Cancer risks and mortality in heterozygous ATM mutation carriers.

Background: Homozygous or compound heterozygous mutations in the ATM gene are the principal cause of ataxia telangiectasia (A-T). Several studies have suggested that heterozygous carriers of ATM mutations are at increased risk of breast cancer and perhaps of other cancers, but the precise risk is uncertain.

Methods: Cancer incidence and mortality information for 1160 relatives of 169 UK A-T patients (including 247 obligate carriers) was obtained through the National Health Service Central Registry. Relative risks (RRs) of cancer in carriers, allowing for genotype uncertainty, were estimated with a maximum-likelihood approach that used the EM algorithm. Maximum-likelihood estimates of cancer risks associated with three groups of mutations were calculated using the pedigree analysis program MENDEL. All statistical tests were two-sided.

Results: The overall relative risk of breast cancer in carriers was 2.23 (95% confidence interval [CI] = 1.16 to 4.28) compared with the general population but was 4.94 (95% CI = 1.90 to 12.9) in those younger than age 50 years. The relative risk for all cancers other than breast cancer was 2.05 (95% CI = 1.09 to 3.84) in female carriers and 1.23 (95% CI = 0.76 to 2.00) in male carriers. Breast cancer was the only site for which a clear risk increase was seen, although there was some evidence of excess risks of colorectal cancer (RR = 2.54, 95% CI = 1.06 to 6.09) and stomach cancer (RR = 3.39, 95% CI = 0.86 to 13.4). Carriers of mutations predicted to encode a full-length ATM protein had cancer risks similar to those of people carrying truncating mutations.

Conclusion: These results confirm a moderate risk of breast cancer in A-T heterozygotes and give some evidence of an excess risk of other cancers but provide no support for large mutation-specific differences in risk.