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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

Authors
Siddhartha Kar,Sara Lindströem
Rayjean Hung,Kate Lawrenson,Marjanka Schmidt,Tracy O’Mara,Dylan Glubb,Jonathan Tyrer,Joellen Schildkraut,Jenny Chang‐Claude,Ahmad Alsulimani,Fernando Antón,Alicia Beeghly–Fadiel,Line Bjørge,Clara Bodelón,Hiltrud Brauch,Stefanie Burghaus,Daniele Campa,Michael Carney,Zhihua Chen,Mary Daly,Andreas Bois,Arif Ekici,Ailith Ewing,Peter Fasching,James Flanagan,Jan Gawełko,Graham Giles,Robert Hamilton,Holly Harris,Florian Heitz,Michelle Hildebrandt,Peter Hillemanns,Ruea‐Yea Huang,Liher Imaz,Arvīds Irmejs,Anna Jakubowska,Allan Jensen,Esther John,Päivi Kannisto,Beth Karlan,Elza Khusnutdinova,Lambertus Kiemeney,Susanne Kjær,Rüdiger Klapdor,Petra Kleiblová,Martin Köebel,B Konopka,Camilla Krakstad,Davor Lessel,Artitaya Lophatananon,Taymaa May,Agnieszka Mieszkowska,Álvaro Monteiro,Kirsten Moysich,Kenneth Muir,Sune Nielsen,Kunle Odunsi,Håkan Olsson,Tjoung‐Won Park‐Simon,Jennifer Permuth,Paolo Peterlongo,Agnieszka Podgorski,Paolo Radice,Harvey Risch,Ingo Runnebaum,Iwona Rzepecka,Veronica Setiawan,Nadeem Siddiqui,Weiva Sieh,Beata Śpiewankiewicz,Lukasz Szafron,Cheryl Thompson,Linda Titus,Clare Turnbull,Nawaid Usmani,Anne Altena,Ana Vega-Gliemmo,Ignace Vergote,Robert Vierkant,Joseph Vijai,Stacey Winham,Robert Winqvist,Herbert Yu,Deborah Thompson,Zheng Wang,Ian Tomlinson,Andrew Berchuck,Susan Ramus,Stephen Chanock,Douglas Easton,Georgia Chenevix-Trench,Simon Gayther,Amanda Spurdle,Rosalind Eeles,Peter Kraft,Paul Pharoah,Alicia Beeghly‐Fadiel,Catherine Huntley,Sara Lindström,Jingmei Li,Fernando Moreno,Michael Quinn,Chu Chen,Mary Terry,Э. Хуснутдинова,Martin Köbel,Iain McNeish,Alvaro Monteiro,Jonas Nielsen,Ana Peixoto,Ross Prentice,Rodney Scott,Lara Sucheston‐Campbell,Ana Vega‐Gliemmo,Diether Lambrechts,Ellen Goode,Wei Zheng
+116 authors
,Georgia Chenevix‐Trench
Published
Jun 19, 2020
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Abstract

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 <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.

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