hui Cai, Michael E. Carney, Stephen J. Chanock, Chu Chen, Xiaohong Chen, Zhihua Chen, Linda S. Cook, Julie M. Cunningham, Immaculata De Vivo, Anna deFazio, Jennifer A. Doherty, Thilo Dörk, Andreas du Bois, Alison M. Dunning, Matthias Dürst, Todd Edwards, Robert P. Edwards, Arif B. Ekici, Ailith Ewing, Peter A. Fasching, Sarah Ferguson, James M. Flanagan, Florentia Fostira, George Fountzilas, Christine M. Friedenreich, Bo Gao, Mia M. Gaudet, Jan Gawełko, Aleksandra Gentry‐Maharaj, Graham G. Giles, Rosalind Glasspool, Marc T. Goodman, Jacek Gronwald, Holly R. Harris, Philipp Harter, Alexander Hein, Florian Heitz, Michelle A.T. Hildebrandt, Peter Hillemanns, Estrid Høgdall, Claus Høgdall, Elizabeth Holliday, David G. Huntsman, Tomasz Huzarski, Anna Jakubowska, Allan Jensen, Michael E. Jones, Beth Y. Karlan, Anthony N. Karnezis, Joseph L. Kelley, Э. К. Хуснутдинова, Jeffrey Killeen, Susanne K. Kjær, Rüdiger Klapdor, Martin Köbel, Bożena Konopka, Irene Konstantopoulou, Reidun Kristin Kopperud, Madhuri Koti, Peter Kraft, Jolanta Kupryjańczyk, Diether Lambrechts, Melissa C. Larson, Loı̈c Le Marchand, Shashikant Lele, Jenny Lester, Andrew J. Li, Dong Liang, Clemens Liebrich, Loren Lipworth, Jolanta Lissowska, Lingeng Lu, Karen H. Lu, Alessandra Macciotta, Amalia Mattiello, Taymaa May, Jessica N. McAlpine, Valerie McGuire, Iain A. McNeish, Usha Menon, Francesmary Modugno, Kirsten B. Moysich, Heli Nevanlinna, Kunle Odunsi, Håkan Olsson, Sandra Oršulić, Ana Osório, Domenico Palli, Tjoung‐Won Park‐Simon, Celeste Leigh Pearce, Tanja Pejović, Jennifer B. Permuth, Agnieszka Podgórska, Susan J. Ramus, Timothy R. Rebbeck, Marjorie J. Riggan, Harvey A. Risch, Joseph H. Rothstein, Ingo B. Runnebaum, Rodney J. Scott, Thomas A. Sellers, Janine Senz, Veronica Wendy Setiawan, Nadeem Siddiqui, Weiva Sieh, Beata Śpiewankiewicz, Rebecca Sutphen, Anthony J. Swerdlow, Lukasz M. Szafron, Soo‐Hwang Teo, Pamela J. Thompson, Liv Cecilie Vestrheim Thomsen, Linda Titus, Alicia Tone, ­Rosario ­Tumino, Constance Turman, Adriaan Vanderstichele, Digna Velez Edwards, Ignace Vergote, Robert A. Vierkant, Zhaoming Wang, Shan Wang‐Gohrke, Penelope M. Webb, Emily White, Alice S. Whittemore, Stacey J. Winham, Xifeng Wu, Anna H. Wu, Drakoulis Yannoukakos, Amanda B. Spurdle, Tracy A. O’Mara,

Genetic Associations and Epidemiology

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.