In order to investigate whether epigenetic signatures could define molecular subgroups of MBCs, we performed promoter methylation analysis of genes involved in signal transduction and hormone signalling in <i>BRCA1/2</i> mutation-positive and -negative MBCs.
Several susceptibility genes have been established for female breast cancer, of which mutations in BRCA1 and especially in BRCA2 are also known risk factors for male breast cancer (MBC).
We carried out comprehensive whole gene RNA analysis on 45 high-risk breast/ovary and male breast cancer families with no identified pathogenic variant on exonic sequencing and copy number analysis of BRCA1/2.
However, only about 10 % of MBCs are caused by BRCA1/2 germ-line mutations, while the largest part are sporadic cancers and may derive from somatic alterations.
Somatic mutations and gene amplification were found only in BRCA1/2 mutation negative MBCs.Significant associations emerged between EGFR amplification and large tumor size (T4), ER-negative and HER2-positive status, between CCND1 amplification and HER2-positive and MIB1-positive status, and between ESR1 deletion and ER-negative status.Our results show that amplification of targetable oncogenes is frequent in BRCA1/2 mutation negative MBCs and may identify MBC subsets characterized by aggressive phenotype that may benefit from potential targeted therapeutic approaches.
High risk features (bilateral breast cancer, diagnosis <40 years, ovarian cancer, male breast cancer) were more commonly associated with an LGR than a non-LGR mutation (p = 0.008), In families with a BRCA1 LGR the mean age of breast cancer diagnosis was younger than in families with a non-LGR BRCA1 mutation (42.5 vs. 46.1 years, p = 0.007).
Using a TruSeq amplicon cancer panel, this study evaluated 48 familial MBCs (3 BRCA1 germline mutant, 17 BRCA2 germline mutant and 28 BRCAX) for hotspot somatic mutations and copy number changes in 48 common cancer genes.
Heterozygous germ line mutations in the Breast CAncer1 (BRCA1) and BRCA2 genes can lead to a high risk of breast and ovarian cancer, in addition to a significantly increased susceptibility of pancreatic, prostate and male breast cancer.
Conclusions Here, we (i) reported that in our population about 9% of MBC cases are accounted for by BRCA1/BRCA2 mutations; (ii) enlarged the BRCA2 mutational spectrum and (iii) characterized a specific phenotype associated with BRCA2-related MBCs suggestive of aggressive behavior.
To evaluate the potential contribution of mutations in the BRCA1 and BRCA2 genes to male breast cancer (MBC), we expanded a previous study to screen a total of 261 Israeli men diagnosed with breast carcinoma.
Here, we investigated the contribution of BRCA1, BRCA2 and CHEK2 alterations to MBC predisposition in Italy by analysing a large series of MBC cases, unselected for breast cancer family history and all negative for BRCA1/BRCA2 germ-line mutations.
The family history selection criteria most likely to indicate the presence of deleterious BRCA1/2 mutations are breast cancer <or=35 years (P = 0.012), two first-degree relatives with breast cancer <or=50 years (P = 0.022), and male breast cancer (P = 0.047).
In summary, we advise restricting BRCA1 MLPA screening to those subgroups that revealed LGRs and recommend BRCA2 MLPA screening only for families presenting with cooccurrence of female and male breast cancer.
Common polymorphic variants in BRCA1 and BRCA2 genes may represent breast cancer (BC) susceptibility alleles and could be associated with a modestly increased risk of MBC at population level.