Male Breast Cancer: Results of the Application of Multigene Panel Testing to an Italian Cohort of Patients

Abstract

Male breast cancer (MBC) is a rare tumor, accounting for less than 1% of all breast cancers. In MBC, genetic predisposition plays an important role; however, only a few studies have investigated in depth the role of genes other than BRCA1 and BRCA2. We performed a Next-Generation Sequencing (NGS) analysis with a panel of 94 cancer predisposition genes on germline DNA from an Italian case series of 70 patients with MBC. Moreover, we searched for large deletions/duplications of BRCA1/2 genes through the Multiplex Ligation-dependent Probe Amplification (MLPA) technique. Through the combination of NGS and MLPA, we identified three pathogenic variants in the BRCA1 gene and six in the BRCA2 gene. Besides these alterations, we found six additional pathogenic/likely-pathogenic variants in PALB2, CHEK2, ATM, RAD51C, BAP1 and EGFR genes. From our study, BRCA1 and BRCA2 emerge as the main genes associated with MBC risk, but also other genes seem to be associated with the disease. Indeed, some of these genes have already been implicated in female breast cancer predisposition, but others are known to be involved in other types of cancer. Consequently, our results suggest that novel genes could be involved in MBC susceptibility, shedding new light on their role in cancer development.

Keywords: BRCA1/2 genes; cancer predisposition; hereditary cancer; male breast cancer; multigene panel testing; multiplex ligation-dependent probe amplification; next-generation sequencing.

Figure 1

Pie chart showing the fraction of cases with/without PVs/LPVs; the number of variant carriers is reported between brackets.

Figure 2

(a) Schematic representation of the BRCA1 gene (transcript NM_007294) and localization of the three PVs identified in our cohort; (b) schematic representation of the BRCA2 gene (transcript NM_000059) and localization of the six PVs identified in our cohort. Exons are represented with grey boxes for non-coding exons and with blue and orange boxes for coding exons of BRCA1 and BRCA2, respectively; the exon numbering has been reported above the exons (the traditional exon numbering of BRCA1 gene lacks exon four that has not been represented).