Clustering of missense mutations in the ataxia-telanglectasia gene in a sporadic T-cell leukaemia

Abstract

Ataxia-telangiectasia (A-T) is a recessive multi-system disorder caused by mutations in the ATM gene at 11q22-q23 (ref. 3). The risk of cancer, especially lymphoid neoplasias, is substantially elevated in A-T patients and has long been associated with chromosomal instability. By analysing tumour DNA from patients with sporadic T-cell prolymphocytic leukaemia (T-PLL), a rare clonal malignancy with similarities to a mature T-cell leukaemia seen in A-T, we demonstrate a high frequency of ATM mutations in T-PLL. In marked contrast to the ATM mutation pattern in A-T, the most frequent nucleotide changes in this leukaemia were missense mutations. These clustered in the region corresponding to the kinase domain, which is highly conserved in ATM-related proteins in mouse, yeast and Drosophila. The resulting amino-acid substitutions are predicted to interfere with ATP binding or substrate recognition. Two of seventeen mutated T-PLL samples had a previously reported A-T allele. In contrast, no mutations were detected in the p53 gene, suggesting that this tumour suppressor is not frequently altered in this leukaemia. Occasional missense mutations in ATM were also found in tumour DNA from patients with B-cell non-Hodgkin's lymphomas (B-NHL) and a B-NHL cell line. The evidence of a significant proportion of loss-of-function mutations and a complete absence of the normal copy of ATM in the majority of mutated tumours establishes somatic inactivation of this gene in the pathogenesis of sporadic T-PLL and suggests that ATM acts as a tumour suppressor. As constitutional DNA was not available, a putative hereditary predisposition to T-PLL will require further investigation.

Risk of breast cancer and other cancers in heterozygotes for ataxia-telangiectasia

“…In addition to the concern about breast cancer, the possible importance of the ATM gene in other sporadic tumours has recently been highlighted by reports of ATM mutations in T-cell prolymphocytic leukaemia (T-PLL) in non-A-T patients (Stilgenbauer et al, 1997;Vorechovsky et al, 1997). Although ATM mutations in some cases of sporadic T-PLL have been shown to be acquired (Stoppa-Lyonnet et al, 1998), and no sporadic T-PLL case has so far been shown to carry a germline ATM mutation, the risk of T-PLL in A-T heterozygotes remains unknown.…”

No mutations in the BACH1 gene in BRCA1 and BRCA2 negative breast‐cancer families linked to 17q22

“…Thus, the 29 families were selected and screened for germline mutations in the BACH1 gene, together with additional 95 familial breast cancer cases without detectable BRCA1 and BRCA2 mutations (Table I). Twenty-four segments of BACH1 coding exons and flanking intronic sequences were amplified 10 The PCR-SSCP analysis showed 4 different alterations. Three alterations turned out to be known polymorphisms (Table II), 5 whereas 1 alteration was a 517C-T transition not previously reported (Table II).…”

The role of ATM in DNA damage responses and cancer

“…AT patients also exhibit an increased risk for the development of epithelial tumors later in life and AT heterozygotes may share a small but measurable risk for developing breast cancer (Swift et al, 1987;Uhrhammer et al, 1998). ATM may also play a role as a classic tumor suppressor in T-prolymphocytic leukemia, which is highly associated with loss or mutation in the ATM locus (Vorechovsky et al, 1997). In addition, frequent loss in heterozygocity (LOH) at the 11q22-q23 loci has been reported for several other cancers as well, including breast cancer (Hampton et al, 1994a,b;Gabra et al, 1996;Winqvist et al, 1995).…”