Malignancy, DNA damage and chromosomal aberrations in ataxia telangiectasia

Ataxia telangiectasia (AT) is a recessively inherited disorder with features that include a greatly increased susceptibility to malignant disease, an immunological defect and increased sensitivity to ionizing radiation and bleomycin. Recently, we and others have shown that AT cells do not show the same decrease in DNA synthesis as normal cells following gamma-irradiation. They may also have a defect in DNA repair following gamma-irradiation. Some of our patients show the presence of one or more cytogenetically abnormal clones involving chromosome 14 in their circulating lymphocytes; these are actively proliferating, in the absence of any clinically diagnosed malignancy, and can exist for several years. A variety of subclones also appear at different times, pointing to an instability in the major clone. Lymphocytic leukaemia arising in such clones in AT patients has been described by others. The defective response of AT cells to some types of damage to DNA may increase the probability of translocations of chromosomal segments to other sites, resulting in the observed chromosomal rearrangements. Furthermore, in vivo, cells with such rearrangements may develop into clones before a malignant change is seen, rather than being a secondary feature of lesser importance.