[Ataxia-telangiectasia and cancer: an open question]

Ataxia-telangiectasia is a rare recessive disorder which, among other clinical signs, is characterized by an extreme sensitivity to ionising radiation. Cells isolated from AT patients show radioresistant DNA synthesis and this has lead to the hypothesis that the product of the genetic determinant of AT may play a role in the detection, signalling or repair of double stranded DNA breaks. The gene to AT, called ATM has been recently cloned and characterized. It codes for a large RNA transcript of 13,000 bp of which a 3,500 aa protein is translated. The gene itself covers 150 kb, spread over 64 exons. The amino acid sequence has revealed the existence, at the carboxyterminal end of the protein, of a domain presenting homology to PI-3 kinase. This characteristic has allowed the description of a new family of nuclear protein, in yeast, drosophila an human, functionally involved in DNA damage signalling. It is interesting to note that a vast majority of mutations described in AT patients lead to the truncation of the protein and consequently to the elimination of the PI-3K domain, thus suggesting an important role in the normal function of the protein. An important question linked to AT mutation concerns the cancer risk associated to heterozygous mutations. It is well established that AT patients, homozygous for the mutation, present a 100-200 fold increased risk of cancer. Epidemiological studies have described a 3-5 fold increase risk of cancer (particular breast cancer in women) associated to the heterozygous mutation. Knowing that the incidence of the heterozygotes can be estimated to range 0.5 to 1% in the general population this question is of great importance in terms of public health.