Microsatellite Instability In Hnpcc And In Sporadic

The MSI-H phenotype is a defining feature of HNPCC patients and is a result of predisposing constitutional mutations in the MMR genes MSH2, MLH1, MSH6, hPMS2, and hMSH3.[8] Most mutations were found in MSH2 and MLH1 and less frequently in MSH6, hPMS2, and hMSH3. Germline mutations in MMR genes predispose not only to CRC but also to endometrial, upper urinary tract, and ovarian malignancies. Small intestinal and gastric cancers as well as tumors of the biliary tract are also seen in HNPCC, but they are relatively rare events. Highly frequent MSI is not restricted to HNPCC but occurs in approximately 12% of sporadic CRC with epigenetically and biallelically silenced MLH1 genes through promoter methylation in the vast majority of cases.

Hereditary and sporadic MSI-H CRCs share several clinicopathological characteristics. These include right-sided location, poor differentiation, a medullary or mu-cinous phenotype, and extensive lymphocytic tumor infiltration, but specific characteristics for HNPCC and sporadic tumors exist as well.[9-12] Hereditary nonpoly-posis colorectal cancer is more common in males and occurs in younger patients compared to sporadic MSI-H colorectal carcinomas. Hereditary nonpolyposis colorectal cancers show more frequently Crohn's-like lesions and peritumoral lymphocytes than sporadic MSI-H CRCs. In contrast, sporadic CRCs are more likely to show two or more tumor subclones with diverse grades of differentiation than HNPCC tumors.[10] Adenomas from HNPCC patients are more often of the MSI-H phenotype than sporadic adenomas.

In addition, different molecular pathways seem to be involved in the carcinogenesis of sporadic and familial CRC. There are disruptions of the wnt pathway and frequent KRAS mutations in HNPCC cancers and/or cell lines, whereas sporadic MSI-H tumors show little evidence of APC-mutation, CTNNB1 (beta-catenin) mutation or abnormal CTNNB1 immunolocalization, and KRAS mutation.[13-16] Little evidence, however, exists regarding these alterations in sporadic MSI-H CRC.[15,16]

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