DNA mismatch repair genes and colorectal cancer
Open Access
- 1 July 2000
- Vol. 47 (1) , 148-153
- https://doi.org/10.1136/gut.47.1.148
Abstract
Positional cloning and linkage analysis have shown that inactivation of one of the mismatch repair genes (hMLH1, hMSH2, hPMS1, hPMS2, GTBP/hMSH6) is responsible for the microsatellite instability or replication error (RER+) seen in more than 90% of hereditary nonpolyposis colorectal cancers (HNPCC) and 15% of sporadic RER+ colorectal cancers. In HNPCC, a germline mutation (usually in hMLH1 or hMSH2) is accompanied by one further event (usually allelic loss) to inactivate a mismatch repair gene. In contrast, somatic mutations in the mismatch repair genes are not frequently found in sporadic RER+ colorectal cancers. Hypermethylation of the hMLH1 promoter region has recently been described, and this epigenetic change is the predominant cause of inactivation of mismatch repair genes in sporadic RER+ colorectal and other cancers. Inactivation of a mismatch repair gene may occur early (before inactivation of the APC gene) and produce a raised mutation rate in a proportion of HNPCC patients, and these cancers will follow a different pathway to other RER+ cancers. However, it is likely that selection for escape from apoptosis is the most important feature in the evolution of an RER+ cancerKeywords
This publication has 96 references indexed in Scilit:
- Chromosome number and structure both are markedly stable in RER colorectal cancers and are not destabilized by mutation of p53Oncogene, 1998
- Defects in mismatch repair occur afterAPC mutations in the pathogenesis of sporadic colorectal tumoursHuman Mutation, 1998
- Sp1 binding is inhibited by mCpmCpG methylationGene, 1997
- Binding of insertion/deletion DNA mismatches by the heterodimer of yeast mismatch repair proteins MSH2 and MSH3Current Biology, 1996
- hMutSβ, a heterodimer of hMSH2 and hMSH3, binds to insertion/deletion loops in DNACurrent Biology, 1996
- Mutation in the DNA mismatch repair gene homologue hMLH 1 is associated with hereditary non-polyposis colon cancerNature, 1994
- Unicryptal loss of heterozygosity in hereditary non-polyposis colorectal cancerPathology, 1994
- The International Collaborative Group on Hereditary Non-Polyposis Colorectal Cancer (ICG-HNPCC)Diseases of the Colon & Rectum, 1991
- Methylation-Sensitive Sequence-Specific DNA Binding by the c-Myc Basic RegionScience, 1991
- Mutation and Cancer: Statistical Study of RetinoblastomaProceedings of the National Academy of Sciences, 1971