RGD Reference Report - DNA mismatch repair defects: role in colorectal carcinogenesis. - Rat Genome Database

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DNA mismatch repair defects: role in colorectal carcinogenesis.

Authors: Jacob, S  Praz, F 
Citation: Jacob S and Praz F, Biochimie. 2002 Jan;84(1):27-47.
RGD ID: 2306714
Pubmed: PMID:11900875   (View Abstract at PubMed)

The inactivation of the DNA mismah repair (MMR) system, which is associated with the predisposition to the hereditary non-polyposis colorectal cancer (HNPCC), has also been documented in nearly 20% of the sporadic colorectal cancers. These tumors are characterized by a high frequency of microsatellite instability (MSI(+) phenotype), resulting from the accumulation of small insertions or deletions that frequently arise during replication of these short repeated sequences. A germline mutation of one of the two major MMR genes (hMSH2 or hMLH1) is found in half to two-thirds of the patients with HNPCC, whereas in sporadic cases hypermethylation of the hMLH1 promoter is the major cause of the MMR defect. Germline mutations in hMSH6 are rare and rather confer predisposition to late-onset familial colorectal cancer, and frequent extracolonic tumors. Yet, the genetic background of a number of HNPCC patients remains unexplained, indicating that other genes participate in MMR and play important roles in cancer susceptibility. The tumor-suppressor genes that are potential targets for the MSI-driven mutations because they contain hypermutable repeated sequences are likely to contribute to the etiology and tissue specificity of the MSI-associated carcinogenesis. Because the prognosis and the chemosensitivity of the MSI(+) colorectal tumors differ from those without instability, the determination of the MSI phenotype is expected to improve the clinical management of patients. This review gives an overview of various aspects of the biochemistry and genetics of the DNA mismah repair system, with particular emphasis in its role in colorectal carcinogenesis.

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Molecular Pathway Annotations    Click to see Annotation Detail View
Objects Annotated

Genes (Rattus norvegicus)
Mlh1  (mutL homolog 1)
Msh2  (mutS homolog 2)
Msh6  (mutS homolog 6)
Pms1  (PMS1 homolog 1, mismatch repair system component)
Pms2  (PMS1 homolog 2, mismatch repair system component)

Genes (Mus musculus)
Mlh1  (mutL homolog 1)
Msh2  (mutS homolog 2)
Msh6  (mutS homolog 6)
Pms1  (PMS1 homolog 1, mismatch repair system component)
Pms2  (PMS1 homolog2, mismatch repair system component)

Genes (Homo sapiens)
MLH1  (mutL homolog 1)
MSH2  (mutS homolog 2)
MSH6  (mutS homolog 6)
PMS1  (PMS1 homolog 1, mismatch repair system component)
PMS2  (PMS1 homolog 2, mismatch repair system component)


Additional Information