Causes of microsatellite instability in colorectal tumors: implications for hereditary non-polyposis colorectal cancer screening

Cancer Genet Cytogenet. 2001 Apr 15;126(2):85-96. doi: 10.1016/s0165-4608(00)00399-x.


Microsatellite instability (MSI) analysis was performed using a "reference panel" of microsatellite markers in 345 unselected primary colorectal cancers (CRC). Thirty-five (10%) tumors were classified as high MSI (MSI-H). We identified 6 (17%) MSI-H tumors with germline mutations in mismatch repair (MMR) genes (tumors from patients with hereditary non-polyposis colorectal cancer (HNPCC) syndrome) and 29 (83%) MSI-H tumors without germline MMR mutations (sporadic MSI-H tumors). Hypermethylation of the hMLH1 promoter was found in 26/29 (90%) sporadic MSI-H tumors but only in 1/6 (17%) HNPCC tumors (P<.001). Somatic alterations were identified in both MMR genes in HNPCC tumors but mainly in the hMSH2 gene in sporadic MSI-H tumors. LOH at MMR loci was detected in 3/6 (50%) HNPCC tumors and in 4/26 (15%) informative sporadic MSI-H tumors. These results together indicate different mode of inactivation of MMR genes in sporadic MSI-H tumors versus MSI-H tumors in HNPCC patients. We therefore propose that MSI analysis of newly diagnosed primary CRC followed by methylation analysis of hMLH1 promoter in MSI-H tumors and mutational analysis of MMR genes in MSI-H tumors lacking hMLH1 promoter methylation might be an efficient molecular genetic approach for HNPCC screening.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Aged
  • Base Sequence
  • Carrier Proteins
  • Colorectal Neoplasms, Hereditary Nonpolyposis / diagnosis
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • DNA Methylation
  • DNA-Binding Proteins*
  • Female
  • Germ-Line Mutation
  • Humans
  • Loss of Heterozygosity
  • Male
  • Mass Screening*
  • Microsatellite Repeats / genetics*
  • Middle Aged
  • Molecular Sequence Data
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein
  • Neoplasm Proteins / genetics
  • Nuclear Proteins
  • Promoter Regions, Genetic
  • Proto-Oncogene Proteins / genetics


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