TY - JOUR
T1 - Common susceptibility loci for male breast cancer
AU - Maguire, Sarah
AU - Perrakis, Eleni
AU - Tomczyk, Katarzyna
AU - Jones, Michael
AU - Fletcher, Olivia
AU - Pugh, Matthew
AU - Winter, Timothy
AU - Thompson, Kyle
AU - Cooke, Rosie
AU - Trainer, Alison H
AU - Paul, James
AU - Bojesen, Stig E
AU - Flyger, Henrik
AU - Nevanlinna, Heli
AU - Mattson, Johanna
AU - Friedman, Eitan
AU - Laitman, Yael
AU - Palli, Domenico
AU - Masala, Giovanna
AU - Zanna, Ines
AU - Ottini, Laura
AU - Silvestri, Valentina
AU - Hollestelle, Antoinette
AU - Hooning, Maartje J
AU - Novaković, Srdjan
AU - Krajc, Mateja
AU - Gago-Dominguez, Manuela
AU - Castelao, Jose Esteban
AU - Olsson, Håkan
AU - Hedenfalk, Ingrid
AU - Saloustros, Emmanouil
AU - Georgoulias, Vasilios
AU - Easton, Douglas F
AU - Pharoah, Paul
AU - Dunning, Alison M
AU - Timothy Bishop, D
AU - Neuhausen, Susan L
AU - Steele, Linda
AU - Ashworth, Alan
AU - García-Closas, Montserrat
AU - Houlston, Richard
AU - Swerdlow, Anthony J
AU - Orr, Nick
PY - 2020/8/12
Y1 - 2020/8/12
N2 - BackgroundThe aetiology 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 (GWAS) of MBC identified two predisposition loci for the disease, both of which were also associated with risk of FBC.MethodsWe performed genome-wide single nucleotide polymorphism (SNP) genotyping of European ancestry MBC case subjects and controls, in three stages. Associations between directly genotyped and imputed SNPs with MBC were assessed using fixed-effects meta-analysis of 1,380 cases and 3,620 controls. Replication genotyping of 810 cases and 1,026 controls was used to validate variants with P-values < 1 x 10-06. Genetic correlation with FBC was evaluated using LD 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 (PRS) and MBC. All statistical tests were two-sided.ResultsThe GWAS identified three novel MBC susceptibility loci that attained genome-wide significance (P < 5 x 10-08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen-receptor (ER) positive FBC. Males in the top quintile of genetic risk had a four-fold 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 x 10-30).ConclusionsThese findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic aetiology with FBC and identifying a four-fold high risk group of susceptible men.
AB - BackgroundThe aetiology 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 (GWAS) of MBC identified two predisposition loci for the disease, both of which were also associated with risk of FBC.MethodsWe performed genome-wide single nucleotide polymorphism (SNP) genotyping of European ancestry MBC case subjects and controls, in three stages. Associations between directly genotyped and imputed SNPs with MBC were assessed using fixed-effects meta-analysis of 1,380 cases and 3,620 controls. Replication genotyping of 810 cases and 1,026 controls was used to validate variants with P-values < 1 x 10-06. Genetic correlation with FBC was evaluated using LD 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 (PRS) and MBC. All statistical tests were two-sided.ResultsThe GWAS identified three novel MBC susceptibility loci that attained genome-wide significance (P < 5 x 10-08). Genetic correlation analysis revealed a strong shared genetic basis with estrogen-receptor (ER) positive FBC. Males in the top quintile of genetic risk had a four-fold 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 x 10-30).ConclusionsThese findings advance our understanding of the genetic basis of MBC, providing support for an overlapping genetic aetiology with FBC and identifying a four-fold high risk group of susceptible men.
U2 - 10.1093/jnci/djaa101
DO - 10.1093/jnci/djaa101
M3 - Article
VL - 2020
JO - Journal of the National Cancer Institute
JF - Journal of the National Cancer Institute
SN - 0027-8874
M1 - dja101
ER -