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Purpose: Mammographic breast density (MBD) is a marker of increased breast cancer (BC) risk, yet much remains to be clarified about the underlying mechanisms. We investigated whether DNA methylation patterns differ between high- vs. low-MBD women who developed BC during an 8.9-year median follow-up in the Florence section of the European Prospective Investigation into Cancer and Nutrition. Methods: We analysed 96 pairs of women with BC arising on high- vs. low-MBD breasts (BI-RADS category III–IV vs. I). DNA methylation was determined on pre-diagnostic blood samples using the Illumina Infinium MethylationEPIC BeadChip assay. The statistical analysis was conducted by performing an epigenome-wide association study (EWAS), by searching differentially methylated regions (DMRs) in gene promoters (followed by functional enrichment and gene annotation analysis); and through a "candidate pathways" approach focusing on pre-defined inflammation-related pathways. Results: In EWAS, no single CpG site was differentially methylated between high- and low-MBD women after correction for multiple testing. A total of 140 DMRs were identified, of which 131 were hyper- and 9 hypo-methylated amongst high-MBD women. These DMRs encompassed an annotation cluster of 35 genes coding for proteins implicated in transcription regulation and DNA binding. The "apoptosis signalling" was the only inflammation-related candidate pathway differentially methylated between high- and low-MBD women. Conclusion: Pre-diagnostic methylation patterns differ between high- vs. low-MBD women who subsequently develop BC, particularly, in genes involved in the regulation of DNA transcription and cell apoptosis. Our study provides novel clues about the mechanisms linking MBD and BC. [ABSTRACT FROM AUTHOR]

Purpose: Male breast cancer (MBC) is a rare disease that shares some similarities with female breast cancer (FBC). Like FBC, genetic susceptibility to MBC can be referred to mutations in BRCA1 and, particularly, BRCA2 genes. 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. EMSY, a BRCA2 inactivating gene, emerged as a candidate gene involved in the pathogenesis of sporadic FBC, and its amplification was suggested to be the somatic counterpart of BRCA2 mutations. Considering the relevant role of BRCA2 in MBC, we aimed at investigating the role of EMSY gene copy number variations in male breast tumors. Methods: EMSY copy number variations were analyzed by quantitative real-time PCR with TaqMan probes in a selected series of 75 MBCs, characterized for BRCA1/2 mutations. Results: We reported EMSY amplification in 34.7 % of MBCs. A significant association emerged between EMSY amplification and BRCA1/2 mutations ( p = 0.03). We identified two amplification subgroups characterized by low and high amplification levels, with BRCA2-related tumors mostly showing low EMSY amplification. Conclusions: Our results show a high frequency of EMSY amplification in MBC, thus pointing to a role of EMSY in the pathogenesis of this disease. EMSY amplification may be a new feature that might uncover underlying molecular pathways of MBCs and may allow for the identification of MBC subgroups with potential clinical implication for targeted therapeutic approaches. [ABSTRACT FROM AUTHOR]

Recently, the number of studies on male breast cancer (MBC) has been increasing. However, as MBC is a rare disease there are difficulties to undertake studies to identify specific MBC subgroups. At present, it is still largely unknown whether BRCA-related breast cancer (BC) in men may display specific characteristics as it is for BRCA-related BC in women. To investigate the clinical-pathologic features of MBC in association with BRCA mutations we established a collaborative Italian Multicenter Study on MBC with the aim to recruit a large series of MBCs. A total of 382 MBCs, including 50 BRCA carriers, were collected from ten Italian Investigation Centres covering the whole country. In MBC patients, BRCA2 mutations were associated with family history of breast/ovarian cancer ( p < 0.0001), personal history of other cancers ( p = 0.044) and contralateral BC ( p = 0.001). BRCA2-associated MBCs presented with high tumor grade ( p = 0.001), PR− ( p = 0.026) and HER2+ ( p = 0.001) status. In a multivariate logistic model BRCA2 mutations showed positive association with personal history of other cancers (OR 11.42, 95 % CI 1.79-73.08) and high tumor grade (OR 4.93, 95 % CI 1.02-23.88) and inverse association with PR+ status (OR 0.19, 95 % CI 0.04-0.92). Based on immunohistochemical (IHC) profile, four molecular subtypes of MBC were identified. Luminal A was the most common subtype (67.7 %), luminal B was observed in 26.5 % of the cases and HER2 positive and triple negative were represented by 2.1 % and 3.7 % of tumors, respectively. Intriguingly, we found that both luminal B and HER2 positive subtypes were associated with high tumor grade ( p = 0.003 and 0.006, respectively) and with BRCA2 mutations ( p = 0.016 and 0.001, respectively). In conclusion, our findings indicate that BRCA2-related MBCs represent a subgroup of tumors with a peculiar phenotype characterized by aggressive behavior. The identification of a BRCA2-associated phenotype might define a subset of MBC patients eligible for personalized clinical management. [ABSTRACT FROM AUTHOR]

Breast cancer (BC) in men is rare compared with BC in women, but its incidence is increasing along with attention toward this uncommon disease. Although with some differences, male and female BC share similar genetic predisposition factors, including BRCA1/2, CHEK2, and PALB2 mutations. As other BRCA1/2 functionally related DNA repair genes, such as CHEK2 and PALB2, BRIP1 is considered a moderate-penetrance BC susceptibility gene. At present, the role of BRIP1 on BC susceptibility in men is unknown. In this study, we aimed to assess whether BRIP1 variants may contribute to male BC (MBC) risk, by screening 97 MBC cases, all negative for BRCA1/2, CHEK2, and PALB2 mutations, selected from a population-based series of 126 MBCs from Central Italy. A total of five BRIP1 germ-line sequence alterations, three coding, and two non-coding variants, were detected in our series. The two non-coding variants IVS4-28G > A and 3′UTR 4049C > T were classified as neutral by in silico analysis. Of the three coding variants, one was a silent variant (E879E) and two resulted in amino acid substitution (R264W and P919S) showing a putative pathogenic role by in silico analysis. However, further analysis of tumor-associated loss of heterozygosity and the frequency of variant alleles, tested in 203 male population controls, suggested a neutral effect for both of these variants. Overall, our results indicate that BRIP1 variants may not play a relevant role in MBC predisposition. [ABSTRACT FROM AUTHOR]