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Cancer Cell. 2003 Aug;4(2):121-31.

Genetics supersedes epigenetics in colon cancer phenotype.

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The Burnham Institute, La Jolla Cancer Center, Cancer Genetics and Epigenetics Program, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.


A CpG island DNA methylator phenotype has been postulated to explain silencing of the hMLH1 DNA mismatch repair gene in cancer of the microsatellite mutator phenotype. To evaluate this model, we analyzed methylation in CpG islands from six mutator and suppressor genes, and thirty random genomic sites, in a panel of colorectal cancers. Tumor-specific somatic hypermethylation was a widespread age-dependent process that followed a normal Gaussian distribution. Because there was no discontinuity in methylation rate, our results challenge the methylator phenotype hypothesis and its hypothetical pathological underlying defect. We also show that the mutator phenotype dominates over the gradual accumulation of DNA hypermethylation in determining the genotypic features that govern the phenotypic peculiarities of colon cancer of the mutator pathway.

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