title: Carcinogenesis and microsatellite instability: the interrelationship between genetics and epigenetics.
abstract: 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 approximately 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.
authors.affiliation: Sapporo Medical University, South 1, West 17, Chuo-ku, Sapporo 060-8556, Japan. imai@sapmed.ac.jp
authors.forename: Kohzoh
authors.initials: K
authors.lastname: Imai
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Yamamoto
mesh_terms: D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000235:genetics; D003123:Colorectal Neoplasms, Hereditary Nonpolyposis / Q000188:drug therapy / Q000235:genetics; D019175:DNA Methylation; D053843:DNA Mismatch Repair; D044127:Epigenesis, Genetic / Q000235:genetics*; D005787:Gene Frequency; D018095:Germ-Line Mutation; D006801:Humans; D053842:Microsatellite Instability; D008957:Models, Genetic; D009369:Neoplasms / Q000235:genetics*; D011379:Prognosis