Breast Cancer Research (Jan 2022)

Common variants in breast cancer risk loci predispose to distinct tumor subtypes

  • Thomas U. Ahearn,
  • Haoyu Zhang,
  • Kyriaki Michailidou,
  • Roger L. Milne,
  • Manjeet K. Bolla,
  • Joe Dennis,
  • Alison M. Dunning,
  • Michael Lush,
  • Qin Wang,
  • Irene L. Andrulis,
  • Hoda Anton-Culver,
  • Volker Arndt,
  • Kristan J. Aronson,
  • Paul L. Auer,
  • Annelie Augustinsson,
  • Adinda Baten,
  • Heiko Becher,
  • Sabine Behrens,
  • Javier Benitez,
  • Marina Bermisheva,
  • Carl Blomqvist,
  • Stig E. Bojesen,
  • Bernardo Bonanni,
  • Anne-Lise Børresen-Dale,
  • Hiltrud Brauch,
  • Hermann Brenner,
  • Angela Brooks-Wilson,
  • Thomas Brüning,
  • Barbara Burwinkel,
  • Saundra S. Buys,
  • Federico Canzian,
  • Jose E. Castelao,
  • Jenny Chang-Claude,
  • Stephen J. Chanock,
  • Georgia Chenevix-Trench,
  • Christine L. Clarke,
  • NBCS Collaborators,
  • J. Margriet Collée,
  • Angela Cox,
  • Simon S. Cross,
  • Kamila Czene,
  • Mary B. Daly,
  • Peter Devilee,
  • Thilo Dörk,
  • Miriam Dwek,
  • Diana M. Eccles,
  • D. Gareth Evans,
  • Peter A. Fasching,
  • Jonine Figueroa,
  • Giuseppe Floris,
  • Manuela Gago-Dominguez,
  • Susan M. Gapstur,
  • José A. García-Sáenz,
  • Mia M. Gaudet,
  • Graham G. Giles,
  • Mark S. Goldberg,
  • Anna González-Neira,
  • Grethe I. Grenaker Alnæs,
  • Mervi Grip,
  • Pascal Guénel,
  • Christopher A. Haiman,
  • Per Hall,
  • Ute Hamann,
  • Elaine F. Harkness,
  • Bernadette A. M. Heemskerk-Gerritsen,
  • Bernd Holleczek,
  • Antoinette Hollestelle,
  • Maartje J. Hooning,
  • Robert N. Hoover,
  • John L. Hopper,
  • Anthony Howell,
  • ABCTB Investigators,
  • kConFab/AOCS Investigators,
  • Milena Jakimovska,
  • Anna Jakubowska,
  • Esther M. John,
  • Michael E. Jones,
  • Audrey Jung,
  • Rudolf Kaaks,
  • Saila Kauppila,
  • Renske Keeman,
  • Elza Khusnutdinova,
  • Cari M. Kitahara,
  • Yon-Dschun Ko,
  • Stella Koutros,
  • Vessela N. Kristensen,
  • Ute Krüger,
  • Katerina Kubelka-Sabit,
  • Allison W. Kurian,
  • Kyriacos Kyriacou,
  • Diether Lambrechts,
  • Derrick G. Lee,
  • Annika Lindblom,
  • Martha Linet,
  • Jolanta Lissowska,
  • Ana Llaneza,
  • Wing-Yee Lo,
  • Robert J. MacInnis,
  • Arto Mannermaa,
  • Mehdi Manoochehri,
  • Sara Margolin,
  • Maria Elena Martinez,
  • Catriona McLean,
  • Alfons Meindl,
  • Usha Menon,
  • Heli Nevanlinna,
  • William G. Newman,
  • Jesse Nodora,
  • Kenneth Offit,
  • Håkan Olsson,
  • Nick Orr,
  • Tjoung-Won Park-Simon,
  • Alpa V. Patel,
  • Julian Peto,
  • Guillermo Pita,
  • Dijana Plaseska-Karanfilska,
  • Ross Prentice,
  • Kevin Punie,
  • Katri Pylkäs,
  • Paolo Radice,
  • Gad Rennert,
  • Atocha Romero,
  • Thomas Rüdiger,
  • Emmanouil Saloustros,
  • Sarah Sampson,
  • Dale P. Sandler,
  • Elinor J. Sawyer,
  • Rita K. Schmutzler,
  • Minouk J. Schoemaker,
  • Ben Schöttker,
  • Mark E. Sherman,
  • Xiao-Ou Shu,
  • Snezhana Smichkoska,
  • Melissa C. Southey,
  • John J. Spinelli,
  • Anthony J. Swerdlow,
  • Rulla M. Tamimi,
  • William J. Tapper,
  • Jack A. Taylor,
  • Lauren R. Teras,
  • Mary Beth Terry,
  • Diana Torres,
  • Melissa A. Troester,
  • Celine M. Vachon,
  • Carolien H. M. van Deurzen,
  • Elke M. van Veen,
  • Philippe Wagner,
  • Clarice R. Weinberg,
  • Camilla Wendt,
  • Jelle Wesseling,
  • Robert Winqvist,
  • Alicja Wolk,
  • Xiaohong R. Yang,
  • Wei Zheng,
  • Fergus J. Couch,
  • Jacques Simard,
  • Peter Kraft,
  • Douglas F. Easton,
  • Paul D. P. Pharoah,
  • Marjanka K. Schmidt,
  • Montserrat García-Closas,
  • Nilanjan Chatterjee

DOI
https://doi.org/10.1186/s13058-021-01484-x
Journal volume & issue
Vol. 24, no. 1
pp. 1 – 13

Abstract

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Abstract 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 at p < 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.

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