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Carcinogenesis and microsatellite instability: the interrelationship between genetics and epigenetics.
Carcinogenesis. 2008 Apr; 29(4):673-80.C

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+Show Affiliations

Sapporo Medical University, South 1, West 17, Chuo-ku, Sapporo 060-8556, Japan. imai@sapmed.ac.jpNo affiliation info available

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't
Review

Language

eng

PubMed ID

17942460

Citation

Imai, Kohzoh, and Hiroyuki Yamamoto. "Carcinogenesis and Microsatellite Instability: the Interrelationship Between Genetics and Epigenetics." Carcinogenesis, vol. 29, no. 4, 2008, pp. 673-80.
Imai K, Yamamoto H. Carcinogenesis and microsatellite instability: the interrelationship between genetics and epigenetics. Carcinogenesis. 2008;29(4):673-80.
Imai, K., & Yamamoto, H. (2008). Carcinogenesis and microsatellite instability: the interrelationship between genetics and epigenetics. Carcinogenesis, 29(4), 673-80.
Imai K, Yamamoto H. Carcinogenesis and Microsatellite Instability: the Interrelationship Between Genetics and Epigenetics. Carcinogenesis. 2008;29(4):673-80. PubMed PMID: 17942460.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Carcinogenesis and microsatellite instability: the interrelationship between genetics and epigenetics. AU - Imai,Kohzoh, AU - Yamamoto,Hiroyuki, Y1 - 2007/10/17/ PY - 2007/10/19/pubmed PY - 2008/4/29/medline PY - 2007/10/19/entrez SP - 673 EP - 80 JF - Carcinogenesis JO - Carcinogenesis VL - 29 IS - 4 N2 - 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. SN - 1460-2180 UR - https://www.unboundmedicine.com/medline/citation/17942460/Carcinogenesis_and_microsatellite_instability:_the_interrelationship_between_genetics_and_epigenetics_ L2 - https://academic.oup.com/carcin/article-lookup/doi/10.1093/carcin/bgm228 DB - PRIME DP - Unbound Medicine ER -