TY - JOUR
T1 - Common variants in breast cancer risk loci predispose to distinct tumor subtypes
AU - Ahearn, Thomas U.
AU - Zhang, Haoyu
AU - Michailidou, Kyriaki
AU - Milne, Roger L.
AU - Bolla, Manjeet K.
AU - Dennis, Joe
AU - Dunning, Alison M.
AU - Lush, Michael
AU - Wang, Qin
AU - Andrulis, Irene L.
AU - Anton-Culver, Hoda
AU - Arndt, Volker
AU - Aronson, Kristan J.
AU - Auer, Paul L.
AU - Augustinsson, Annelie
AU - Baten, Adinda
AU - Becher, Heiko
AU - Behrens, Sabine
AU - Benitez, Javier
AU - Bermisheva, Marina
AU - Blomqvist, Carl
AU - Bojesen, Stig E.
AU - Bonanni, Bernardo
AU - Børresen-Dale, Anne Lise
AU - Brauch, Hiltrud
AU - Brenner, Hermann
AU - Brooks-Wilson, Angela
AU - Brüning, Thomas
AU - Burwinkel, Barbara
AU - Buys, Saundra S.
AU - Canzian, Federico
AU - Castelao, Jose E.
AU - Chang-Claude, Jenny
AU - Chanock, Stephen J.
AU - Chenevix-Trench, Georgia
AU - Clarke, Christine L.
AU - Sahlberg, Kristine K.
AU - Ottestad, Lars
AU - Kåresen, Rolf
AU - Schlichting, Ellen
AU - Holmen, Marit Muri
AU - Sauer, Toril
AU - Haakensen, Vilde
AU - Engebråten, Olav
AU - Naume, Bjørn
AU - Fosså, Alexander
AU - Kiserud, Cecile E.
AU - Reinertsen, Kristin V.
AU - Dahlstrom, Jane
AU - Morey, Adrienne
N1 - Publisher Copyright:
© 2021, The Author(s).
PY - 2022/12/1
Y1 - 2022/12/1
N2 - 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.
AB - 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.
KW - Breast cancer
KW - Common breast cancer susceptibility variants
KW - Etiologic heterogeneity
KW - Genetic predisposition
UR - http://www.scopus.com/inward/record.url?scp=85122468719&partnerID=8YFLogxK
U2 - 10.1186/s13058-021-01484-x
DO - 10.1186/s13058-021-01484-x
M3 - Article
SN - 1465-5411
VL - 24
JO - Breast Cancer Research
JF - Breast Cancer Research
IS - 1
M1 - 2
ER -