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

UBC Faculty Research and Publications

Common variants in breast cancer risk loci predispose to distinct tumor subtypes Ahearn, Thomas U.; Zhang, Haoyu; Michailidou, Kyriaki; Milne, Roger L.; Bolla, Manjeet K.; Dennis, Joe; Dunning, Alison M.; Lush, Michael; Wang, Qin; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Aronson, Kristan J.; Auer, Paul L.; Augustinsson, Annelie; Baten, Adinda; Becher, Heiko; Behrens, Sabine; Benitez, Javier; Bermisheva, Marina; Blomqvist, Carl; Bojesen, Stig E.; Bonanni, Bernardo; Børresen-Dale, Anne-Lise; Brauch, Hiltrud; Brenner, Hermann; Brooks-Wilson, Angela; Brüning, Thomas; Burwinkel, Barbara; Buys, Saundra S.; Canzian, Federico; Castelao, Jose E.; Chang-Claude, Jenny; Chanock, Stephen J.; Chenevix-Trench, Georgia; Clarke, Christine L.; Collée, J. M.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Daly, Mary B.; Devilee, Peter; Dörk, Thilo; Dwek, Miriam; Eccles, Diana M.; Evans, D. G.; Fasching, Peter A.; Figueroa, Jonine; Floris, Giuseppe; Gago-Dominguez, Manuela; Gapstur, Susan M.; García-Sáenz, José A.; Gaudet, Mia M.; Giles, Graham G.; Goldberg, Mark S.; González-Neira, Anna; Alnæs, Grethe I. G.; Grip, Mervi; Guénel, Pascal; Haiman, Christopher A.; Hall, Per; Hamann, Ute; Harkness, Elaine F.; Heemskerk-Gerritsen, Bernadette A. M.; Holleczek, Bernd; Hollestelle, Antoinette; Hooning, Maartje J.; Hoover, Robert N.; Hopper, John L.; Howell, Anthony; Jakimovska, Milena; Jakubowska, Anna; John, Esther M.; Jones, Michael E.; Jung, Audrey; Kaaks, Rudolf; Kauppila, Saila; Keeman, Renske; Khusnutdinova, Elza; Kitahara, Cari M.; Ko, Yon-Dschun; Koutros, Stella; Kristensen, Vessela N.; Krüger, Ute; Kubelka-Sabit, Katerina; Kurian, Allison W.; Kyriacou, Kyriacos; Lambrechts, Diether; Lee, Derrick G.; Lindblom, Annika; Linet, Martha; Lissowska, Jolanta; Llaneza, Ana; Lo, Wing-Yee; MacInnis, Robert J.; Mannermaa, Arto; Manoochehri, Mehdi; Margolin, Sara; Martinez, Maria E.; McLean, Catriona; Meindl, Alfons; Menon, Usha; Nevanlinna, Heli; Newman, William G.; Nodora, Jesse; Offit, Kenneth; Olsson, Håkan; Orr, Nick; Park-Simon, Tjoung-Won; Patel, Alpa V.; Peto, Julian; Pita, Guillermo; Plaseska-Karanfilska, Dijana; Prentice, Ross; Punie, Kevin; Pylkäs, Katri; Radice, Paolo; Rennert, Gad; Romero, Atocha; Rüdiger, Thomas; Saloustros, Emmanouil; Sampson, Sarah; Sandler, Dale P.; Sawyer, Elinor J.; Schmutzler, Rita K.; Schoemaker, Minouk J.; Schöttker, Ben; Sherman, Mark E.; Shu, Xiao-Ou; Smichkoska, Snezhana; Southey, Melissa C.; Spinelli, John, 1955-; Swerdlow, Anthony J.; Tamimi, Rulla M.; Tapper, William J.; Taylor, Jack A.; Teras, Lauren R.; Terry, Mary B.; Torres, Diana; Troester, Melissa A.; Vachon, Celine M.; van Deurzen, Carolien H. M.; van Veen, Elke M.; Wagner, Philippe; Weinberg, Clarice R.; Wendt, Camilla; Wesseling, Jelle; Winqvist, Robert; Wolk, Alicja; Yang, Xiaohong R.; Zheng, Wei; Couch, Fergus J.; Simard, Jacques; Kraft, Peter; Easton, Douglas F.; Pharoah, Paul D. P.; Schmidt, Marjanka K.; García-Closas, Montserrat; Chatterjee, Nilanjan

