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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

By Dylan A Glubb, Deborah J. Thompson, Katja K.H. Aben, Ahmad Alsulimani, Frederic Amant, Daniela Annibali, John Attia, Aurelio Barricarte, Matthias W. Beckmann, Andrew Berchuck, Marina Bermisheva, Marcus Q Bernardini, Line Bjorge, Clara Bodelon, Alison H. Brand, James Brenton, Louise Brinton, Fiona Bruinsma, Daniel D Buchanan, Stefanie Burghaus, Ralf Butzow, Hui Cai, Michael E. Carney, Stephen J. Chanock, Chu Chen, Xiao Qing Chen, Zhihua Chen, Linda S. Cook, Julie M. Cunningham, Immaculata De Vivo, Anna deFazio, Jennifer A Doherty, Thilo Dork, Andreas du Bois, Alison M Dunning, Matthias Durst, Todd 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 Gawelko, Aleksandra Gentry-Maharaj, Graham G Giles, Rosalind Glasspool, Marc T. Goodman, Jacek Gronwald, OPAL Study, AOCS, Holly R. Harris, Philipp Harter, Alexander Hein, Florian Heitz, Michelle A.T. Hildebrandt, Peter Hillemanns, Estrid Hogdall, Claus K. Hogdall, Elizabeth G. Holliday, David G. Huntsman, Tomasz Huzarski, Anna Jakubowska, Allan Jensen, Michael E. Jones, Beth Y Karlan, Anthony Karnezis, Elza Khusnutdinova, Jeffrey L. Killeen, Susanne K. Kjaer, Rudiger Klapdor, Martin Kobel, Bozena Konopka, Irene Konstantopoulou, Reidun K. Kopperud, Madhuri Koti, Peter Kraft, Jolanta Kupryjanczyk, Diether Lambrechts, Melissa C Larson, Loic Le Marchand, Shashikant B. 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 McAlpine, Valerie McGuire, Iain A. McNeish, Usha Menon, Francesmary Modugno, Kirsten B. Moysich, Heli Nevanlinna, Kunle Odunsi, HÃ¥kan Olsson, Sandra Orsulic, Ana Osorio, Domenico Palli, Tjoung-Won Park-Simon, Celeste Pearce, Tanja Pejovic, Jennifer B Permuth, Agnieszka Podgorska, Susan J. Ramus, Timothy R Rebbeck, Marjorie J. Riggan, Harvey A. Risch, Joseph H. Rothstein, Ingo Runnebaum, Rodney J. Scott, Thomas A Sellers, Janine Senz, V. Wendy Setiawan, Nadeem Siddiqui, Weiva Sieh, Beata Spiewankiewicz, Anthony J. Swerdlow, Rebecca Sutphen, Lukasz 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

Posted 02 May 2020
medRxiv DOI: 10.1101/2020.04.29.20084095

Accumulating evidence suggests a relationship between endometrial cancer and epithelial ovarian cancer. For example, endometrial cancer and epithelial ovarian cancer share epidemiological risk factors and molecular features observed across histotypes are held in common (e.g. serous, endometrioid and clear cell). Independent genome-wide association studies (GWAS) for endometrial cancer and epithelial ovarian cancer have identified 16 and 27 risk regions, respectively, four of which overlap between the two cancers. Using GWAS summary statistics, we explored the shared genetic etiology between endometrial cancer and epithelial ovarian cancer. Genetic correlation analysis using LD Score regression revealed significant genetic correlation between the two cancers (rG = 0.43, P = 2.66 x 10-5). To identify loci associated with the risk of both cancers, we implemented a pipeline of statistical genetic analyses (i.e. inverse-variance meta-analysis, co-localization, and M-values), and performed analyses by stratified by subtype. We found seven loci associated with risk for both cancers (PBonferroni < 2.4 x 10-9). In addition, four novel regions at 7p22.2, 7q22.1, 9p12 and 11q13.3 were identified at a sub-genome wide threshold (P < 5 x 10-7). Integration with promoter-associated HiChIP chromatin loops from immortalized endometrium and epithelial ovarian cell lines, and expression quantitative trait loci (eQTL) data highlighted candidate target genes for further investigation.

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