Genome-wide association study identifies 32 novel breast cancer susceptibility loci from overall and subtype-specific analyses
Authors: Zhang Haoyu , Ahearn Thomas U. , Lecarpentier Julie , Barnes Daniel , Beesley Jonathan , Jiang Xia , O’Mara Tracy A. , Qi Guanghao , Zhao Ni , Bolla Manjeet K. , Dunning Alison M. , Dennis Joe , Wang Qin , Ful Zumuruda Abu , Aittomäki Kristiina , Andrulis Irene L. , Anton-Culver Hoda , Arndt Volker , Aronson Kristan J. , Arun Banu K. , Auer Paul L. , Azzollini Jacopo , Barrowdale Daniel , Becher Heiko , Beckmann Matthias W. , Behrens Sabine , Benitez Javier , Bermisheva Marina , Bialkowska Katarzyna , Blanco Ana , Blomqvist Carl , Bogdanova Natalia V. , Bojesen Stig E. , Bonanni Bernardo , Bondavalli Davide , Borg Ake , Brauch Hiltrud , Brenner Hermann , Briceno Ignacio , Broeks Annegien , Brucker Sara Y. , Brüning Thomas , Burwinkel Barbara , Buys Saundra S. , Byers Helen , Caldés Trinidad , Caligo Maria A. , Calvello Mariarosaria , Campa Daniele , Castelao Jose E. , Chang-Claude Jenny , Chanock Stephen J. , Christiaens Melissa , Christiansen Hans , Chung Wendy K. , Claes Kathleen B.M. , Clarke Christine L. , Cornelissen Sten , Couch Fergus J. , Cox Angela , Cross Simon S. , Czene Kamila , Daly Mary B. , Devilee Peter , Diez Orland , Domchek Susan M. , Dörk Thilo , Dwek Miriam , Eccles Diana M. , Ekici Arif B. , Evans D.Gareth , Fasching Peter A. , Figueroa Jonine , Foretova Lenka , Fostira Florentia , Friedman Eitan , Frost Debra , Gago-Dominguez Manuela , Gapstur Susan M. , Garber Judy , García-Sáenz José A. , Gaudet Mia M. , Gayther Simon A. , Giles Graham G. , Godwin Andrew K. , Goldberg Mark S. , Goldgar David E. , González-Neira Anna , Greene Mark H. , Gronwald Jacek , Guénel Pascal , Häberle Lothar , Hahnen Eric , Haiman Christopher A. , Hake Christopher R. , Hall Per , Hamann Ute , Harkness Elaine F. , Heemskerk-Gerritsen Bernadette A.M. , Hillemanns Peter , Hogervorst Frans B.L. , Holleczek Bernd , Hollestelle Antoinette , Hooning Maartje J. , Hoover Robert N. , Hopper John L. , Howell Anthony , Huebner Hanna , Hulick Peter J. , Imyanitov Evgeny N. ,   kConFab Investigators,   ABCTB Investigators, Isaacs Claudine , Izatt Louise , Jager Agnes , Jakimovska Milena , Jakubowska Anna , James Paul , Janavicius Ramunas , Janni Wolfgang , John Esther M. , Jones Michael E. , Jung Audrey , Kaaks Rudolf , Kapoor Pooja Middha , Karlan Beth Y. , Keeman Renske , Khan Sofia , Khusnutdinova Elza , Kitahara Cari M. , Ko Yon-Dschun , Konstantopoulou Irene , Koppert Linetta B. , Koutros Stella , Kristensen Vessela N. , Laenkholm Anne-Vibeke , Lambrechts Diether , Larsson Susanna C. , Laurent-Puig Pierre , Lazaro Conxi , Lazarova Emilija , Lejbkowicz Flavio , Leslie Goska , Lesueur Fabienne , Lindblom Annika , Lissowska Jolanta , Lo Wing-Yee , Loud Jennifer T. , Lubinski Jan , Lukomska Alicja , MacInnis Robert J. , Mannermaa Arto , Manoochehri Mehdi , Manoukian Siranoush , Margolin Sara , Martinez Maria Elena , Matricardi Laura , McGuffog Lesley , McLean Catriona , Mebirouk Noura , Meindl Alfons , Menon Usha , Miller Austin , Mingazheva Elvira , Montagna Marco , Mulligan Anna Marie , Mulot Claire , Muranen Taru A. , Nathanson Katherine L. , Neuhausen Susan L. , Nevanlinna Heli , Neven Patrick , Newman William G. , Nielsen