ATM, radiation, and the risk of second primary breast cancer

Abstract

Purpose It was first suggested more than 40 years ago that heterozygous carriers for the human autosomal recessive disorder Ataxia-Telangiectasia (A-T) might also be at increased risk for cancer. Subsequent studies have identified the responsible gene, Ataxia-Telangiectasia Mutated (ATM), characterized genetic variation at this locus in A-T and a variety of different cancers, and described the functions of the ATM protein with respect to cellular DNA damage responses. However, an overall model of how ATM contributes to cancer risk, and in particular, the role of DNA damage in this process, remains lacking. This review considers these questions in the context of contralateral breast cancer (CBC). Conclusions Heterozygous carriers of loss of function mutations in ATM that are A-T causing, are at increased risk of breast cancer. However, examination of a range of genetic variants, both rare and common, across multiple cancers, suggests that ATM may have additional effects on cancer risk that are allele dependent. In the case of CBC, selected common alleles at ATM are associated with a reduced incidence of CBC, while other rare and predicted deleterious variants may act jointly with radiation exposure to increase risk. Further studies that characterize germline and somatic ATM mutations in breast cancer and relate the detected genetic changes to functional outcomes, particularly with regard to radiation responses, are needed to gain a complete picture of the complex relationship between ATM, radiation and breast cancer.

Contralateral Prophylactic Mastectomy in Women with Unilateral Breast Cancer Who Are Genetic Carriers, Have a Strong Family History or Are just Young at Presentation

“…The protective mechanisms may occur through an alteration in ATM activity as an initiator of DNA damage response or through its role in TP53 regulation [42]. Bernstein suggested that common ATM variants may exert a protective effect and reduce contralateral breast cancer risk, while rare ATM missense, deleterious variants may act synergistically with radiation exposure to increase this risk [43]. In this study, the variants: c.1899-55T>G (RR 0.5, 95% CI 0.3-0.8), c.3161C>G (RR 0.5, 95% CI 0.3-0.9), c.5558A>T (RR 0.2, 95% CI 0.1-0.6), and c.6348-54T>C (RR 0.2, 95% CI 0.1-0.8) were associated with significantly reduced risk.…”

Differences in physician opinions about controversial issues surrounding contralateral prophylactic mastectomy (CPM): A survey of physicians from accredited breast centers in the United States

“…Few studies have examined CBC risk for male patients or male BRCA carriers. CBC risk for other non‐ BRCA mutations is still largely unknown although some studies have shown higher CBC risk for CHEK2 and PALB2 although not for ATM . CBC risk for patients having a significant family history is greater than for those patients without a family history although differences are small.…”

Radiogenomic Predictors of Adverse Effects following Charged Particle Therapy

“…In the general population, most studies of genetic modifiers of radiation therapy–related risks have focused on genetic variation in DNA damage detection and repair mechanisms [58]. Among adults, the most comprehensive study to date was the Women’s Environmental Cancer and Radiation Epidemiology (WECARE) Study, a multicenter US-based case-control study of contralateral breast cancer designed to investigate the joint effects of radiation therapy, systemic therapies, genetic susceptibility, and other lifestyle and medical history factors on breast cancer risk [59–61]. Among the women in the WECARE study, the polygenic risk score, which was calculated by summing the number of risk alleles for each SNP, was associated with breast cancer risk.…”