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Title: Common Susceptibility Loci for Male Breast Cancer.
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
Journal: J Natl Cancer Inst
Date: 2021 Apr 6
Branches: OD, TDRP
PubMed ID: 32785646
PMC ID: PMC8023850
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.