Common variants in breast cancer risk loci predispose to distinct tumor subtypes
Authors: Ahearn Thomas U. , Zhang Haoyu , Michailidou Kyriaki , Milne Roger L. , Bolla Manjeet K. , Dennis Joe , Dunning Alison M. , Lush Michael , Wang Qin , Andrulis Irene L. , Anton-Culver Hoda , Arndt Volker , Aronson Kristan J. , Auer Paul L. , Augustinsson Annelie , Baten Adinda , Becher Heiko , Behrens Sabine , Benitez Javier , Bermisheva Marina , Blomqvist Carl , Bojesen Stig E. , Bonanni Bernardo , Børresen-Dale Anne-Lise , Brauch Hiltrud , Brenner Hermann , Brooks-Wilson Angela , Brüning Thomas , Burwinkel Barbara , Buys Saundra S. , Canzian Federico , Castelao Jose E. , Chang-Claude Jenny , Chanock Stephen J. , Chenevix-Trench Georgia , Clarke Christine L. ,   NBCS Collaborators, Sahlberg Kristine K. , Ottestad Lars , Kåresen Rolf , Schlichting Ellen , Holmen Marit Muri , Sauer Toril , Haakensen Vilde , Engebråten Olav , Naume Bjørn , Fosså Alexander , Kiserud Cecile E. , Reinertsen Kristin V. , Helland Åslaug , Riis Margit , Geisler Jürgen , Collée J. Margriet , Cox Angela , Cross Simon S. , Czene Kamila , Daly Mary B. , Devilee Peter , Dörk Thilo , Dwek Miriam , Eccles Diana M. , Evans D. Gareth , Fasching Peter A. , Figueroa Jonine , Floris Giuseppe , Gago-Dominguez Manuela , Gapstur Susan M. , García-Sáenz José A. , Gaudet Mia M. , Giles Graham G. , Goldberg Mark S. , González-Neira Anna , Alnæs Grethe I. Grenaker , Grip Mervi , Guénel Pascal , Haiman Christopher A. , Hall Per , Hamann Ute , Harkness Elaine F. , Heemskerk-Gerritsen Bernadette A. M. , Holleczek Bernd , Hollestelle Antoinette , Hooning Maartje J. , Hoover Robert N. , Hopper John L. , Howell Anthony ,   ABCTB Investigators, Clarke Christine , Balleine Rosemary , Baxter Robert , Braye Stephen , Carpenter Jane , Dahlstrom Jane , Forbes John , Lee CSoon , Marsh Deborah , Morey Adrienne , Pathmanathan Nirmala , Scott Rodney , Simpson Peter , Spigelman Allan , Wilcken Nicholas , Yip Desmond , Zeps Nikolajs ,   kConFab/AOCS Investigators, Fox Stephen , Campbell Ian , Bowtell David , Chenevix-Trench Georgia , Spurdle Amanda , Webb Penny , de Fazio Anna , Tassell Margaret , Kirk Judy , Lindeman Geoff , Price Melanie , Southey Melissa , Milne Roger , Deb Sid , Jakimovska Milena , Jakubowska Anna , John Esther M. , Jones Michael E. , Jung Audrey , Kaaks Rudolf , Kauppila Saila , Keeman Renske , Khusnutdinova Elza , Kitahara Cari M. , Ko Yon-Dschun , Koutros Stella , Kristensen Vessela N. , Krüger Ute , Kubelka-Sabit Katerina , Kurian Allison W. , Kyriacou Kyriacos , Lambrechts Diether , Lee Derrick G. , Lindblom Annika , Linet Martha , Lissowska Jolanta , Llaneza Ana , Lo Wing-Yee , MacInnis Robert J. , Mannermaa Arto , Manoochehri Mehdi , Margolin Sara , Martinez Maria Elena , McLean Catriona , Meindl Alfons , Menon Usha , Nevanlinna Heli , Newman William G. , Nodora Jesse , Offit Kenneth , Olsson Håkan , Orr Nick , Park-Simon Tjoung-Won , Patel Alpa V. , Peto Julian , Pita Guillermo , Plaseska-Karanfilska Dijana , Prentice Ross , Punie Kevin , Pylkäs Katri , Radice Paolo , Rennert Gad , Romero Atocha , Rüdiger Thomas , Saloustros Emmanouil , Sampson Sarah , Sandler Dale P. , Sawyer Elinor J. , Schmutzler Rita K. , Schoemaker Minouk J. , Schöttker Ben , Sherman Mark E. , Shu Xiao-Ou , Smichkoska Snezhana , Southey Melissa C. , Spinelli John J. , Swerdlow Anthony J. , Tamimi Rulla M. , Tapper William J. , Taylor Jack A. , Teras Lauren R. , Terry Mary Beth , Torres Diana , Troester Melissa A. , Vachon Celine M. , van Deurzen Carolien H. M. , van Veen Elke M. , Wagner Philippe , Weinberg Clarice R. , Wendt Camilla , Wesseling Jelle , Winqvist Robert , Wolk Alicja , Yang Xiaohong R. , Zheng Wei , Couch Fergus J. , Simard Jacques , Kraft Peter , Easton Douglas F. , Pharoah Paul D. P. , Schmidt Marjanka K. , García-Closas Montserrat , Chatterjee Nilanjan 
Published: January 2022

Background

Genome-wide association studies (GWAS) have identified multiple common breast cancer susceptibility variants. Many of these variants have differential associations by estrogen receptor (ER) status, but how these variants relate with other tumor features and intrinsic molecular subtypes is unclear.

Methods

Among 106,571 invasive breast cancer cases and 95,762 controls of European ancestry with data on 173 breast cancer variants identified in previous GWAS, we used novel two-stage polytomous logistic regression models to evaluate variants in relation to multiple tumor features (ER, progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2) and grade) adjusting for each other, and to intrinsic-like subtypes.

Results

Eighty-five of 173 variants were associated with at least one tumor feature (false discovery rate < 5%), most commonly ER and grade, followed by PR and HER2. Models for intrinsic-like subtypes found nearly all of these variants (83 of 85) associated atp < 0.05 with risk for at least one luminal-like subtype, and approximately half (41 of 85) of the variants were associated with risk of at least one non-luminal subtype, including 32 variants associated with triple-negative (TN) disease. Ten variants were associated with risk of all subtypes in different magnitude. Five variants were associated with risk of luminal A-like and TN subtypes in opposite directions.

Conclusion

This report demonstrates a high level of complexity in the etiology heterogeneity of breast cancer susceptibility variants and can inform investigations of subtype-specific risk prediction.