Mutations in BRCA2 and PALB2 in male breast cancer cases from the United States

Male breast cancer (MBC) is an uncommon disease with a frequency of approximately one in 1000. Due to the rarity of MBC, it is understudied and its etiology is poorly understood. Our objectives are to determine the frequency of pathogenic mutations in BRCA2 and PALB2 in MBC cases and to investigate the correlations between mutation status and cancer phenotypes. Single strand conformation polymorphism analysis, direct sequencing, and multiplex ligation-dependent probe amplification were employed to screen for mutations in the BRCA2 gene, followed by direct sequencing of the PALB2 gene in BRCA2-negative MBC cases. Pathogenic BRCA2 mutations were identified in 18 of the 115 MBC cases, including four of the ten cases (40%) from breast cancer families and 14 of the 105 cases (13%) unselected for family history of breast cancer. The difference in BRCA2-mutation frequencies between cases with and without family history of breast cancer was not statistically significant (P = 0.145), suggesting that family history is not a strong predictor of carrying a mutation in males. We observed a highly significant association of carrying a pathogenic BRCA2 mutation with high tumor grade (P < 0.001) and a weak association with positive lymph nodes (P < 0.02). Of the 97 BRCA2-negative MBC cases, we identified one PALB2 mutation with confirmed pathogenicity and one mutation predicted to be pathogenic, a prevalence of pathogenic PALB2-mutation of 1–2%. Based on our results and previous studies, genetic testing for BRCA2 should be recommended for any diagnosed MBC case, regardless of family history of breast cancer.