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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Title	Common variants in breast cancer risk loci predispose to distinct tumor subtypes
Creator	Ahearn, Thomas U.; Zhang, Haoyu; Michailidou, Kyriaki; Milne, Roger L.; Bolla, Manjeet K.; Dennis, Joe; Dunning, Alison M.; Lush, Michael; Wang, Qin; Andrulis, Irene L.; Anton-Culver, Hoda; Arndt, Volker; Aronson, Kristan J.; Auer, Paul L.; Augustinsson, Annelie; Baten, Adinda; Becher, Heiko; Behrens, Sabine; Benitez, Javier; Bermisheva, Marina; Blomqvist, Carl; Bojesen, Stig E.; Bonanni, Bernardo; Børresen-Dale, Anne-Lise; Brauch, Hiltrud; Brenner, Hermann; Brooks-Wilson, Angela; Brüning, Thomas; Burwinkel, Barbara; Buys, Saundra S.; Canzian, Federico; Castelao, Jose E.; Chang-Claude, Jenny; Chanock, Stephen J.; Chenevix-Trench, Georgia; Clarke, Christine L.; Collée, J. M.; Cox, Angela; Cross, Simon S.; Czene, Kamila; Daly, Mary B.; Devilee, Peter; Dörk, Thilo; Dwek, Miriam; Eccles, Diana M.; Evans, D. G.; Fasching, Peter A.; Figueroa, Jonine; Floris, Giuseppe; Gago-Dominguez, Manuela; Gapstur, Susan M.; García-Sáenz, José A.; Gaudet, Mia M.; Giles, Graham G.; Goldberg, Mark S.; González-Neira, Anna; Alnæs, Grethe I. G.; Grip, Mervi; Guénel, Pascal; Haiman, Christopher A.; Hall, Per; Hamann, Ute; Harkness, Elaine F.; Heemskerk-Gerritsen, Bernadette A. M.; Holleczek, Bernd; Hollestelle, Antoinette; Hooning, Maartje J.; Hoover, Robert N.; Hopper, John L.; Howell, Anthony; Jakimovska, Milena; Jakubowska, Anna; John, Esther M.; Jones, Michael E.; Jung, Audrey; Kaaks, Rudolf; Kauppila, Saila; Keeman, Renske; Khusnutdinova, Elza; Kitahara, Cari M.; Ko, Yon-Dschun; Koutros, Stella; Kristensen, Vessela N.; Krüger, Ute; Kubelka-Sabit, Katerina; Kurian, Allison W.; Kyriacou, Kyriacos; Lambrechts, Diether; Lee, Derrick G.; Lindblom, Annika; Linet, Martha; Lissowska, Jolanta; Llaneza, Ana; Lo, Wing-Yee; MacInnis, Robert J.; Mannermaa, Arto; Manoochehri, Mehdi; Margolin, Sara; Martinez, Maria E.; McLean, Catriona; Meindl, Alfons; Menon, Usha; Nevanlinna, Heli; Newman, William G.; Nodora, Jesse; Offit, Kenneth; Olsson, Håkan; Orr, Nick; Park-Simon, Tjoung-Won; Patel, Alpa V.; Peto, Julian; Pita, Guillermo; Plaseska-Karanfilska, Dijana; Prentice, Ross; Punie, Kevin; Pylkäs, Katri; Radice, Paolo; Rennert, Gad; Romero, Atocha; Rüdiger, Thomas; Saloustros, Emmanouil; Sampson, Sarah; Sandler, Dale P.; Sawyer, Elinor J.; Schmutzler, Rita K.; Schoemaker, Minouk J.; Schöttker, Ben; Sherman, Mark E.; Shu, Xiao-Ou; Smichkoska, Snezhana; Southey, Melissa C.; Spinelli, John, 1955-; Swerdlow, Anthony J.; Tamimi, Rulla M.; Tapper, William J.; Taylor, Jack A.; Teras, Lauren R.; Terry, Mary B.; Torres, Diana; Troester, Melissa A.; Vachon, Celine M.; van Deurzen, Carolien H. M.; van Veen, Elke M.; Wagner, Philippe; Weinberg, Clarice R.; Wendt, Camilla; Wesseling, Jelle; Winqvist, Robert; Wolk, Alicja; Yang, Xiaohong R.; Zheng, Wei; Couch, Fergus J.; Simard, Jacques; Kraft, Peter; Easton, Douglas F.; Pharoah, Paul D. P.; Schmidt, Marjanka K.; García-Closas, Montserrat; Chatterjee, Nilanjan
Contributor	BC Cancer Research Centre
Publisher	BioMed Central
Date Issued	2022-01-04
Description	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.
Subject	Breast cancer; Etiologic heterogeneity; Genetic predisposition; Common breast cancer susceptibility variants
Genre	Article
Type	Text
Language	eng
Date Available	2022-01-26
Provider	Vancouver : University of British Columbia Library
Rights	Attribution 4.0 International (CC BY 4.0)
DOI	10.14288/1.0406358
URI	http://hdl.handle.net/2429/80733
Affiliation	Medicine, Faculty of; Non UBC; Population and Public Health (SPPH), School of
Citation	Breast Cancer Research. 2022 Jan 04;24(1):2
Publisher DOI	10.1186/s13058-021-01484-x
Peer Review Status	Reviewed
Scholarly Level	Faculty; Researcher; Other
Copyright Holder	The Author(s)
Rights URI	http://creativecommons.org/licenses/by/4.0/
Aggregated Source Repository	DSpace

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