Finn C. , Nikitina-Zake Liene , Nodora Jesse , Offit Kenneth , Olah Edith , Olopade Olufunmilayo I. , Olsson Håkan , Orr Nick , Papi Laura , Papp Janos , Park-Simon Tjoung-Won , Parsons Michael T. , Peissel Bernard , Peixoto Ana , Peshkin Beth , Peterlongo Paolo , Peto Julian , Phillips Kelly-Anne , Piedmonte Marion , Plaseska-Karanfilska Dijana , Prajzendanc Karolina , Prentice Ross , Prokofyeva Darya , Rack Brigitte , Radice Paolo , Ramus Susan J. , Rantala Johanna , Rashid Muhammad U. , Rennert Gad , Rennert Hedy S. , Risch Harvey A. , Romero Atocha , Rookus Matti A. , Rübner Matthias , Rüdiger Thomas , Saloustros Emmanouil , Sampson Sarah , Sandler Dale P. , Sawyer Elinor J. , Scheuner Maren T. , Schmutzler Rita K. , Schneeweiss Andreas , Schoemaker Minouk J. , Schöttker Ben , Schürmann Peter , Senter Leigha , Sharma Priyanka , Sherman Mark E. , Shu Xiao-Ou , Singer Christian F. , Smichkoska Snezhana , Soucy Penny , Southey Melissa C. , Spinelli John J. , Stone Jennifer , Stoppa-Lyonnet Dominique ,   EMBRACE Study,   GEMO Study Collaborators, Swerdlow Anthony J. , Szabo Csilla I. , Tamimi Rulla M. , Tapper William J. , Taylor Jack A. , Teixeira Manuel R. , Terry MaryBeth , Thomassen Mads , Thull Darcy L. , Tischkowitz Marc , Toland Amanda E. , Tollenaar Rob A.E.M. , Tomlinson Ian , Torres Diana , Troester Melissa A. , Truong Thérèse , Tung Nadine , Untch Michael , Vachon Celine M. , van den Ouweland Ans M.W. , van der Kolk Lizet E. , van Veen Elke M. , van Rensburg Elizabeth J. , Vega Ana , Wappenschmidt Barbara , Weinberg Clarice R. , Weitzel Jeffrey N. , Wildiers Hans , Winqvist Robert , Wolk Alicja , Yang Xiaohong R. , Yannoukakos Drakoulis , Zheng Wei , Zorn Kristin K. , Zuradelli Monica , Milne Roger L. , Kraft Peter , Simard Jacques , Pharoah Paul D.P. , Michailidou Kyriaki , Antoniou Antonis C. , Schmidt Marjanka K. , Chenevix-Trench Georgia , Easton Douglas F. , Chatterjee Nilanjan , García-Closas Montserrat 
Published: September 2019

Breast cancer susceptibility variants frequently show heterogeneity in associations by tumor subtype. To identify novel loci, we performed a genome-wide association study (GWAS) including 133,384 breast cancer cases and 113,789 controls, plus 18,908BRCA1mutation carriers (9,414 with breast cancer) of European ancestry, using both standard and novel methodologies that account for underlying tumor heterogeneity by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2) status and tumor grade. We identified 32 novel susceptibility loci (P<5.0×10-8), 15 of which showed evidence for associations with at least one tumor feature (false discovery rate <0.05). Five loci showed associations (P<0.05) in opposite directions between luminal- and non-luminal subtypes.In-silicoanalyses showed these five loci contained cell-specific enhancers that differed between normal luminal and basal mammary cells. The genetic correlations between five intrinsic-like subtypes ranged from 0.35 to 0.80. The proportion of genome-wide chip heritability explained by all known susceptibility loci was 37.6% for triple-negative and 54.2% for luminal A-like disease. These findings provide an improved understanding of genetic predisposition to breast cancer subtypes and will inform the development of subtype-specific polygenic risk scores.