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

Ahearn, Thomas U and Zhang, Haoyu and Michailidou, Kyriaki and Milne, Roger L and Bolla, Manjeet K and Dennis, Joe and Dunning, Alison M and Lush, Michael and Wang, Qin and Andrulis, Irene L and Anton-Culver, Hoda and Arndt, Volker and Aronson, Kristan J and Auer, Paul L and Augustinsson, Annelie and Baten, Adinda and Becher, Heiko and Behrens, Sabine and Benitez, Javier and Bermisheva, Marina and Blomqvist, Carl and Bojesen, Stig E and Bonanni, Bernardo and Børresen-Dale, Anne-Lise and Brauch, Hiltrud and Brenner, Hermann and Brooks-Wilson, Angela and Brüning, Thomas and Burwinkel, Barbara and Buys, Saundra S and Canzian, Federico and Castelao, Jose E and Chang-Claude, Jenny and Chanock, Stephen J and Chenevix-Trench, Georgia and Clarke, Christine L and Collée, J Margriet and Cox, Angela and Cross, Simon S and Czene, Kamila and Daly, Mary B and Devilee, Peter and Dörk, Thilo and Dwek, Miriam and Eccles, Diana M and Evans, D Gareth and Fasching, Peter A and Figueroa, Jonine and Floris, Giuseppe and Gago-Dominguez, Manuela and Gapstur, Susan M and García-Sáenz, José A and Gaudet, Mia M and Giles, Graham G and Goldberg, Mark S and González-Neira, Anna and Alnæs, Grethe I Grenaker and Grip, Mervi and Guénel, Pascal and Haiman, Christopher A and Hall, Per and Hamann, Ute and Harkness, Elaine F and Heemskerk-Gerritsen, Bernadette A M and Holleczek, Bernd and Hollestelle, Antoinette and Hooning, Maartje J and Hoover, Robert N and Hopper, John L and Howell, Anthony and Jakimovska, Milena and Jakubowska, Anna and John, Esther M and Jones, Michael E and Jung, Audrey and Kaaks, Rudolf and Kauppila, Saila and Keeman, Renske and Khusnutdinova, Elza and Kitahara, Cari M and Ko, Yon-Dschun and Koutros, Stella and Kristensen, Vessela N and Krüger, Ute and Kubelka-Sabit, Katerina and Kurian, Allison W and Kyriacou, Kyriacos and Lambrechts, Diether and Lee, Derrick G and Lindblom, Annika and Linet, Martha and Lissowska, Jolanta and Llaneza, Ana and Lo, Wing-Yee and MacInnis, Robert J and Mannermaa, Arto and Manoochehri, Mehdi and Margolin, Sara and Martinez, Maria Elena and McLean, Catriona and Meindl, Alfons and Menon, Usha and Nevanlinna, Heli and Newman, William G and Nodora, Jesse and Offit, Kenneth and Olsson, Håkan and Orr, Nick and Park-Simon, Tjoung-Won and Patel, Alpa V and Peto, Julian and Pita, Guillermo and Plaseska-Karanfilska, Dijana and Prentice, Ross and Punie, Kevin and Pylkäs, Katri and Radice, Paolo and Rennert, Gad and Romero, Atocha and Rüdiger, Thomas and Saloustros, Emmanouil and Sampson, Sarah and Sandler, Dale P and Sawyer, Elinor J and Schmutzler, Rita K and Schoemaker, Minouk J and Schöttker, Ben and Sherman, Mark E and Shu, Xiao-Ou and Smichkoska, Snezhana and Southey, Melissa C and Spinelli, John J and Swerdlow, Anthony J and Tamimi, Rulla M and Tapper, William J and Taylor, Jack A and Teras, Lauren R and Terry, Mary Beth and Torres, Diana and Troester, Melissa A and Vachon, Celine M and van Deurzen, Carolien H M and van Veen, Elke M and Wagner, Philippe and Weinberg, Clarice R and Wendt, Camilla and Wesseling, Jelle and Winqvist, Robert and Wolk, Alicja and Yang, Xiaohong R and Zheng, Wei and Couch, Fergus J and Simard, Jacques and Kraft, Peter and Easton, Douglas F and Pharoah, Paul D P and Schmidt, Marjanka K and García-Closas, Montserrat and Chatterjee, Nilanjan (2022) Common variants in breast cancer risk loci predispose to distinct tumor subtypes. Breast cancer research : BCR, 24 (1). p. 2. ISSN 1465-542X

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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.


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.


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.


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.

Item Type: Article
Impact Factor Value: 8.408
Subjects: Medical and Health Sciences > Basic medicine
Medical and Health Sciences > Clinical medicine
Divisions: Faculty of Medical Science
Depositing User: Katerina Kubelka-Sabit
Date Deposited: 13 Jan 2023 10:47
Last Modified: 13 Jan 2023 10:47

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