Combining genome-wide studies of breast, prostate, ovarian and endometrial cancers maps cross-cancer susceptibility loci and identifies new genetic associations
Authors: Kar Siddhartha P. , Lindström Sara , Hung Rayjean J. , Lawrenson Kate , Schmidt Marjanka K. , O’Mara Tracy A. , Glubb Dylan M. , Tyrer Jonathan P. , Schildkraut Joellen M. , Chang-Claude Jenny , Alsulimani Ahmad G. M. , Antón Fernando M. , Beeghly-Fadiel Alicia , Bjørge Line , Bodelon Clara , Brauch Hiltrud , Burghaus Stefanie , Campa Daniele , Carney Michael , Chen Chu , Chen Zhihua , Daly Mary B. , Bois Andreas du , Ekici Arif B. , Ewing Ailith , Fasching Peter , Flanagan James M. , Gawelko Jan , Giles Graham G. , Hamilton Robert J. , Harris Holly R. , Heitz Florian , Hildebrandt Michelle , Hillemanns Peter , Huang Ruea-Yea , Imaz Liher , Irmejs Arvids , Jakubowska Anna , Jensen Allan , John Esther M. , Kannisto Päivi , Karlan Beth Y. , Khusnutdinova Elza , Kiemeney Lambertus A. , Kjaer Susanne K. , Klapdor Rüdiger , Kleiblova Petra , Köbel Martin , Konopka Bozena , Krakstad Camilla , Lessel Davor , Lophatananon Artitaya , May Taymaa , Mieszkowska Agnieszka D. , Monteiro Alvaro N. , Moysich Kirsten , Muir Kenneth , Nielsen Sune F. , Odunsi Kunle , Olsson Håkan , Park-Simon Tjoung-Won , Permuth Jennifer B. , Peterlongo Paolo , Podgorski Agnieszka , Prentice Ross , Radice Paolo , Risch Harvey A. , Runnebaum Ingo B. , Rzepecka Iwona K. , Scott Rodney J. , Setiawan Veronica W. , Siddiqui Nadeem , Sieh Weiva , Śpiewankiewicz Beata , Szafron Lukasz M. , Thompson Cheryl L. , Titus Linda J. , Turnbull Clare , Usmani Nawaid , van Altena Anne M. , Vega-Gliemmo Ana , Vergote Ignace , Vierkant Robert A. , Vijai Joseph , Winham Stacey J. , Winqvist Robert , Yu Herbert ,   the PRACTICAL consortium, CRUK, BPC3, CAPS, PEGASUS, Lambrechts Diether , Thompson Deborah J. , Goode Ellen L. , Zheng Wei , Tomlinson Ian P. M. , Berchuck Andrew , Ramus Susan J. , Chanock Stephen J. , Easton Douglas F. , Chenevix-Trench Georgia , Gayther Simon A. , Spurdle Amanda B. , Eeles Rosalind A. , Kraft Peter , Pharoah Paul D. P. 
Published: June 2020

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<5×10−8) 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<2.6×10−6) 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.