Common variants in breast cancer risk loci predispose to distinct tumor subtypes
Author(s)
Ahearn, TU; Zhang, H; Michailidou, K; Milne, RL; Bolla, MK; Dennis, J; Dunning, AM; Lush, M; Wang, Q; Andrulis, IL; Anton-Culver, H; Arndt, V; Aronson, KJ; Auer, PL; Augustinsson, A; Baten, A; Becher, H; Behrens, S; Benitez, J; Bermisheva, M; Blomqvist, C; Bojesen, SE; Bonanni, B; Borresen-Dale, AL; Brauch, H; Brenner, H; Brooks-Wilson, A; Bruning, T; Burwinkel, B; Buys, SS; Canzian, F; Castelao, JE; Chang-Claude, J; Chanock, SJ; Chenevix-Trench, G; Clarke, CL; NBCS Collaborators; Collee, JM; Cox, A; Cross, SS; Czene, K; Daly, MB; Devilee, P; Dork, T; Dwek, M; Eccles, DM; Evans, DG; Fasching, PA; Figueroa, J; Floris, G; Gago-Dominguez, M; Gapstur, SM; Garcia-Saenz, JA; Gaudet, MM; Giles, GG; Goldberg, MS; Gonzalez-Neira, A; Grenaker Alnaes, GI; Grip, M; Guenel, P; Haiman, CA; Hall, P; Hamann, U; Harkness, EF; Heemskerk-Gerritsen, BAM; Holleczek, B; Hollestelle, A; Hooning, MJ; Hoover, RN; Hopper, JL; Howell, A; ABCTB Investigators; kConFab/AOCS Investigators; Jakimovska, M; Jakubowska, A; John, EM; Jones, ME; Jung, A; Kaaks, R; Kauppila, S; Keeman, R; Khusnutdinova, E; Kitahara, CM; Ko, YD; Koutros, S; Kristensen, VN; Kruger, U; Kubelka-Sabit, K; Kurian, AW; Kyriacou, K; Lambrechts, D; Lee, DG; Lindblom, A; Linet, M; Lissowska, J; Llaneza, A; Lo, WY; MacInnis, RJ; Mannermaa, A; Manoochehri, M; Margolin, S; Martinez, ME; McLean, C; Meindl, A; Menon, U; Nevanlinna, H; Newman, WG; Nodora, J; Offit, K; Olsson, H; Orr, N; Park-Simon, TW; Patel, AV; Peto, J; Pita, G; Plaseska-Karanfilska, D; Prentice, R; Punie, K; Pylkas, K; Radice, P; Rennert, G; Romero, A; Rudiger, T; Saloustros, E; Sampson, S; Sandler, DP; Sawyer, EJ; Schmutzler, RK; Schoemaker, MJ; Schottker, B; Sherman, ME; Shu, XO; Smichkoska, S; Southey, MC; Spinelli, JJ; Swerdlow, AJ; Tamimi, RM; Tapper, WJ; Taylor, JA; Teras, LR; Terry, MB; Torres, D; Troester, MA; Vachon, CM; van Deurzen, CHM; van Veen, EM; Wagner, P; Weinberg, CR; Wendt, C; Wesseling, J; Winqvist, R; Wolk, A; Yang, XR; Zheng, W; Couch, FJ; Simard, J; Kraft, P; Easton, DF; Pharoah, PDP; Schmidt, MK; Garcia-Closas, M; Chatterjee, N;
Journal Title
Breast Cancer Research
Publication Type
Research article
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.
Keywords
Biomarkers, Tumor/genetics/metabolism; *Breast Neoplasms/epidemiology/genetics/metabolism; Female; Genome-Wide Association Study; Humans; Receptor, ErbB-2/genetics/metabolism; Receptors, Estrogen/genetics/metabolism; Receptors, Progesterone/genetics/metabolism; Risk
Department(s)
Laboratory Research
PubMed ID
34983606
Open Access at Publisher's Site
https://doi.org/10.1186/s13058-021-01484-x
Terms of Use/Rights Notice
Refer to copyright notice on published article.


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