Epigenetics, mismatch repair genes and colorectal cancer.
The recent discovery of hypermethylation of the promoter of genes is a powerful epigenetic mechanism for the inactivation of tumour suppressor genes in colorectal and other cancers. Approximately 95% of hereditary non-polyposis colorectal cancers (HNPCCs) and 15% of sporadic colorectal cancers (CRCs) are replication error positive (RER(+)). Although DNA mutations are found in mismatch repair genes in the majority of HNPCC CRC, mutations are rare in sporadic RER(+) CRCs. We have shown that the principal cause of an RER(+) phenotype is hypermethylation of the promoter of hMLH1, resulting in the absence of hMLH1 protein. In contrast to sporadic RER(+) CRCs, we found that hypermethylation of hMLH1 does not occur in HNPCC CRC, suggesting the possibility of further differences between the two types of RER(+) tumours in the adenoma to carcinoma pathway. Other known tumour suppressor genes with few or no mutations may be candidates for epigenetic changes. One such gene is E-cadherin, and we described the first mutations of this gene in CRCs. Half of all CRCs were found to be hypermethylated in the Ecadherin promoter and this correlated with reduced E-cadherin expression. Epigenetic changes occur in CRCs and arise in different frequencies in separate genes. Hypermethylation of the promoter may be reversed and gene function restored to a cell, thus partially undoing the cancer phenotype.
Wheeler
J M D
JM
Department of Colorectal Surgery, John Radcliffe Hospital, Oxford, UK. jameswheeler@doctors.org.uk
D048868:Adaptor Proteins, Signal Transducing; D000230:Adenocarcinoma / Q000235:genetics*; D020137:Base Pair Mismatch / Q000235:genetics*; D015820:Cadherins; D002352:Carrier Proteins; D015179:Colorectal Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D004260:DNA Repair / Q000235:genetics*; D004261:DNA Replication / Q000235:genetics; D006801:Humans; D018895:Microsatellite Repeats; D008875:Middle Aged; D000070957:MutL Protein Homolog 1; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins; D011401:Promoter Regions, Genetic / Q000235:genetics
D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins; D002352:Carrier Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D000070957:MutL Protein Homolog 1