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

Male breast cancer (MBC) is a rare disease whose etiology appears to be largely associated with genetic factors.BRCA1andBRCA2mutations 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 genetic susceptibility for MBC, whole-exome sequencing (WES) and targeted genesequencing were applied to high-risk,BRCA1/2mutation–negative MBC cases.METHODS:Germ-line DNA of 1 male and 2 femaleBRCA1/2mutation–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,BRCA1/2mutation–negativeMBC cases from an Italian multicenter study of MBC. A case-control series of 433BRCA1/2mutation–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 theN-acetyltransferase 1 (NAT1) c.97C>T nonsense mutation carried by the proband’s maternal aunt. TargetedPALB2sequencing detected the c.1984A>T nonsense mutation in 1 of the 48BRCA1/2mutation–negative MBC cases.NAT1c.97C>T was notfound in the case-control series.CONCLUSIONS:These results add strength to the evidence showing thatPALB2is involved in BCrisk for both sexes and indicate that consideration should be given to clinical testing ofPALB2forBRCA1/2mutation–negative fami-lies with multiple MBC and FBC cases.Cancer2016;000:000–000.VC2016 American Cancer Society.KEYWORDS:genetic susceptibility, male breast cancer,N-acetyltransferase 1 (NAT1), partner and localizer of BRCA2 (PALB2), whole-exome sequencing.