A systematic evaluation of the ataxia telangiectasia mutated gene does not show an association with non-Hodgkin lymphoma

  • Sipahimalani P
  • Spinelli J
  • MacArthur A
 et al. 
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Abstract

The ataxia telangiectasia mutated (ATM) gene is critical for the detection and repair of DNA double-stranded breaks. Mutations in this gene cause the autosomal recessive syndrome ataxia telangiectasia (AT), an attribute of which is an increased risk of cancer, particularly lymphoma. We have undertaken a population-based case/control study to assess the influence of genetic variation in ATM on the risk of non-Hodgkin lymphoma (NHL). A number of the subtypes that constitute NHL have in common the occurrence of specific somatic translocations that contribute to lymphomagenesis. We hypothesize that ATM function is slightly attenuated by some variants, which could reduce double-stranded break repair capacity, contributing to the occurrence of translocations and subsequent lymphomas. We sequenced the promoter and all exons of ATM in the germline DNA of 86 NHL patients and identified 79 variants. Eighteen of these variants correspond to nonsynonymous amino acid differences, 6 of which were predicted to be deleterious to protein function; these variants were all rare. Eleven common variants make up 10 haplotypes that are specified by 7 tagSNPs. Linkage disequilibrium across the ATM gene is high but incomplete. TagSNPs and the 6 putatively deleterious variants were genotyped in 798 NHL cases and 793 controls. Our results indicate that common variants of ATM do not significantly contribute to the risk of NHL in the general population. However, some rare, functionally deleterious variants may contribute to an increased risk of development of rare subtypes of the disease.

Author-supplied keywords

  • Association study
  • Ataxia telangiectasia mutated (ATM)
  • Cancer susceptibility
  • Haplotype prediction
  • Non-Hodgkin lymphoma

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Authors

  • Payal Sipahimalani

  • John J. Spinelli

  • Amy C. MacArthur

  • Agnes Lai

  • Stephen R. Leach

  • Rozmin T. Janoo-Gilani

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