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Clin Genet. 2014 May;85(5):403-12. doi: 10.1111/cge.12349. Epub 2014 Feb 17.

Epigenetic mechanisms in the pathogenesis of Lynch syndrome.

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Department of Medical Genetics, Haartman Institute, University of Helsinki, Helsinki, Finland.


Inherited defects in the DNA mismatch repair (MMR) system, MLH1, MSH2, MSH6, and PMS2 genes, underlie Lynch syndrome, one of the most prevalent cancer syndromes in man. The syndrome offers a model for cancers arising through MMR defects and microsatellite instability, which applies to ~ 15% of all colorectal, endometrial, and other cancers. Lynch syndrome also illustrates the significance of the epigenetic component in cancer development. Inactivation of tumor suppressor genes by epigenetic mechanisms is an acquired property of many tumors developing in Lynch syndrome. Furthermore, constitutional epimutations of MMR genes may explain a proportion of mutation-negative families lacking MLH1 or MSH2 protein expression in tumor tissue. This review provides an update of the molecular basis of Lynch syndrome by focusing on the role of epigenetic mechanisms in the pathogenesis of the disease.


DNA mismatch repair genes; EPCAM; Lynch syndrome; MLH1; MSH2; epimutation; methylation; microsatellite instability; mutation

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