Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry

Mueller, Stefanie H. and Lai, Alvina G. and Valkovskaya, Maria and Michailidou, Kyriaki and Bolla, Manjeet K. and Wang, Qin and Dennis, Joe and Lush, Michael and Abu-Ful, Zomoruda and Ahearn, Thomas U. and Andrulis, Irene L. and Anton-Culver, Hoda and Antonenkova, Natalia N. and Arndt, Volker and Aronson, Kristan J. and Augustinsson, Annelie and Baert, Thais and Freeman, Laura E. Beane and Beckmann, Matthias W. and Behrens, Sabine and Benitez, Javier and Bermisheva, Marina and Blomqvist, Carl and Bogdanova, Natalia and Bojesen, Stig E. and Bonanni, Bernardo and Brenner, Hermann and Brucker, Sara Y. and Buys, Saundra S. and Castelao, Jose E. and Chan, Tsun L. and Chang-Claude, Jenny and Chanock, Stephen J. and Choi, Ji-Yeob and Chung, Wendy K. and Colonna, Sarah and Cornelissen, Sten and Couch, Fergus J. and Czene, Kamila and Daly, Mary B. and Devilee, Peter and Dork, Thilo and Dossus, Laure and Dwek, Miriam and Eccles, Diana M. and Ekici, Arif B. and Eliassen, A. Heather and Engel, Christoph and Evans, D. Gareth and Fasching, Peter A. and Fletcher, Olivia and Flyger, Henrik and Gago-Dominguez, Manuela and Gao, Yu-Tang and Garcia-Closas, Montserrat and Garcia-Saenz, Jose A. and Genkinger, Jeanine and Gentry-Maharaj, Aleksandra and Grassmann, Felix and Guenel, Pascal and Gundert, Melanie and Haeberle, Lothar and Hahnen, Eric and Haiman, Christopher A. and Hakansson, Niclas and Hall, Per and Harkness, Elaine F. and Harrington, Patricia A. and Hartikainen, Jaana M. and Hartman, Mikael and Hein, Alexander and Ho, Weang-Kee and Hooning, Maartje J. and Hoppe, Reiner and Hopper, John L. and Houlston, Richard S. and Howell, Anthony and Hunter, David J. and Huo, Dezheng and Investigators, Abctb and Ito, Hidemi and Iwasaki, Motoki and Jakubowska, Anna and Janni, Wolfgang and John, Esther M. and Jones, Michael E. and Jung, Audrey and Kaaks, Rudolf and Kang, Daehee and Khusnutdinova, Elza K. and Kim, Sung-Won and Kitahara, Cari M. and Koutros, Stella and Kraft, Peter and Kristensen, Vessela N. and Kubelka-Sabit, Katerina and Kurian, Allison W. and Kwong, Ava and Lacey, James and Lambrechts, Diether and Le Marchand, Loic and Li, Jingmei and Linet, Martha and Lo, Wing-Yee and Long, Jirong and Lophatananon, Artitaya and Mannermaa, Arto and Manoochehri, Mehdi and Margolin, Sara and Matsuo, Keitaro and Mavroudis, Dimitrios and Menon, Usha and Muir, Kenneth and Murphy, Rachel A. and Nevanlinna, Heli and Newman, William G. and Niederacher, Dieter and O'Brien, Katie M. and Obi, Nadia and Offit, Kenneth and Olopade, Olufunmilayo and Olshan, Andrew F. and Olsson, Hakan and Park, Sue K. and Patel, Alpa and Patel, Achal and Perou, Charles M. and Peto, Julian and Pharoah, Paul D. P. and Plaseska-Karanfilska, Dijana and Presneau, Nadege and Rack, Brigitte and Radice, Paolo and Ramachandran, Dhanya and Rashid, Muhammad U. and Rennert, Gad and Romero, Atocha and Ruddy, Kathryn J. and Ruebner, Matthias and Saloustros, Emmanouil and Sandler, Dale P. and Sawyer, Elinor J. and Schmidt, Marjanka K. and Schmutzler, Rita K. and Schneider, Michael O. and Scott, Christopher and Shah, Mitul and Sharma, Priyanka and Shen, Chen-Yang and Shu, Xiao-Ou and Simard, Jacques and Surowy, Harald and Tamimi, Rulla M. and Tapper, William J. and Taylor, Jack A. and Teo, Soo Hwang and Teras, Lauren R. and Toland, Amanda E. and Tollenaar, Rob A. E. M. and Torres, Diana and Torres-Mejia, Gabriela and Troester, Melissa A. and Truong, Therese and Vachon, Celine M. and Vijai, Joseph and Weinberg, Clarice R. and Wendt, Camilla and Winqvist, Robert and Wolk, Alicja and Wu, Anna H. and Yamaji, Taiki and Yang, Xiaohong R. and Yu, Jyh-Cherng and Zheng, Wei and Ziogas, Argyrios and Ziv, Elad and Dunning, Alison M. and Easton, Douglas F. and Hemingway, Harry and Hamann, Ute and Kuchenbaecker, Karoline B. and Collaborators, NBCS and Consortium, CTS (2023) Aggregation tests identify new gene associations with breast cancer in populations with diverse ancestry. Genome Medicine, 15 (1). ISSN 1756-994X, DOI

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Background Low-frequency variants play an important role in breast cancer (BC) susceptibility. Gene-based methods can increase power by combining multiple variants in the same gene and help identify target genes. Methods We evaluated the potential of gene-based aggregation in the Breast Cancer Association Consortium cohorts including 83,471 cases and 59,199 controls. Low-frequency variants were aggregated for individual genes' coding and regulatory regions. Association results in European ancestry samples were compared to single-marker association results in the same cohort. Gene-based associations were also combined in meta-analysis across individuals with European, Asian, African, and Latin American and Hispanic ancestry. Results In European ancestry samples, 14 genes were significantly associated (q < 0.05) with BC. Of those, two genes, FMNL3 (P = 6.11 x 10(-6)) and AC058822.1 (P = 1.47 x 10(-4)), represent new associations. High FMNL3 expression has previously been linked to poor prognosis in several other cancers. Meta-analysis of samples with diverse ancestry discovered further associations including established candidate genes ESR1 and CBLB. Furthermore, literature review and database query found further support for a biologically plausible link with cancer for genes CBLB, FMNL3, FGFR2, LSP1, MAP3K1, and SRGAP2C. Conclusions Using extended gene-based aggregation tests including coding and regulatory variation, we report identification of plausible target genes for previously identified single-marker associations with BC as well as the discovery of novel genes implicated in BC development. Including multi ancestral cohorts in this study enabled the identification of otherwise missed disease associations as ESR1 (P = 1.31 x 10(-5)), demonstrating the importance of diversifying study cohorts.

Item Type: Article
Funders: European Research Council (ERC) No.948561
Uncontrolled Keywords: Breast cancer susceptibility; Diverse ancestry; Rare variants; Gene regulation; Genome-wide association study
Subjects: Q Science > QH Natural history > QH426 Genetics
R Medicine
Divisions: Faculty of Medicine > Surgery Department
Depositing User: Ms Zaharah Ramly
Date Deposited: 22 Nov 2023 03:19
Last Modified: 22 Nov 2023 03:19

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