Analysis of Epigenetic Alterations in Homologous Recombination DNA Repair Genes in Male Breast Cancer

Abstract

Background: Male breast cancer (BC) is a distinct neoplasm with low but rising incidence, frequently diagnosed as advanced stage disease. Considering the relevance of altered homologous recombination repair (HRR) in male BC, we aimed to explore the biomarker potential of aberrant promoter methylation of ATM, BRCA1, PALB2, RAD51B, and XRCC3. Methods: Formalin-fixed paraffin-embedded (FFPE) tissue samples from 128 male BC patients, paired adjacent normal tissue and 19 gynecomastia cases were collected and assessed by quantitative methylation-specific PCR (qMSP). Non-parametric tests were used to compare methylation levels between tumor and non-tumor samples and to seek for associations with clinicopathological variables. Results: Only RAD51B and XRCC3 disclosed significant differences between tumor and gynecomastia (p < 0.0001 and p = 0.020, respectively). Assembled in a panel, RAD51B and XRCC3 promoter methylation discriminated male BC from gynecomastia with 91.5% sensitivity, 89.5% specificity, and 91.2% accuracy. Moreover, promoter methylation levels were lower in paired non-tumor tissues, comparing to tumor samples. No associations were found between epigenetic alterations and clinicopathological features, as well as with RAD51 and XRCC3 immunoexpression and methylation levels. Conclusion: Quantitative promoter methylation of RAD51B and XRCC3 constitutes a promising and accurate biomarker for male BC. Validation in larger series and in liquid biopsies is warranted to confirm its usefulness in detection and monitoring settings.

Genetic Landscape of Male Breast Cancer

“…The epigenetic signatures of ATM , BRCA1 , PALB2 , RAD51B , and XRCC3 have also been explored in MBC (32.4% with germline BRCA2 PV) in matched normal and gynecomastia tissue samples (obtained from patients without cancer or a family history of BC) [ 76 ]. Remarkably, the methylation panel in tissue samples combining RAD51B and XRCC3 accurately discriminated MBC from gynecomastia.…”

An introduction to male breast cancer for urologists: epidemiology, diagnosis, principles of treatment, and special situations

“…According to the National Comprehensive Cancer Network (NCCN) criteria (10) ATM, BRCA1, PALB2, RAD51B, and XRCC3 have epigenetic signatures in MaBC that are absent in corresponding normal tissue and gynecomastia samples obtained from patients without cancer or with a family history of BC. The RAD51B and XRCC3 signatures can accurately discriminate MaBC from gynecomastia, with normal breast tissues showing methylation of these gene promoters at lower levels than in MaBC, suggesting the existence of a tumorigenesis pathway (3,14).…”

DNA methylation variations in familial female and male breast cancer

“…At present, the epigenetic alterations in MBC have been the focus of a limited number of studies (14). Among them, some investigated the differences in the DNA methylation level of putative genes between FBC and MBC.…”

“…In fact, even though MBC treatment follows the same indications as postmenopausal FBC, the clinical and pathological characteristics of MBC do not overlap with those of FBC, which could explain why mortality and survival rates are significantly worse in men, as compared to women ( 13 ). At present, the epigenetic alterations in MBC have been the focus of a limited number of studies ( 14 ). Among them, some investigated the differences in the DNA methylation level of putative genes between FBC and MBC.…”