Common susceptibility loci for male breast cancer

Sarah Maguire, Eleni Perrakis, Katarzyna Tomczyk, Michael Jones, Olivia Fletcher, Matthew Pugh, Timothy Winter, Kyle Thompson, Rosie Cooke, Alison H Trainer, James Paul, Stig E Bojesen, Henrik Flyger, Heli Nevanlinna, Johanna Mattson, Eitan Friedman, Yael Laitman, Domenico Palli, Giovanna Masala, Ines ZannaLaura Ottini, Valentina Silvestri, Antoinette Hollestelle, Maartje J Hooning, Srdjan Novaković, Mateja Krajc, Manuela Gago-Dominguez, Jose Esteban Castelao, Håkan Olsson, Ingrid Hedenfalk, Emmanouil Saloustros, Vasilios Georgoulias, Douglas F Easton, Paul Pharoah, Alison M Dunning, D Timothy Bishop, Susan L Neuhausen, Linda Steele, Alan Ashworth, Montserrat García-Closas, Richard Houlston, Anthony J Swerdlow, Nick Orr*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

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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.

Original languageEnglish
Article numberdja101
JournalJournal of the National Cancer Institute
Volume2020
Early online date12 Aug 2020
DOIs
Publication statusEarly online date - 12 Aug 2020

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