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.
Original language | English |
---|---|
Article number | 2 |
Number of pages | 13 |
Journal | Breast Cancer Research |
Volume | 24 |
Issue number | 1 |
DOIs | |
Publication status | Published - 1 Dec 2022 |
Keywords
- Breast cancer
- Common breast cancer susceptibility variants
- Etiologic heterogeneity
- Genetic predisposition
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In: Breast Cancer Research, Vol. 24, No. 1, 2, 01.12.2022.
Research output: Contribution to journal › Article › Research › peer-review
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 - Helland, Åslaug
AU - Riis, Margit
AU - Geisler, Jürgen
AU - Collée, J. Margriet
AU - Cox, Angela
AU - Cross, Simon S.
AU - Czene, Kamila
AU - Daly, Mary B.
AU - Devilee, Peter
AU - Dörk, Thilo
AU - Dwek, Miriam
AU - Eccles, Diana M.
AU - Evans, D. Gareth
AU - Fasching, Peter A.
AU - Figueroa, Jonine
AU - Floris, Giuseppe
AU - Gago-Dominguez, Manuela
AU - Gapstur, Susan M.
AU - García-Sáenz, José A.
AU - Gaudet, Mia M.
AU - Giles, Graham G.
AU - Goldberg, Mark S.
AU - González-Neira, Anna
AU - Alnæs, Grethe I.Grenaker
AU - Grip, Mervi
AU - Guénel, Pascal
AU - Haiman, Christopher A.
AU - Hall, Per
AU - Hamann, Ute
AU - Harkness, Elaine F.
AU - Heemskerk-Gerritsen, Bernadette A.M.
AU - Holleczek, Bernd
AU - Hollestelle, Antoinette
AU - Hooning, Maartje J.
AU - Hoover, Robert N.
AU - Hopper, John L.
AU - Howell, Anthony
AU - Clarke, Christine
AU - Balleine, Rosemary
AU - Baxter, Robert
AU - Braye, Stephen
AU - Carpenter, Jane
AU - Dahlstrom, Jane
AU - Forbes, John
AU - Lee, CSoon S.
AU - Marsh, Deborah
AU - Morey, Adrienne
AU - Pathmanathan, Nirmala
AU - Scott, Rodney
AU - Simpson, Peter
AU - Spigelman, Allan
AU - Wilcken, Nicholas
AU - Yip, Desmond
AU - Zeps, Nikolajs
AU - Fox, Stephen
AU - Campbell, Ian
AU - Bowtell, David
AU - Spurdle, Amanda
AU - Webb, Penny
AU - de Fazio, Anna
AU - Tassell, Margaret
AU - Kirk, Judy
AU - Lindeman, Geoff
AU - Price, Melanie
AU - Deb, Sid
AU - Jakimovska, Milena
AU - Jakubowska, Anna
AU - John, Esther M.
AU - Jones, Michael E.
AU - Jung, Audrey
AU - Kaaks, Rudolf
AU - Kauppila, Saila
AU - Keeman, Renske
AU - Khusnutdinova, Elza
AU - Kitahara, Cari M.
AU - Ko, Yon Dschun
AU - Koutros, Stella
AU - Kristensen, Vessela N.
AU - Krüger, Ute
AU - Kubelka-Sabit, Katerina
AU - Kurian, Allison W.
AU - Kyriacou, Kyriacos
AU - Lambrechts, Diether
AU - Lee, Derrick G.
AU - Lindblom, Annika
AU - Linet, Martha
AU - Lissowska, Jolanta
AU - Llaneza, Ana
AU - Lo, Wing Yee
AU - MacInnis, Robert J.
AU - Mannermaa, Arto
AU - Manoochehri, Mehdi
AU - Margolin, Sara
AU - Martinez, Maria Elena
AU - McLean, Catriona
AU - Meindl, Alfons
AU - Menon, Usha
AU - Nevanlinna, Heli
AU - Newman, William G.
AU - Nodora, Jesse
AU - Offit, Kenneth
AU - Olsson, Håkan
AU - Orr, Nick
AU - Park-Simon, Tjoung Won
AU - Patel, Alpa V.
