Carcinogenesis Advance Access published online on October 17, 2007
Carcinogenesis, doi:10.1093/carcin/bgm228
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Carcinogenesis and microsatellite instability: The interrelationship between genetics and epigenetics
1 Sapporo Medical University, South 1, West 17, Chuo-ku, Sapporo 060-8556 Japan
2 First Department of Internal Medicine, Sapporo Medical University School of Medicine, South 1, West 16, Chuo-ku, Sapporo 060-8543 Japan
* To whom correspondence should be addressed. Tel: +81 11 611 2111 ext. 2100; Fax: +81 11 613 3485; E-mail: imai{at}sapmed.ac.jp or Tel: +81 11 611 2111 ext. 3211; Fax: +81 11 611 2282; E-mail: h-yama{at}sapmed.ac.jp
DNA mismatch repair (MMR) deficiency results in a strong mutator phenotype and high frequency microsatellite instability (MSI-H), which are the hallmarks of tumors arising within Lynch syndrome. MSI-H is characterized by length alterations within simple repeated sequences, microsatellites. Lynch syndrome is primarily due to germline mutations in one of the DNA MMR genes; mainly hMLH1 or hMSH2 and less frequently hMSH6 and rarely hPMS2. Germline hemiallelic methylation of MLH1, which termed epimutation, has been reported to be a new cause of Lynch syndrome. MSI-H is also observed in about 15% of colorectal, gastric, and endometrial cancers and in lower frequencies in a minority of other tumors, where it is associated with the hypermethylation of the promoter region of hMLH1. MSI-H underlies a distinctive tumorigenic pathway because cancers with MSI-H exhibit many differences in genotype and phenotype relative to cancers without MSI-H, irrespective of their hereditary or sporadic origins. Genetic, epigenetic, and transcriptomic differences exist between cancers with and those without the MSI-H. The BRAF V600E mutation is associated with sporadic MSI-H colorectal cancers harboring hMLH1 methylation but not Lynch syndrome-related colorectal cancers. The differences in genotype and phenotype between cancers with and those without MSI-H are likely to be causally linked to their differences in biological and clinical features. Therefore, the diagnosis of MSI-H in cancers is thus considered to be of increasing relevance, because MSI-H is useful screening marker for identifying patients with Lynch syndrome, a better prognostic factor, and could affect the efficacy of chemotherapy. This review addresses recent advances in the field of MSI research.
Received May 14, 2007; revised September 8, 2007; accepted October 5, 2007.