ATM, radiation, and the risk of second primary breast cancer.
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 regard 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.
['Bernstein|Jonine L|JL|', '|||', 'Concannon|Patrick|P|']
D000818:Animals D064007:Ataxia Telangiectasia Mutated Proteins D001943:Breast Neoplasms D020022:Genetic Predisposition to Disease D006801:Humans D009154:Mutation D009381:Neoplasms, Radiation-Induced D016609:Neoplasms, Second Primary
ATM breast cancer Ataxia-Telangiectasia allelic heterogeneity radiation therapy