Inactivation of ataxia telangiectasia mutated gene in B-cell chronic lymphocytic leukaemia

Summary Background Patients with the inherited disorder ataxia telangiectasia (A-T) have an increased susceptibility to lymphoid malignancies. In these patients mutations affect both alleles of the A-T gene ( ATM ). We have looked for mutations in the ATM gene in sporadic cases of B-cell chronic lymphocytic leukaemia (B-CLL). Methods 32 cases of B-CLL were analysed by restriction endonuclease fingerprinting to detect mutations within ATM. In six of the cases in which mutations were detected in tumour samples, germline DNA was screened to assess ATM carrier status. The samples in 20 cases were also studied by western blot for abnormal expression of ATM protein. Findings Expression of the ATM protein was impaired in eight (40%) of the 20 tumours analysed, being absent in three and decreased in five. Mutations within ATM were detected in six (18%) of the 32 patients. These point mutations, deletions, and one insertion were distributed across the coding sequence of ATM. Germline mutations, which indicate ATM carrier status, were found in two of these six patients compared with a frequency within the general population of below 1 in 200. Interpretation Abnormal expression of ATM protein is a frequent finding in B-CLL. Although the precise function of this protein is unknown, it is thought to have a role in programmed cell death, a deficiency of which would fit with the characteristic phenotype of prolonged cell survival seen in B-CLL tumour cells. Our results also suggest that carriers of ATM mutations may be at a particular risk for the development of B-CLL and this may partly explain the known genetic susceptibility to this disease.