Germline Mutations of the Ataxia-Telangiectasia Gene, ATM, as a Risk Factor for Radiation-Associated Breast Cancer

Ataxia-telangiectasia AT is an autosomal recessive disorder characterized by neurologic and other abnormalities as well as an approximately 100-fold increase in cancer incidence. A single gene, ATM appears to be mutated in the majority of AT families. ATM functions as a central component of the cellular response to DNA damage. It has been postulated that heterozygotes for ATM mutations have an increased susceptibility to radiation-induced breast cancer. To test this hypothesis we performed a study to test the frequency of ATM mutations in woman with breast cancer after therapeutic radiation therapy for Hodgkins disease. Cases were compared to matched controls treated for Hodgkins disease with no breast cancer. We observed no truncating mutations of ATM in either group, and no difference in the rate of missense mutations 37 controls vs 21 cases. Some missense mutations were observed at polymorphic 1 frequencies. Further studies analyzing the frequencies of these mutations in the general population, as well as functional studies, will be necessary to resolve their potential role as susceptibility alleles for lymphoid cancers.