ATM-heterozygous germline mutations contribute to breast cancer-susceptibility

Approximately 0.5%-1% of the general population has been estimated to be he terozygous for a germline mutation in the ATM gene. Mutations in the ATM ge ne are responsible for the autosomal recessive disorder ataxia-telangiectas ia (A-T) (MIM 208900). The finding that ATM-heterozygotes have an increased relative risk for breast cancer was supported by some studies but not conf irmed by others. In view of this discrepancy, we examined the frequency of ATM germline mutations in a selected group of Dutch patients with breast ca ncer. We have analyzed ATM germline mutations in normal blood lymphocytes, using the protein-truncation test followed by genomic-sequence analysis. A high percentage of ATM germline mutations was demonstrated among patients w ith sporadic breast cancer. The 82 patients included in this study had deve loped breast cancer at age <45 and had survived greater than or equal to 5 years (mean 15 years), and in 33 (40%) of the patients a contralateral brea st tumor had been diagnosed. Among these patients we identified seven (8.5% ) ATM germline mutations, of which five are distinct. One splice-site mutat ion (IVS10-6T-->G) was detected three times in our series. Four heterozygou s carriers were patients with bilateral breast cancer. Our results indicate that the mutations identified in this study are "A-T disease-causing" muta tions that might be associated with an increased risk of breast cancer in h eterozygotes. We conclude that ATM heterozygotes have an approximately nine fold-increased risk of developing a type of breast cancer characterized by frequent bilateral occurrence, early age at onset, and long-term survival. The specific characteristics of our population of patients may ex-plain why such a high frequency was not found in other series.