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Knowing that mutations of a specific gene predispose to certain cancers is an important step toward more effective preventive or therapeutic measures for those cancers. The history of ataxia-telangiectasia (A-T) research illustrates how advances in genetic and molecular genetic technology are clarifying and quantifying the role of mutations at this genetic locus in common diseases and mortality in the general population. An exceptionally high incidence of cancer was observed in patients with the rare autosomal recessive syndrome A-T (1) shortly after Boder and Sedgewick (2) published their remarkably complete initial characterization of this disorder in 1958. I hypothesized (3) that mutations at the A-T locus (sometimes referred to as the ATM, for “ataxia-telangiectasia mutated,” locus) might contribute substantially to the public health burden of cancer, despite the rarity of A-T homozygotes, because individuals who carry a single mutation at this locus—A-T heterozygotes—are relatively common in the general population according to the genetic Hardy–Weinberg principle. When we began to test this hypothesis in 1970, A-T heterozygotes could not be identified through molecular testing; they still cannot be distinguished by physical examination or by conventional laboratory tests. Such carriers are, however, a high proportion of blood relatives in A-T families. In the first study of 26 A-T families, we found substantially more deaths from cancer among the blood relatives than among the spouse control subjects (3). The public health implications of our initial findings and the interest expressed by other scientists led my research group in 1981 to undertake a comprehensive nationwide study of A-T families. From a retrospective comparison of cancer incidence in blood relatives and spouse control subjects in 110 A-T families, female breast cancer emerged as the leading cancer associated with A-T heterozygosity (4). A prospective analysis of newly incident cancers in these and additional families, published in 1991 (5), confirmed this specific association as well as the overall predisposition of A-T heterozygotes to cancer. Although prospective studies are the “gold standard” in epidemiology, the interpretation of data from A-T families was limited by the fact that only the parents, and certain grandparents in consanguineous families, were definite—obligate—carriers of the A-T mutations segregating in these families. Reliable methods for determining carrier status, originally through marker haplotypes, made it possible to measure the relative risk of breast cancer for A-T heterozygotes (6) by use of a statistically powerful bias-resistant approach (7) that is now called the “index-test method.” This method uses highly reliable intrafamilial genotyping to compare cancer incidence rates in carriers with those in noncarriers in the same families, the best possible comparison group in terms of matching for important confounders. Studies of A-T families in the U.K. (8), in France (9), and now in the Nordic countries by Olsen et al. (10) reporting in this issue of the Journal have confirmed the association of A-T heterozygosity with breast cancer risk. The most reliable and informative data in these three studies come from the obligate heterozygotes, the mothers. The relative risk estimates of breast cancer for these mothers were 3.37, 3.32, and 7.1, respectively, based on comparisons with population mortality or incidence rates. With the index-test method, we had estimated the relative risk of breast cancer for A-T heterozygotes to be 3.8 (6). Our recently reported comparison of the mortality of carrier and noncarrier grandparents in A-T families (11), which is based on comprehensive data collection and genotyping, is consistent with these findings. The relative risk of death from all cancers for male and female carriers was 2.6. A relative risk of breast cancer greater than 3 is compatible with three recent studies (12–14), which found the proportion of A-T mutation carriers to be 8%–10% in populations of breast cancer patients. Two of these studies (12,13) employed exonby-exon screening, and one (14) used the protein truncation test. Earlier studies that had yielded lower estimates of the heterozygote frequency in narrowly selected populations had detected only truncating mutations (15,16) or had dismissed missense mutations as neutral polymorphisms (17). These data may be compared with those of “control” population samples. In two studies in the United States (12,15), approximately 1% of the population has been found to be A-T mutation carriers. Even though only a single truncating A-T mutation was sought in a sample from the general Dutch population, it was found in 0.7% of this sample (14). Estimates (10,18) of the population frequency of A-T heterozygotes based on the Hardy–Weinberg principle are inevitably too low because this calculation depends on accurate measurement of the birth incidence of the homozygotes, which is not currently feasible. The important point is that prevalence surveys (10,18) typically underestimate the birth incidence of genetic syndromes severalfold. Therefore, reliable estimates of the frequency of A-T heterozygotes in the general population and in groups of breast cancer patients will require highly sensitive, specific, and cost-effective methods of mutation screening. Mutation detection at the A-T locus is challenging because the gene has 66 exons that span 150 kb of genomic DNA. Exon-by-exon screening methods have detected mutations in 57%–85% of the specific chromosomes 11 that must be mutated because they were found in patients with A-T (19,20). It is likely that many of the “missing” mutations are due to sequence changes deep within introns that lead to splicing errors that produce an altered gene product. On the positive side, hundreds of different mutations—truncating, missense, splicing, and in-frame insertions or deletions—have already been found in the DNA of A-T patients or their parents. In all reported studies of A-T patients, truncating mutations constituted more than 50% of all identified mutations.

Public Health Burden of Cancer in Ataxia-Telangiectasia Heterozygotes