Carcinogenesis Advance Access originally published online on October 17, 2007
Carcinogenesis 2008 29(4):673-680; doi:10.1093/carcin/bgm228
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Carcinogenesis and microsatellite instability: the interrelationship between genetics and epigenetics
Sapporo Medical University, South 1, West 17, Chuo-ku, Sapporo 060-8556, Japan
1 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; Email: imai{at}sapmed.ac.jp Correspondence may also be addressed to Hiroyuki Yamamoto. Tel: +81 11 611 2111 ext. 3211; Fax: +81 11 611 2282; Email: 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, termed epimutation, has been reported to be a new cause of Lynch syndrome. MSI-H is also observed in 
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 (CRCs) harboring hMLH1 methylation but not Lynch syndrome-related CRCs. 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 a 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 microsatellite instability research.
Abbreviations: CIMP, CpG island hypermethylator phenotype; CIMP-H, CIMP-high; CIMP-L, CIMP-low; CIN, chromosomal instability; CRC, colorectal cancer; HDAC, histone deacetylase; HNPCC, hereditary non-polyposis colorectal cancer; LOH, loss of heterozygosity; MMR, mismatch repair; MSI, microsatellite instability; MSI-H, high-frequency MSI; MSI-L, low-frequency MSI; MSS, microsatellite stable; NMD, nonsense-mediated decay; 5-FU, 5-fluorouracil
Received May 14, 2007; revised September 8, 2007; accepted October 5, 2007.