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Age related shift in the mutation spectra of germline and somatic NF2 mutations: hypothetical role of DNA repair mechanisms
  1. D G R Evans1,
  2. E R Maher2,
  3. M E Baser3
  1. 1University Department of Medical Genetics, St. Mary’s Hospital, Manchester M13 0JH, UK
  2. 2Section of Medical and Molecular Genetics, University of Birmingham School of Medicine, Birmingham B15 2TT, UK
  3. 3Los Angeles, CA, 90024 USA
  1. Correspondence to:
 Dr M E Baser
 10622 Kinnard Avenue, 203, Los Angeles, CA 90024, USA;


It has been suggested that somatic mutations that accumulate due to an age related decline in the efficiency of DNA repair mechanisms might contribute to the increased incidence of cancer in older people. However, there is little direct evidence for this phenomenon. The spectra of germline and somatic mutations can be compared in cancer genes that cause inherited tumour syndromes and sporadic tumours, respectively. In addition, mosaic patients reflect the nature of mutations that occur in early development. Hence, we hypothesised that the “temporal mutation record” of a human cancer gene might provide insight into mechanisms of mutagenesis in the germline, in early development, and in adulthood. We compared the ratio of frameshift to nonsense mutations in three diseases that are related to the NF2 tumour suppressor gene: classic neurofibromatosis 2 (NF2), caused by germline NF2 mutations; mosaic NF2; and unilateral sporadic vestibular schwannoma (USVS), caused by somatic NF2 inactivation. Nonsense mutations predominated in both classic and mosaic NF2, but the ratio of nonsense to frameshift mutations was reversed in USVS. Moreover, in USVS patients, the ratio of somatic frameshift to nonsense mutations increased significantly with increasing age at diagnosis. This pattern is consistent with an age related decline in the efficiency of DNA repair mechanisms. Similar studies for other familial cancer genes may provide further evidence for this hypothesis.

  • FAP, familial adenomatous polyposis
  • NF2, neurofibromatosis 2
  • USVS, unilateral sporadic vestibular schwannoma
  • Aging
  • DNA repair
  • NF2

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  • Competing interests: none declared