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.

Genetic Landscape of Male Breast Cancer

“…Studies that applied MGPT in cohorts of MBC found PVs in new genes of lower frequency in addition to those previously described [ 25 , 92 , 97 , 120 ]. Most studies applied gene panels containing between a dozen to a hundred of cancer predisposing genes, including some with unknown association with MBC ( Table 2 ).…”

“…The estimated lifetime risk of BC is 5–10% among male BRCA2 PV carriers, compared to a 0.1% risk in the general population [ 85 , 86 , 87 ]. Germline PVs frequencies in the BRCA2 gene in MBC cohorts vary from 3.7% to 40%, depending on the characteristics of the studied population and their ancestral background [ 13 , 79 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 ]. As it has been shown in FBC, the MBC phenotype is peculiar in men harboring BRCA1 / 2 PVs ( Table 1 ).…”

“…On the other hand, the frequency of BRCA1 PVs is low in unselected populations of MBC, ranging from 0% to 5% [ 13 , 79 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 ]. It is higher in populations in which a founder PV exists (10–16%) [ 79 ].…”

BRCA Germline Mutations in Prostate Cancer: The Future Is Tailored

“…A substantial inherited component has been estimated to be present in 40-50% of PCA, and several genetic mutations have been implicated [4]. Among these, BRCA1 and BRCA2 mutations stand out for their renowned role in carcinogenesis in ovarian and female breast cancer, with recent evidence reporting mutated BRCA genes as a risk factor also for the development of male breast cancer [5]. BRCA genes are indeed tumour suppressor factors involved in DNA repair, in particular in the homologous recombination repair (HRR) process of double-strand breaks.…”

Male and female breast cancer: the two faces of the same genetic susceptibility coin

“…The most frequent use of Next-Generation Sequencing (NGS) has identified an increasing number of genes suspected to be involved in cancer predisposition, especially for cancers with a familial component such as BC [32]. The current use of multigene panel testing for breast cancer predisposition has been a remarkable tool, although the genes included were based on female studies, limiting its use in male breast cancer [4] and creating a partiality in the genetic predisposition analysis.…”