Neurofibromatosis type 1 gene as a mutational target in a mismatch repair-deficient cell type

Hum Genet. 2003 Feb;112(2):117-23. doi: 10.1007/s00439-002-0858-4. Epub 2002 Nov 21.


DNA mismatch repair (MMR) is the process by which incorrectly paired DNA nucleotides are recognized and repaired. A germline mutation in one of the genes involved in the process may be responsible for a dominantly inherited cancer syndrome, hereditary nonpolyposis colon cancer. Cancer progression in predisposed individuals results from the somatic inactivation of the normal copy of the MMR gene, leading to a mutator phenotype affecting preferentially repeat sequences (microsatellite instability, MSI). Recently, we identified children with a constitutional deficiency of MMR activity attributable to a mutation in the h MLH1 gene. These children exhibited a constitutional genetic instability associated with clinical features of de novo neurofibromatosis type 1 (NF1) and early onset of extracolonic cancer. Based on these observations, we hypothesized that somatic NF1 gene mutation was a frequent and possibly early event in MMR-deficient cells. To test this hypothesis, we screened for NF1 mutations in cancer cells. Genetic alterations were identified in five out of ten tumor cell lines with MSI, whereas five MMR-proficient tumor cell lines expressed a wild-type NF1 gene. Somatic NF1 mutations were also detected in two primary tumors exhibiting an MSI phenotype. Finally, a 35-bp deletion in the murine Nf1 coding region was identified in mlh1-/- mouse embryonic fibroblasts. These observations demonstrate that the NF1 gene is a mutational target of MMR deficiency and suggest that its inactivation is an important step of the malignant progression of MMR-deficient cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Base Pair Mismatch*
  • Carrier Proteins
  • Codon
  • DNA Repair / genetics*
  • DNA, Neoplasm / genetics
  • DNA-Binding Proteins*
  • Female
  • Fibroblasts / pathology
  • Genes, Neurofibromatosis 1 / physiology*
  • Genetic Predisposition to Disease*
  • Germ-Line Mutation*
  • Homozygote
  • Humans
  • Male
  • Mice
  • Microsatellite Repeats
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein
  • Neoplasm Proteins / deficiency*
  • Neoplasm Proteins / genetics
  • Neoplasms / genetics*
  • Neoplasms / pathology
  • Neurofibromatosis 1 / genetics*
  • Nuclear Proteins
  • Proto-Oncogene Proteins / genetics
  • RNA, Neoplasm / genetics
  • RNA, Neoplasm / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Tumor Cells, Cultured / pathology


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • Codon
  • DNA, Neoplasm
  • DNA-Binding Proteins
  • MLH1 protein, human
  • Mlh1 protein, mouse
  • Neoplasm Proteins
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • RNA, Neoplasm
  • MSH2 protein, human
  • Msh2 protein, mouse
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein