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• W2995792007 abstract "Abstract Background Aberrations in DNA methylation are widespread in colon cancer (CC). Understanding origin and progression of DNA methylation aberrations is essential to develop effective preventive and therapeutic strategies. Here, we aimed to dissect CC subtype-specific methylation instability to understand underlying mechanisms and functions. Methods We have assessed genome-wide DNA methylation in the healthy normal colon mucosa (HNM), precursor lesions and CCs in a first comprehensive study to delineate epigenetic change along the process of colon carcinogenesis. Mechanistically, we used stable cell lines, genetically engineered mouse model of mutant BRAF V600E and molecular biology analysis to establish the role of BRAF V600E -mediated-TET inhibition in CpG-island methylator phenotype (CIMP) inititation. Results We identified two distinct patterns of CpG methylation instability, determined either by age–lifestyle (CC-neutral CpGs) or genetically (CIMP-CpGs). CC-neutral-CpGs showed age-dependent hypermethylation in HNM, all precursors, and CCs, while CIMP-CpGs showed hypermethylation specifically in sessile serrated adenomas/polyps (SSA/Ps) and CIMP-CCs. BRAF V600E -mutated CCs and precursors showed a significant downregulation of TET1 and TET2 DNA demethylases. Stable expression of BRAF V600E in nonCIMP CC cells and in a genetic mouse model was sufficient to repress TET1/TET2 and initiate hypermethylation at CIMP-CpGs, reversible by BRAF V600E inhibition. BRAF V600E -driven CIMP-CpG hypermethylation occurred at genes associated with established CC pathways, effecting functional changes otherwise achieved by genetic mutation in carcinogenesis. Conclusions Hence, while age–lifestyle-driven hypermethylation occurs generally in colon carcinogenesis, BRAF V600E - driven hypermethylation is specific for the “serrated” pathway. This knowledge will advance the use of epigenetic biomarkers to assess subgroup-specific CC risk and disease progression." @default.
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• W2995792007 date "2019-12-01" @default.
• W2995792007 modified "2023-10-16" @default.
• W2995792007 title "DNA methylation instability by BRAF-mediated TET silencing and lifestyle-exposure divides colon cancer pathways" @default.
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• W2995792007 doi "https://doi.org/10.1186/s13148-019-0791-1" @default.
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