Molecular genetics of hereditary nonpolyposis colorectal cancer.
The initial paradigm developed for colorectal carcinogenesis was derived from the observation that these tumors suffer a large number of chromosomal losses. This phenomenon results from unbalanced mitoses, and to date there is no clear explanation for this type of genomic instability. In 1993, a second type of genomic instability was detected and linked to 12-15% of sporadic tumors, as well as 90% or more of the colon cancers in hereditary nonpolyposis colorectal cancer (HNPCC). HNPCC tumors are typically diploid and do not have the inactivating mutations at the tumor suppressor genes commonly found in the other cancers. These tumors were found because they have a very large number (perhaps in excess of 10(5)) of insertion or deletion mutations at microsatellite sequences; as a result, this has been termed microsatellite instability (MSI). The majority of HNPCC families can be linked to germline mutations in the DNA mismatch repair (MMR) genes hMSH2 or hMLH1. Germline mutations in hMSH6 and hPMS2 in HNPCC families are much less common. HNPCC tumors develop through the accumulation of mutations at genes that control cellular growth, and these genes are not the same as those recognized in the initial pathway outlined by Vogelstein et al. The genetic targets of MSI all contain repetitive sequences in coding regions that are unstable when the DNA MMR system is inoperative. Certain pathological features have been identified that suggest that colon cancers have developed in the setting of defective DNA MMR.
Boland
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Department of Medicine, University of California at San Diego, California 92037, USA. crboland@ucsd.edu
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000209:etiology / Q000235:genetics*; D004268:DNA-Binding Proteins; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins / Q000235:genetics*
D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; D004268:DNA-Binding Proteins; C501486:MLH1 protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D011518:Proto-Oncogene Proteins; C497172:MSH2 protein, human; D000070957:MutL Protein Homolog 1; D051718:MutS Homolog 2 Protein