[HNPCC syndrome, microsatellite instability and NF1 gene alteration]

Hereditary predisposition to non polyposis colorectal cancer is caused by a heterozygous germline mutation in a DNA mismatch repair gene (essentially hMLH1 or hMSH2). Cancer progression in predisposed individuals results from the occurrence of a somatic alteration of the normal copy of the gene. Recently, we identified children with a constitutional deficiency of mismatch repair activity, due to a homozygous germline mutation of the hMLH1 gene. These children exhibited clinical features of de novo neurofibromatosis type 1 and early onset of hematopoietic cancers. This observation demonstrates that mismatch repair deficiency is compatible with human development. However, the subsequent genetic instability leads to a high cancer susceptibility. In this context, the NF1 gene appears to be a preferential mutational target. Implications of this observation are discussed.