Common Susceptibility Loci for Male Breast Cancer.
Embargo End Date
Authors
Maguire, S
Perraki, E
Tomczyk, K
Jones, ME
Fletcher, O
Pugh, M
Winter, T
Thompson, K
Cooke, R
kConFab Consortium,
Trainer, A
James, P
Bojesen, S
Flyger, H
Nevanlinna, H
Mattson, J
Friedman, E
Laitman, Y
Palli, D
Masala, G
Zanna, I
Ottini, L
Silvestri, V
Hollestelle, A
Hooning, MJ
Novaković, S
Krajc, M
Gago-Dominguez, M
Castelao, JE
Olsson, H
Hedenfalk, I
Saloustros, E
Georgoulias, V
Easton, DF
Pharoah, P
Dunning, AM
Bishop, DT
Neuhausen, SL
Steele, L
Ashworth, A
Garcia Closas, M
Houlston, R
Swerdlow, A
Orr, N
Perraki, E
Tomczyk, K
Jones, ME
Fletcher, O
Pugh, M
Winter, T
Thompson, K
Cooke, R
kConFab Consortium,
Trainer, A
James, P
Bojesen, S
Flyger, H
Nevanlinna, H
Mattson, J
Friedman, E
Laitman, Y
Palli, D
Masala, G
Zanna, I
Ottini, L
Silvestri, V
Hollestelle, A
Hooning, MJ
Novaković, S
Krajc, M
Gago-Dominguez, M
Castelao, JE
Olsson, H
Hedenfalk, I
Saloustros, E
Georgoulias, V
Easton, DF
Pharoah, P
Dunning, AM
Bishop, DT
Neuhausen, SL
Steele, L
Ashworth, A
Garcia Closas, M
Houlston, R
Swerdlow, A
Orr, N
Document Type
Journal Article
Date
2021-04-06
Date Accepted
2020-07-10
Abstract
BACKGROUND: The etiology of male breast cancer (MBC) is poorly understood. In particular, the extent to which the genetic basis of MBC differs from female breast cancer (FBC) is unknown. A previous genome-wide association study of MBC identified 2 predisposition loci for the disease, both of which were also associated with risk of FBC. METHODS: We performed genome-wide single nucleotide polymorphism genotyping of European ancestry MBC case subjects and controls in 3 stages. Associations between directly genotyped and imputed single nucleotide polymorphisms with MBC were assessed using fixed-effects meta-analysis of 1380 cases and 3620 controls. Replication genotyping of 810 cases and 1026 controls was used to validate variants with P values less than 1 × 10-06. Genetic correlation with FBC was evaluated using linkage disequilibrium score regression, by comprehensively examining the associations of published FBC risk loci with risk of MBC and by assessing associations between a FBC polygenic risk score and MBC. All statistical tests were 2-sided. RESULTS: The genome-wide association study identified 3 novel MBC susceptibility loci that attained genome-wide statistical significance (P < 5 × 10-08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen receptor-positive FBC. Men in the top quintile of genetic risk had a fourfold increased risk of breast cancer relative to those in the bottom quintile (odds ratio = 3.86, 95% confidence interval = 3.07 to 4.87, P = 2.08 × 10-30). CONCLUSIONS: These findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic etiology with FBC and identifying a fourfold high-risk group of susceptible men.
Citation
Journal of the National Cancer Institute, 2020
Source Title
Publisher
OXFORD UNIV PRESS INC
ISSN
0027-8874
eISSN
1460-2105
Research Team
Complex Trait Genetics
Functional Genetic Epidemiology
Aetiological Epidemiology
Cancer Genomics
Functional Genetic Epidemiology
Aetiological Epidemiology
Cancer Genomics