Missense mutations in hMLH1 associated with colorectal cancer

Hum Genet. 1999 Nov;105(5):437-41. doi: 10.1007/s004390051127.


One of the most prevalent hereditary syndromes associated with colorectal cancer is hereditary nonpolyposis colorectal cancer (HNPCC). The inherited gene defects in HNPCC have been shown to reside in DNA mismatch repair genes, mostly hMSH2 or hMLH1. Most HNPCC patients are heterozygous with regard to the relevant mismatch repair gene; they have one normal and one mutated allele, and mismatch repair in normal somatic cells is functional. Cancer predisposition in HNPCC is believed to be associated with the loss of the wild-type allele in somatic cells, resulting in defective DNA mismatch repair. This gives rise to DNA microsatellite instability (MSI), an increased somatic mutation rate, and eventually, to the accumulation of mutations in genes involved in colorectal carcinogenesis. In support of this theory, colorectal tumors in HNPCC patients and in mice deficient for hMSH2 or hMLH1 show MSI. Here, we describe two missense mutations in hMLH1 exon 16 associated with colorectal cancer. Interestingly, the tumors do not show MSI. This raises some potentially important issues. First, even microsatellite-negative colorectal tumors can be associated with germline mutations and these will be missed if an MSI test is used to select patients for mutation screening. Second, the lack of MSI in these cases suggests that the mechanism involved in carcinogenesis could be different from that generally hypothesized.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Base Pair Mismatch / genetics
  • Base Sequence
  • Carrier Proteins
  • Colorectal Neoplasms, Hereditary Nonpolyposis / genetics*
  • DNA Primers / genetics
  • DNA Repair / genetics
  • Exons
  • Female
  • Germ-Line Mutation
  • Humans
  • Loss of Heterozygosity
  • Male
  • Mice
  • Microsatellite Repeats
  • MutL Protein Homolog 1
  • Mutation, Missense*
  • Neoplasm Proteins / genetics*
  • Nuclear Proteins


  • Adaptor Proteins, Signal Transducing
  • Carrier Proteins
  • DNA Primers
  • MLH1 protein, human
  • Mlh1 protein, mouse
  • Neoplasm Proteins
  • Nuclear Proteins
  • MutL Protein Homolog 1