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Inherited epimutation or a haplotypic basis for the propensity to silence?

Nature Genetics volume 39, page 573 (2007)Cite this article

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To the Editor:

Chan and colleagues report a kindred in which a specific haplotype at the MSH2 locus is associated with mosaic promoter hypermethylation and cancers suggestive of hereditary nonpolyposis colorectal cancer (HNPCC)1; they describe this as an example of germline epimutation similar to that which we and others have reported in another DNA mismatch repair gene, MLH1 (refs. 2,4,5,6). We have followed the terminology of Holliday7 in defining epimutation as epigenetic (transcriptional) silencing of a gene that is normally active3; epimutation may occur in the soma or the germline and is often accompanied by hypermethylation (the term may also be applied to activation or hypomethylation of a normally silent sequence8). The phenomena described by us and by Chan et al. seem to share an association between promoter hypermethylation in normal tissues and the risk of developing cancers with defective DNA mismatch repair. However, we suggest that what Chan and colleagues have found is distinctly different from the germline epimutation of MLH1, although no less interesting. Our conclusion rests on two features of the MSH2 epimutation: its mosaicism with prominent tissue specificity and its strong heritability.

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Authors and Affiliations

  1. Victor Chang Cardiac Research Institute, Sydney, Australia

    Catherine M Suter

  2. Children's Hospital Oakland Research Institute, Oakland, California, USA

    David I K Martin

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  1. Catherine M Suter
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  2. David I K Martin
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Suter, C., Martin, D. Inherited epimutation or a haplotypic basis for the propensity to silence?. Nat Genet 39, 573 (2007). https://doi.org/10.1038/ng0507-573a

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