Inactivation of ataxia telangiectasia mutated gene in B-cell chronic lymphocytic leukaemia
T Stankovic, P Weber, G Stewart, T Bedenham… - The Lancet, 1999 - thelancet.com
The Lancet, 1999•thelancet.com
Background Patients with the inherited disorder ataxia telangiectasia (AT) have an
increased susceptibility to lymphoid malignancies. In these patients mutations affect both
alleles of the AT 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 …
increased susceptibility to lymphoid malignancies. In these patients mutations affect both
alleles of the AT 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 …
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.
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