Aggregation Tests Identify New Gene Associations with Breast Cancer in Populations with Diverse Ancestry

Citation

Mueller, Stefanie H.; Lai, Alvina G.; Valkovskaya, Maria; Michailidou, Kyriaki; Bolla, Manjeet K.; Wang, Qin; Dennis, Joe; Lush, Michael; Abu-Ful, Zomoruda; & Ahearn, Thomas U., et al. (2023). Aggregation Tests Identify New Gene Associations with Breast Cancer in Populations with Diverse Ancestry. Genome Medicine, 15(1), 7. PMCID: PMC9878779

Abstract

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 × 10(-6)) and AC058822.1 (P = 1.47 × 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 × 10(-5)), demonstrating the importance of diversifying study cohorts.

URL

http://dx.doi.org/10.1186/s13073-022-01152-5

Reference Type

Journal Article

Year Published

2023

Journal Title

Genome Medicine

Author(s)

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

Article Type

Regular

PMCID

PMC9878779

Data Set/Study

Breast Cancer Association Consortium (BCAC)

Continent/Country

Nonspecific

Race/Ethnicity

European Ancestry
Hispanic Ancestry
Asian Ancestry
African Ancestry

ORCiD

Olshan - 0000-0001-9115-5128