Whole-exome sequencing and targeted gene sequencing provide insights into the role of PALB2 as a male breast cancer susceptibility gene

BACKGROUND: Male breast cancer (MBC) is a rare disease whose etiology appears to be largely associated with genetic factors.BRCA1 and BRCA2 mutations account for about 10% of all MBC cases. Thus, a fraction of MBC cases are expected to be due to genet-ic factors not yet identified. To further explain the genet ic susceptibility for MBC, whole-exome sequencing (WES) and targeted genesequencing were applied to high-risk, BRCA1/2 mutation–negative MBC cases. METHODS: Germ-line DNA of 1 male and 2 femaleBRCA1/2 mutation–negative breast cancer (BC) cases from a pedigree showing a first-degree family history of MBC was analyzedwith WES. Targeted gene sequencing for the validation of WES results was performed for 48 high-risk, BRCA1/2 mutation–negativeMBC cases from an Italian multicenter study of MBC. A case-control series of 433 BRCA1/2 mutation–negative MBC and female breastcancer (FBC) cases and 849 male and female controls was included in the study. RESULTS: WES in the family identified the partnerand localizer of BRCA2 (PALB2) c.419delA truncating mutation carried by the proband, her father, and her paternal uncle (all affectedwith BC) and the N-acetyltransferase 1 (NAT1) c.97C>T nonsense mutation carried by the proband’s maternal aunt. Targeted PALB2sequencing detected the c.1984A>T nonsense mutation in 1 of the 48 BRCA1/2 mutation–negative MBC cases. NAT1 c.97C>T was notfound in the case-control series. CONCLUSIONS: These results add strength to the evidence showing that PALB2 is involved in BCrisk for both sexes and indicate that consideration should be given to clinical testing of PALB2 for BRCA1/2 mutation–negative fami-lies with multiple MBC and FBC cases