Missense mutations at ATM gene and cancer risk

Abstract

Two studies published this year, one by Tatjana Stankovic and colleagues (Jan 2, p 26)1Bullrich F Rasio D Kitada S et al.ATM mutations in B-cell chronic lymphocytic leukemia.Cancer Res. 1999; 59: 24-27PubMed Google Scholar, showed the presence of mutations in the ATM gene, which is defective in ataxia-telangiectasia (A-T), in B-cell chronic lymphocytic leukaemia (B-CLL). After the discovery of missense mutations in T-cell and B-cell malignant disease and our suggestion of a putative increase of A-T heterozygotes in patients with T-cell prolymphocytic leukaemia (T-PLL),3Vorechovsky I Luo L Dyer MJ et al.Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia.Nat Genet. 1997; 17: 96-99Crossref PubMed Scopus (228) Google Scholar both studies reported two missense mutations in the germ-line of patients with B-CLL, supporting the increased prevalence of the germ-line carriers of mutated ATM alleles among B-CLL patients. Stankovic and co-workers2Stankovic T Weber P Stewart G et al.Inactivation of ataxia telangiectasia mutated gene in B-cell chronic lymphocytic leukaemia.Lancet. 1999; 353: 26-29Summary Full Text Full Text PDF PubMed Scopus (290) Google Scholar argued that the transversion 3161C to G is a pathogenic ATM mutation since the change was not found in 68 A-T families and controls and the aminoacid substitution represents a nonconservative change. Although we have shown this substitution in a breast tumour sample, we observed a loss of the rare allele in tumour cells,4Vorechovsky I Rasio D Luo L et al.The ATM gene and susceptibility to breast cancer: analysis of 38 breast tumors reveals no evidence for mutation.Cancer Res. 1996; 56 (4130–33.): 2726-2732PubMed Google Scholar inconsistent with ATM being a tumour suppressor, as suggested for T-PLL.3Vorechovsky I Luo L Dyer MJ et al.Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia.Nat Genet. 1997; 17: 96-99Crossref PubMed Scopus (228) Google Scholar In addition, we found this variation five of 224 chromosomes in North European white people.4Vorechovsky I Rasio D Luo L et al.The ATM gene and susceptibility to breast cancer: analysis of 38 breast tumors reveals no evidence for mutation.Cancer Res. 1996; 56 (4130–33.): 2726-2732PubMed Google Scholar Four guanosine-containing alleles were identified on 176 chromosomes in Swedish patients with familial breast cancer and the same number on 126 chromosomes in a control group of Swedish women.4Vorechovsky I Rasio D Luo L et al.The ATM gene and susceptibility to breast cancer: analysis of 38 breast tumors reveals no evidence for mutation.Cancer Res. 1996; 56 (4130–33.): 2726-2732PubMed Google Scholar We also found 52 heterozygotes at this nucleotide position in 880 German patients with breast cancer, which did not differ from 22 heterozygotes in 335 controls. We identified five heterozygotes in 93 unrelated Iranians, although no heterozygotes were detected in 93 Gambians. Since the overall frequency of this rare allele is in excess of the estimated population frequency of A-T heterozygotes and does not differ between controls and cancer patients in the same population, this particular change can hardly represent a genuine A-T or allele that predisposes to breast cancer. Can this substitution still confer a risk of developing B-CLL? Could such a risk be conferred by other changes found on the same haplotype? At least a partial answer to these questions can be provided by the combination of mutation and large-scale allelic association/haplotype studies of B-CLL, which is more common that TPLL, and so studies can yield sufficient cases. It will be crucial, however, to ensure a valid selection and sufficient number of controls, free of confounding effects of the population stratification or admixture. To distinguish rare variants in ATM4Vorechovsky I Rasio D Luo L et al.The ATM gene and susceptibility to breast cancer: analysis of 38 breast tumors reveals no evidence for mutation.Cancer Res. 1996; 56 (4130–33.): 2726-2732PubMed Google Scholar from genuine cancerpredisposing mutations, each rare allele identified in cancer patients should be analysed independently and in the context of a particular haplotype in cases versus controls. For example, we found that a subset of the guanosine-bearing alleles at position 3161 had a thymine to cytosine transition at position 2572. Similarly, A-T mutations such as the exon skipping 3576G to A substitution occur in cis on the 3161G haplotype.5Sandoval N Platzer M Rosenthal A et al.Characterization of ATM mutations in 66 ataxia-telangiectasia families.Hum Mol Genet. 1999; 8: 69-79Crossref PubMed Scopus (179) Google Scholar Such linkage disequilibria may contribute to disease associations and differential overall frequencies of missense changes in controls versus cancer patients. We believe it is incorrect to regard the 3161G transversion as an A-T allele and premature at this stage to see it as a BCLL-predisposing variant, in particular if a truncating ATM mutation was found in the same patient with B-CLL.2Stankovic T Weber P Stewart G et al.Inactivation of ataxia telangiectasia mutated gene in B-cell chronic lymphocytic leukaemia.Lancet. 1999; 353: 26-29Summary Full Text Full Text PDF PubMed Scopus (290) Google Scholar