Common Susceptibility Loci for Male Breast Cancer.
Journal
Journal of the National Cancer Institute
ISSN: 1460-2105
Titre abrégé: J Natl Cancer Inst
Pays: United States
ID NLM: 7503089
Informations de publication
Date de publication:
06 04 2021
06 04 2021
Historique:
received:
12
11
2019
revised:
14
05
2020
accepted:
10
07
2020
pubmed:
14
8
2020
medline:
16
9
2021
entrez:
14
8
2020
Statut:
ppublish
Résumé
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. 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. 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). 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.
Sections du résumé
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.
Identifiants
pubmed: 32785646
pii: 5885091
doi: 10.1093/jnci/djaa101
pmc: PMC8023850
doi:
Substances chimiques
Receptors, Estrogen
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
453-461Subventions
Organisme : Wellcome Trust
Pays : United Kingdom
Organisme : NCI NIH HHS
ID : R01 CA074415
Pays : United States
Organisme : Medical Research Council
ID : G0000934
Pays : United Kingdom
Organisme : Wellcome Trust
ID : 068545/Z/02
Pays : United Kingdom
Organisme : Cancer Research UK
ID : CA8197/A10865
Pays : United Kingdom
Organisme : Cancer Research UK
ID : C588/A10589
Pays : United Kingdom
Informations de copyright
© The Author(s) 2020. Published by Oxford University Press.
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