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Combining genome-wide studies of breast, prostate, ovarian and endometrial cancers maps cross-cancer susceptibility loci and identifies new genetic associations

By Siddhartha P. Kar, Sara Lindström, Rayjean J Hung, Kate Lawrenson, Marjanka K. Schmidt, Tracy A O'Mara, Dylan A Glubb, Jonathan P. Tyrer, Joellen M. Schildkraut, Jenny Chang-Claude, Ahmad G. M. Alsulimani, Fernando M. Antón, Alicia Beeghly-Fadiel, Line Bjørge, Clara Bodelon, Hiltrud Brauch, Stefanie Burghaus, Daniele Campa, Michael Carney, Chu Chen, Zhihua Chen, Mary B. Daly, Andreas du Bois, Arif B. Ekici, Ailith Ewing, Peter Fasching, James M. Flanagan, Jan Gawelko, Graham G Giles, Robert J. Hamilton, Holly R. Harris, Florian Heitz, Michelle Hildebrandt, Peter Hillemanns, Ruea-Yea Huang, Liher Imaz, Arvids Irmejs, Anna Jakubowska, Allan Jensen, Esther M. John, Päivi Kannisto, Beth Y Karlan, Elza Khusnutdinova, Lambertus A Kiemeney, Susanne K. Kjaer, Rüdiger Klapdor, Petra Kleiblova, Martin Köbel, Bozena Konopka, Camilla Krakstad, Davor Lessel, Artitaya Lophatananon, Taymaa May, Agnieszka D. Mieszkowska, Alvaro N Monteiro, Kirsten Moysich, Kenneth Muir, Sune F. Nielsen, Kunle Odunsi, Håkan Olsson, Tjoung-Won Park-Simon, Jenny B. Permuth, Paolo Peterlongo, Agnieszka Podgorski, Ross Prentice, Paolo Radice, Harvey A. Risch, Ingo B. Runnebaum, Iwona K. Rzepecka, Rodney J Scott, Veronica W Setiawan, Nadeem Siddiqui, Weiva Sieh, Beata Śpiewankiewicz, Lukasz M. Szafron, Cheryl L. Thompson, Linda J. Titus, Clare Turnbull, Nawaid Usmani, Anne M. van Altena, Ana Vega-Gliemmo, Ignace Vergote, Robert A. Vierkant, Joseph Vijai, Stacey J Winham, Robert Winqvist, Herbert Yu, the PRACTICAL consortium, CRUK, BPC3, CAPS, PEGASUS, Diether Lambrechts, Deborah J. Thompson, Ellen L Goode, Wei Zheng, Ian P. M. Tomlinson, Andrew Berchuck, Susan J. Ramus, Stephen J. Chanock, Douglas F. Easton, Georgia Chenevix-Trench, Simon A Gayther, Amanda B Spurdle, Rosalind A. Eeles, Peter Kraft, Paul Pharoah

Posted 19 Jun 2020
bioRxiv DOI: 10.1101/2020.06.16.146803

We report a meta-analysis of breast, prostate, ovarian, and endometrial cancer genome-wide association data (effective sample size: 237,483 cases/317,006 controls). This identified 465 independent lead variants ( P <5x10-8) across 192 genomic regions. Four lead variants were >1Mb from previously identified risk loci for the four cancers and an additional 23 lead variant-cancer associations were novel for one of the cancers. Bayesian models supported pleiotropic effects involving at least two cancers at 222/465 lead variants in 118/192 regions. Gene-level association analysis identified 13 shared susceptibility genes ( P <2.6x10-6) in 13 regions not previously implicated in any of the four cancers and not uncovered by our variant-level meta-analysis. Several lead variants had opposite effects across cancers, including a cluster of such variants in the TP53 pathway. Fifty-four lead variants were associated with blood cell traits and suggested genetic overlaps with clonal hematopoiesis. Our study highlights the remarkable pervasiveness of pleiotropy across hormone-related cancers, further illuminating their shared genetic and mechanistic origins at variant- and gene-level resolution. ### Competing Interest Statement Since completing the work included in this paper, D.J.T. has left the University of Cambridge and is now employed by Genomics plc.

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