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

Saudade André,Carmen Jerónimo,Fernanda Silva,Rui Henrique,Sandra P Nunes,Ana Félix

doi:10.3390/ijms21082715

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.

Highlights

Male breast carcinoma (BC) is a multifactorial neoplasm lacking specific guidelines for detection, therapy and surveillance
Owing to the relevance of homologous recombination repair (HRR) deficiency in male breast cancer (BC) and the lack of systematic studies on altered methylation patterns of HRR genes in this specific context, we aimed to explore the epigenetic signature of the HRR genes ATM, BRCA1, PALB2, RAD51B, and XRCC3 in a large, well characterized series of male BC patients, to identify novel detection, diagnostic and/or prognostic biomarkers that might perfect clinical management
Germline BRCA1 mutations were not found in this series

Summary

Introduction

Male breast carcinoma (BC) is a multifactorial neoplasm lacking specific guidelines for detection, therapy and surveillance. It constitutes a rare entity, comparatively to its female counterpart, incidence has been rising over the last decades [1,2]. Aberrant methylation, occurring mostly at gene promoter regions, is associated with gene transcription repression [5]. This alteration is among the most common and earliest events involved in cancer initiation and promotion, being measured [6]. No associations were found between epigenetic alterations and clinicopathological features, as well as with RAD51 and XRCC3 immunoexpression and methylation levels. Validation in larger series and in liquid biopsies is warranted to confirm its usefulness in detection and monitoring settings

Objectives

Methods

Results