MOLECULAR GENOTYPING SHOWS THAT ATAXIA-TELANGIECTASIA HETEROZYGOTES ARE PREDISPOSED TO BREAST-CANCER

About 1.4% of the general population are heterozygous carriers of the gene for ataxiatelangiectasia (A-T), an autosomal recessive progressiv e neurologic syndrome In which cancer incidence of homozygotes is appr oximately 100-fold greater than the general population's rates. The hy pothesis that A-T heterozygotes are predisposed to breast cancer was t ested by the unbiased statistically powerful index-test method based o n molecular genotyping. The A-T gene carrier status of 775 blood relat ives in 99 A-T families was determined by tracing the A-T gene in each family through tightly linked flanking DNA markers. There were 33 wom en with breast cancer who could be genotyped; 25 of these were A-T het erozygotes, compared to an expected 14.9 (odds ratio 3.8, 95% confiden ce limits 1.7-8.4, one-sided p = .0001). This demonstrates that the A- T gene predisposes heterozygotes to breast cancer. For the 21 breast c ancers with onset before age 60, the odds ratio was 2.9 (1.1-7.6, p = .009) and for the 12 cases with onset at age 60 or older, the odds rat io was 6.4 (1.4-28.8, p = .002). Thus the breast cancer risk for A-T h eterozygous women is not limited to young women but appears even highe r at older ages. Of all breast cancers in the United States, 6.6% may occur in women who are A-T heterozygotes. This proportion is several f old greater than the estimated proportion of carriers of BRCA1 mutatio ns in breast cancer cases with onset at any age. (C) Elsevier Science Inc., 1996