Constitutive BRCA1 Promoter Hypermethylation Can Be a Predisposing Event in Isolated Early-Onset Breast Cancer.

Jacopo Azzollini,Monica Miozzo,Laura Fontana,Silvia Tabano,Roberta Villa,Chiara Pesenti,Bernard Peissel,Maddalena Plebani,Silvia Maria Sirchia,Sara Pizzamiglio,Patrizia Colapietro,Carmela Guarino,Biagio Paolini,Paolo Verderio,Siranoush Manoukian

doi:10.3390/cancers11010058

Abstract

Early age at onset of breast cancer (eoBC) is suggestive of an increased genetic risk. Although genetic testing is offered to all eoBC-affected women, in isolated cases the detection rate of pathogenic variants is <10%. This study aimed at assessing the role of constitutive promoter methylation at BC-associated loci as an underlying predisposing event in women with eoBC and negative family history. Promoter methylation at 12 loci was assessed by the MassARRAY technology in blood from 154 BRCA1/2 negative patients with eoBC and negative family history, and 60 healthy controls. Hypermethylation was determined, within each promoter, by comparing the patient’s mean methylation value with thresholds based on one-sided 95% bootstrap confidence interval of the controls’ mean. Three patients had hypermethylated results, two at BRCA1 and one at RAD51C. Analyses on tumor tissue from the patient exceeding the highest threshold at BRCA1 revealed a mean methylation >60% and loss of heterozygosity at chromosome 17q. The patient hypermethylated at RAD51C showed low methylation in the tumor sample, ruling out a role for methylation-induced silencing in tumor development. In isolated eoBC patients, BRCA1 constitutive promoter methylation may be a predisposing event. Further studies are required to define the impact of methylation changes occurring at BC-predisposing genes and their role in tumorigenesis.

Highlights

Breast cancer (BC) is the most common malignancy and the main cause of cancer-related deaths in women worldwide [1]
As concerns BRCA1 promoter hypermethylation detected in blood, the estimated prevalence ranges between 10% and 63% in BC patients and between 3% and 63% in healthy controls [25,28,29]
Selection criteria included: women affected with BC, either invasive or ductal carcinoma in situ (DCIS); age at onset before the age of 36 years or before the age of 45 years, in case of documented triple negative phenotype; available and updated information on family history (FH) and no additional cases of BC or ovarian cancer (OC) up to the 3rd degree of kinship; no pathogenic variants or variants of uncertain significance (VUS) identified by the BRCA1 and

Summary

Introduction

Breast cancer (BC) is the most common malignancy and the main cause of cancer-related deaths in women worldwide [1]. While most cases occur after menopause, BC is ranked first in terms of incidence and mortality among women in the age range of 20–39 years [2]. 41% of all cancer cases in women aged

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