1. Combining genome-wide studies of breast, prostate, ovarian and endometrial cancers maps cross-cancer susceptibility loci and identifies new genetic associations
- Author
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Rosalind A. Eeles, Anne van Altena, Rüdiger Klapdor, Rayjean J. Hung, Graham G. Giles, Ingo B. Runnebaum, Stacey J. Winham, Alicia Beeghly-Fadiel, Michelle A.T. Hildebrandt, Ruea-Yea Huang, Amanda B. Spurdle, Ahmad Alsulimani, Robert Winqvist, Robert J. Hamilton, Clare Turnbull, James M. Flanagan, Jan Gawełko, Kenneth Muir, Peter Kraft, Joseph Vijai, Anna Jakubowska, Paul D.P. Pharoah, Stephen J. Chanock, Ailith Ewing, Mary B. Daly, Artitaya Lophatananon, Arvids Irmejs, Hiltrud Brauch, Paolo Radice, Camilla Krakstad, Liher Imaz, Lambertus A. Kiemeney, Clara Bodelon, Nadeem Siddiqui, Alvaro N.A. Monteiro, Bozena Konopka, Taymaa May, Herbert Yu, Stefanie Burghaus, Michael E. Carney, Siddhartha Kar, Beata Spiewankiewicz, Fernando Moreno Antón, Andreas du Bois, Sune F. Nielsen, Ian Tomlinson, Elza Khusnutdinova, Paolo Peterlongo, Zhihua Chen, Deborah J. Thompson, Agnieszka Podgorski, Päivi Kannisto, Andrew Berchuck, Jenny Chang-Claude, Susan J. Ramus, Florian Heitz, Nawaid Usmani, Tracy A. O'Mara, Joellen M. Schildkraut, Jennifer Permuth, Beth Y. Karlan, Ignace Vergote, Douglas F. Easton, Sara Lindstroem, Agnieszka Mieszkowska, Kirsten B. Moysich, Ana Vega-Gliemmo, Simon A. Gayther, Arif B. Ekici, Lukasz Szafron, Kunle Odunsi, Marjanka K. Schmidt, Harvey A. Risch, Linda J. Titus, Weiva Sieh, Robert A. Vierkant, Davor Lessel, Line Bjørge, Allan Jensen, Wei Zheng, Holly R. Harris, Petra Kleiblova, Peter A. Fasching, Jonathan Tyrer, Iwona K. Rzepecka, Georgia Chenevix-Trench, Tjoung-Won Park-Simon, Susanne K. Kjaer, Esther M. John, Daniele Campa, Veronica Wendy Setiawan, Martin Koebel, Cheryl L. Thompson, Håkan Olsson, Dylan M. Glubb, Peter Hillemanns, and Kate Lawrenson
- Subjects
Oncology ,medicine.medical_specialty ,Endometrial cancer ,Cancer susceptibility ,Susceptibility gene ,Effective sample size ,Biology ,medicine.disease ,Genome ,medicine.anatomical_structure ,Prostate ,Internal medicine ,medicine ,Genetic association - Abstract
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−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−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.
- Published
- 2020