Background: The 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. Methods: We 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. Results: The 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). Conclusions: These 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.

Common susceptibility loci for male breast cancer / Maguire, Sarah; Perraki, Eleni; Tomczyk, Katarzyna; Jones, Michael E; Fletcher, Olivia; Pugh, Matthew; Winter, Timothy; Thompson, Kyle; Cooke, Rosie; Trainer, Alison; James, Paul; Bojesen, Stig; Flyger, Henrik; Nevanlinna, Heli; Mattson, Johanna; Friedman, Eitan; Laitman, Yael; Palli, Domenico; Masala, Giovanna; Zanna, Ines; Ottini, Laura; Silvestri, Valentina; Hollestelle, Antoinette; Hooning, Maartje J; Novaković, Srdjan; Krajc, Mateja; Gago-Dominguez, Manuela; Castelao, Jose Esteban; Olsson, Hakan; Hedenfalk, Ingrid; Saloustros, Emmanouil; Georgoulias, Vasilios; Easton, Douglas F; Pharoah, Paul; Dunning, Alison M; Bishop, D Timothy; Neuhausen, Susan L; Steele, Linda; Ashworth, Alan; Closas, Montserrat Garcia; Houlston, Richard; Swerdlow, Anthony; Orr, Nick. - In: JOURNAL OF THE NATIONAL CANCER INSTITUTE. - ISSN 0027-8874. - 113:4(2021). [10.1093/jnci/djaa101]

Common susceptibility loci for male breast cancer

Ottini, Laura;Silvestri, Valentina;
2021

Abstract

Background: The 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. Methods: We 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. Results: The 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). Conclusions: These 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.
2021
male breast cancer; SNPs; GWAS; cancer risk
01 Pubblicazione su rivista::01a Articolo in rivista
Common susceptibility loci for male breast cancer / Maguire, Sarah; Perraki, Eleni; Tomczyk, Katarzyna; Jones, Michael E; Fletcher, Olivia; Pugh, Matthew; Winter, Timothy; Thompson, Kyle; Cooke, Rosie; Trainer, Alison; James, Paul; Bojesen, Stig; Flyger, Henrik; Nevanlinna, Heli; Mattson, Johanna; Friedman, Eitan; Laitman, Yael; Palli, Domenico; Masala, Giovanna; Zanna, Ines; Ottini, Laura; Silvestri, Valentina; Hollestelle, Antoinette; Hooning, Maartje J; Novaković, Srdjan; Krajc, Mateja; Gago-Dominguez, Manuela; Castelao, Jose Esteban; Olsson, Hakan; Hedenfalk, Ingrid; Saloustros, Emmanouil; Georgoulias, Vasilios; Easton, Douglas F; Pharoah, Paul; Dunning, Alison M; Bishop, D Timothy; Neuhausen, Susan L; Steele, Linda; Ashworth, Alan; Closas, Montserrat Garcia; Houlston, Richard; Swerdlow, Anthony; Orr, Nick. - In: JOURNAL OF THE NATIONAL CANCER INSTITUTE. - ISSN 0027-8874. - 113:4(2021). [10.1093/jnci/djaa101]
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11573/1439362
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