A hereditary nonpolyposis colorectal carcinoma case associated with hypermethylation of the MLH1 gene in normal tissue and loss of heterozygosity of the unmethylated allele in the resulting microsatellite instability-high tumor

Cancer Res. 2002 Jul 15;62(14):3925-8.


Fourteen suspected hereditary nonpolyposis colorectal carcinoma cases with microsatellite unstable(microsatellite instability-high; MSI-H) tumors but no germ-line MSH2, MSH6, or MLH1 mutations were examined for hypermethylation of CpG sites in the critical promoter region of MLH1. The methylation patterns were determined using methylation-specific PCR and by sequence analysis of sodium bisulfite-treated genomic DNA. In one case, DNA hypermethylation of one allele was detected in DNA isolated from blood. In the MSI-H tumor from this case, the unmethylated MLH1 allele was eliminated by loss of heterozygosity, and the methylated allele was retained. This biallelic inactivation resulted in loss of expression of MLH1 in the tumor as confirmed by immunohistochemistry. These results suggest a novel mode of germ-line inactivation of a cancer susceptibility gene.

Publication types

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

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Alleles*
  • Carrier Proteins
  • Colorectal Neoplasms, Hereditary Nonpolyposis / blood
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • CpG Islands
  • DNA Methylation*
  • DNA, Neoplasm / blood
  • DNA, Neoplasm / genetics
  • Humans
  • Loss of Heterozygosity*
  • Microsatellite Repeats / genetics
  • MutL Protein Homolog 1
  • Neoplasm Proteins / genetics*
  • Nuclear Proteins
  • Polymerase Chain Reaction
  • Promoter Regions, Genetic


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • DNA, Neoplasm
  • MLH1 protein, human
  • Neoplasm Proteins
  • Nuclear Proteins
  • MutL Protein Homolog 1