Founding mutations and Alu-mediated recombination in hereditary colon cancer

Nat Med. 1995 Nov;1(11):1203-6. doi: 10.1038/nm1195-1203.


By screening members of Finnish families displaying hereditary nonpolyposis colorectal cancer (HNPCC) for predisposing germline mutations in MSH2 and MLH1, we show that two mutations in MLH1 together account for 63% (19/30) of kindreds meeting international diagnostic criteria. Mutation 1, originally detected as a 165-base pair deletion in MLH1 cDNA comprising exon 16, was shown to consist of a 3.5-kilobase genomic deletion most likely resulting from Alu-mediated recombination. Mutation 2 destroys the splice acceptor site of exon 6. A simple diagnostic test based on polymerase chain reaction was designed for both mutations. Our results show that these two ancestral founding mutations account for a majority of Finnish HNPCC kindreds and represent the first report of Alu-mediated recombination causing a prevalent, dominantly inherited predisposition to cancer.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Base Sequence
  • Cloning, Molecular
  • Colorectal Neoplasms, Hereditary Nonpolyposis / epidemiology
  • Colorectal Neoplasms, Hereditary Nonpolyposis / etiology
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • Disease Susceptibility
  • Exons
  • Finland / epidemiology
  • Founder Effect*
  • Genes, Dominant
  • Humans
  • Introns
  • Molecular Sequence Data
  • Mutation*
  • Pedigree
  • Polymerase Chain Reaction
  • Recombination, Genetic*
  • Repetitive Sequences, Nucleic Acid*
  • Sequence Analysis, DNA