Hereditary nonpolyposis colorectal cancer: frequent occurrence of large genomic deletions in MSH2 and MLH1 genes

Int J Cancer. 2003 Feb 20;103(5):636-41. doi: 10.1002/ijc.10869.


Hereditary nonpolyposis colorectal cancer (HNPCC) is often caused by a deficiency in DNA mismatch repair. By using conventional methods of mutation analysis, point mutations in the DNA mismatch repair genes MSH2 and MLH1 have been detected in up to 64% of patients suspected of HNPCC. However, large genomic deletions cannot be detected by these methods. In our study, we applied a semiquantitative multiplex PCR to detect the proportion of large deletions in patients meeting the Bethesda criteria whose tumours exhibited microsatellite instability (MSI). Of 368 unrelated patients, 180 exhibited MSI. In these patients, 68 disease-causing point mutations (38%) had previously been detected in the MSH2 and MLH1 genes by SSCP, heteroduplex analysis or DHPLC followed by direct sequencing. The remaining 112 patients (including 24 patients with rare missense or other unclarified variants) were examined for large deletions. We identified deletions in 19 patients (10.6%); 11/19 (58%) deletions were located in MSH2 and 8/19 (42%) in MLH1, respectively. The size of deletions ranged from 1 exon to a deletion of a whole gene. Five breakpoints of deletions were sequenced; Alu-repetitive elements were involved in all of them. In patients meeting the Amsterdam criteria the proportion of large deletions was 12.6%. A similar proportion of deletions was found in the group of patients with a positive family history for colorectal cancer and MSI tumours, not meeting the Amsterdam criteria. The results of our study suggest that large genomic deletions in both MSH2 and MLH1 genes play a considerable role in the pathogenesis of HNPCC and should be part of the routine HNPCC mutation detection protocols.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Base Pair Mismatch / genetics
  • Base Sequence
  • Carrier Proteins
  • Colorectal Neoplasms / genetics*
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • DNA Mutational Analysis
  • DNA Primers / chemistry
  • DNA Repair / genetics
  • DNA, Neoplasm / metabolism
  • DNA-Binding Proteins*
  • Gene Deletion*
  • Humans
  • Microsatellite Repeats
  • Middle Aged
  • Molecular Sequence Data
  • MutL Protein Homolog 1
  • MutS Homolog 2 Protein
  • Mutation / genetics
  • Neoplasm Proteins / genetics*
  • Nuclear Proteins
  • Polymerase Chain Reaction
  • Proto-Oncogene Proteins / genetics*
  • Sequence Homology, Nucleic Acid


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