AU - Peto, Julian
AU - Pita, Guillermo
AU - Plaseska-Karanfilska, Dijana
AU - Prentice, Ross
AU - Punie, Kevin
AU - Pylkäs, Katri
AU - Radice, Paolo
AU - Rennert, Gad
AU - Romero, Atocha
AU - Rüdiger, Thomas
AU - Saloustros, Emmanouil
AU - Sampson, Sarah
AU - Sandler, Dale P.
AU - Sawyer, Elinor J.
AU - Schmutzler, Rita K.
AU - Schoemaker, Minouk J.
AU - Schöttker, Ben
AU - Sherman, Mark E.
AU - Shu, Xiao Ou
AU - Smichkoska, Snezhana
AU - Southey, Melissa C.
AU - Spinelli, John J.
AU - Swerdlow, Anthony J.
AU - Tamimi, Rulla M.
AU - Tapper, William J.
AU - Taylor, Jack A.
AU - Teras, Lauren R.
AU - Terry, Mary Beth
AU - Torres, Diana
AU - Troester, Melissa A.
AU - Vachon, Celine M.
AU - van Deurzen, Carolien H.M.
AU - van Veen, Elke M.
AU - Wagner, Philippe
AU - Weinberg, Clarice R.
AU - Wendt, Camilla
AU - Wesseling, Jelle
AU - Winqvist, Robert
AU - Wolk, Alicja
AU - Yang, Xiaohong R.
AU - Zheng, Wei
AU - Couch, Fergus J.
AU - Simard, Jacques
AU - Kraft, Peter
AU - Easton, Douglas F.
AU - Pharoah, Paul D.P.
AU - Schmidt, Marjanka K.
AU - García-Closas, Montserrat
AU - Chatterjee, Nilanjan
AU - NBCS Collaborators
AU - ABCTB Investigators
AU - kConFab/AOCS Investigators
N1 - Funding Information: Open Access funding provided by the National Institutes of Health (NIH) This project has been funded in part with Federal funds from the National Cancer Institute Intramural Research Program, National Institutes of Health. Dr. Nilanjan Chatterjee was supported by NHGRI (1R01 HG010480-01). Dr. Haoyu Zhang was supported by National Cancer Institute (1K99 CA256513). OncoArray genotyping was funded by the government of Canada through Genome Canada and the Canadian Institutes of Health Research (GPH-129344), the Ministère de l'Économie, de la Science et de l'Innovation du Québec through Génome Québec, the Quebec Breast Cancer Foundation for the PERSPECTIVE project, the US National Institutes of Health (NIH) (1 U19 CA 148065 for the Discovery, Biology and Risk of Inherited Variants in Breast Cancer (DRIVE) project and X01HG007492 to the Center for Inherited Disease Research (CIDR) under contract HHSN268201200008I), Cancer Research UK (C1287/A16563), the Odense University Hospital Research Foundation (Denmark), the National R&D Program for Cancer Control–Ministry of Health and Welfare (Republic of Korea) (1420190), the Italian Association for Cancer Research (AIRC; IG16933), the Breast Cancer Research Foundation, the National Health and Medical Research Council (Australia) and German Cancer Aid (110837). iCOGS genotyping was funded by the European Union (HEALTH-F2-2009–223175), Cancer Research UK (C1287/A10710, C1287/A10118 and C12292/A11174]), NIH grants (CA128978, CA116167 and CA176785) and the Post-Cancer GWAS initiative (1U19 CA148537, 1U19 CA148065 and 1U19 CA148112 (GAME-ON initiative)), an NCI Specialized Program of Research Excellence (SPORE) in Breast Cancer (CA116201), the Canadian Institutes of Health Research (CIHR) for the CIHR Team in Familial Risks of Breast Cancer, the Ministère de l'Économie, Innovation et Exportation du Québec (PSR-SIIRI-701), the Komen Foundation for the Cure, the Breast Cancer Research Foundation and the Ovarian Cancer Research Fund. A full description of the funding is provided in the Additional file : Funding and Acknowledgement. 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
C2 - 34983606
AN - SCOPUS:85122468719
SN - 1465-542X
VL - 24
JO - Breast Cancer Research
JF - Breast Cancer Research
IS - 1
M1 - 2
ER -