The ATM Gene in Breast Cancer: Its Relevance in Clinical Practice.

Luigia Stefania Stucci,Valeria Internò,Francesco Mannavola,Raffaele Palmirotta,Marco Tucci,Martina Perrone,Camillo Porta

doi:10.3390/genes12050727

Abstract

Molecular alterations of the Ataxia-telangiectasia (AT) gene are frequently detected in breast cancer (BC), with an incidence ranging up to 40%. The mutated form, the Ataxia-telangiectasia mutated (ATM) gene, is involved in cell cycle control, apoptosis, oxidative stress, and telomere maintenance, and its role as a risk factor for cancer development is well established. Recent studies have confirmed that some variants of ATM are associated with an increased risk of BC development and a worse prognosis. Thus, many patients harboring ATM mutations develop intermediate- and high-grade disease, and there is a higher rate of lymph node metastatic involvement. The evidence concerning a correlation of ATM gene mutations and the efficacy of therapeutic strategies in BC management are controversial. In fact, ATM mutations may sensitize cancer cells to platinum-derived drugs, as BRCA1/2 mutations do, whereas their implications in objective responses to hormonal therapy or target-based agents are not well defined. Herein, we conducted a review of the role of ATM gene mutations in BC development, prognosis, and different treatment strategies.

Highlights

The Ataxia-telangiectasia mutated (ATM) gene is an oncosuppressor, located on chromosome 11q23, that encodes a 350-KDa protein consisting of 3056 amino acids [1]
Epidemiological studies based on relatives affected by both AT and breast cancer (BC) suggested that heterozygous carriers of ATM mutations have a two- to thirteen-fold increased risk of BC development, with a higher relative risk under 50 years old [8,9,10,11]
ATM missense mutations among women diagnosed with BC before the age of 45 years could enhance the risk of contralateral breast cancer in radio-treated repair gene alterations; we could hypothesize that ATM mutations could enhance the genomic instability of DNA and enhance the immunotherapy response in triple-negative BC patients

Summary

Introduction

The Ataxia-telangiectasia mutated (ATM) gene is an oncosuppressor, located on chromosome 11q23, that encodes a 350-KDa protein consisting of 3056 amino acids [1]. It belongs to the superfamily of phosphatidylinositol 3-kinase-related protein kinases (PIKKs). Many ATM mutations have been described and associated with a moderate risk of BC development [7]. Previous studies emphasized the evidence of a strong association between ATM variants and the risk of BC development. In wider large-scale studies including solid cancers, 5% of patients showed ATM aberrations (either mutation or loss). 8% of lung cancer patients showed ATM mutations that were largely mutually exclusive with those of TP53. ATM mutations increase the risk for development of a second tumor after RT [16,17,18,19]

The ATM Gene and Its Role in Cancer

Role of ATM Gene Mutations in BC Susceptibility and Prognosis

Therapeutic Implications of ATM Gene Mutations in BC

Findings

Discussion