Analysis of BRCA1 and RAD51C Promoter Methylation in Italian Families at High-Risk of Breast and Ovarian Cancer.

Silvia Tabano,Laura Fontana,Jole Costanza,Chiara Pesenti,Bernard Peissel,Sara Lovati,Monica Miozzo,Siranoush Manoukian,Jacopo Azzollini

doi:10.3390/cancers12040910

Abstract

Previous studies on breast and ovarian carcinoma (BC and OC) revealed constitutional BRCA1 and RAD51C promoter hypermethylation as epigenetic alterations leading to tumor predisposition. Nevertheless, the impact of epimutations at these genes is still debated. One hundred and eight women affected by BC, OC, or both and considered at very high risk of carrying BRCA1 germline mutations were studied. All samples were negative for pathogenic variants or variants of uncertain significance at BRCA testing. Quantitative BRCA1 and RAD51C promoter methylation analyses were performed by Epityper mass spectrometry on peripheral blood samples and results were compared with those in controls. All the 108 analyzed cases showed methylation levels at the BRCA1/RAD51C promoter comparable with controls. Mean methylation levels (± stdev) at the BRCA1 promoter were 4.3% (± 1.4%) and 4.4% (± 1.4%) in controls and patients, respectively (p > 0.05; t-test); mean methylation levels (± stdev) at the RAD51C promoter were 4.3% (± 0.9%) and 3.7% (± 0.9%) in controls and patients, respectively (p > 0.05; t-test). Based on these observations; the analysis of constitutional methylation at promoters of these genes does not seem to substantially improve the definition of cancer risks in patients. These data support the idea that epimutations represent a very rare event in high-risk BC/OC populations.

Highlights

Epigenetic alterations, i.e., epimutations, are an emerging mechanism that plays a pivotal role in carcinogenesis
Evans and colleagues reported the first case of germline BRCA1 methylation in two families affected by Hereditary Breast and Ovarian Cancer Syndrome
Constitutional BRCA1 methylation was analyzed by different groups with multiple technical approaches and it has been demonstrated to be associated with an increased risk of developing BC and/or OC [6,7,8,9,10,11]

Summary

Introduction

Epigenetic alterations, i.e., epimutations, are an emerging mechanism that plays a pivotal role in carcinogenesis. Cancers 2020, 12, 910 event that could be present: (i) only in tumor cells, i.e., somatic epimutations, (ii) at the germline level, with evidence of inheritance, i.e., linked to cis-acting mutations [1,2] or, (iii) in multiple tissues of different embryonic origin with no evidence of inheritance and often in a mosaic state, i.e., constitutional epimutations. Epimutations were confined to one of the two parental alleles always at the mosaic level in tissues of different embryonic origins This indicated that they occurred in a single cell relatively early during the embryonic development. This model was further supported by recent studies demonstrating that the majority of constitutional BRCA1 methylation events arose early during development and seemed to remain quite stable during life and potentially were inherited from mother to daughter [12,13]

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Discussion

Conclusion