Abstract
BackgroundAberrations 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.MethodsWe 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 BRAFV600E and molecular biology analysis to establish the role of BRAFV600E-mediated-TET inhibition in CpG-island methylator phenotype (CIMP) inititation.ResultsWe 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. BRAFV600E-mutated CCs and precursors showed a significant downregulation of TET1 and TET2 DNA demethylases. Stable expression of BRAFV600E in nonCIMP CC cells and in a genetic mouse model was sufficient to repress TET1/TET2 and initiate hypermethylation at CIMP-CpGs, reversible by BRAFV600E inhibition. BRAFV600E-driven CIMP-CpG hypermethylation occurred at genes associated with established CC pathways, effecting functional changes otherwise achieved by genetic mutation in carcinogenesis.ConclusionsHence, while age–lifestyle-driven hypermethylation occurs generally in colon carcinogenesis, BRAFV600E-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.
Highlights
Aberrations in DNA methylation are widespread in colon cancer (CC)
In CC, TET1 silencing was shown to be associated with BRAFV600E and with CpG-island methylator phenotype (CIMP)-CC and its precursors [13], but mutations in TET genes are very rare in CC [14]
Unsupervised hierarchical clustering of the DNA methylation data of the remaining 55 cancers identified two main clusters (Fig. 1b); cluster A contained all cancers with a wild-type BRAF (BRAFWT) status, most of them located in the distal colon (21/33, 63%), cluster B mainly contained BRAFV600E-mutated cancers (14/22, 64%) located in the proximal colon (20/22, 91%)
Summary
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. We aimed to dissect CC subtype-specific methylation instability to understand underlying mechanisms and functions. Initiation and progression of cancer is facilitated by genetic and epigenetic instability [1]. The “classical” polyp to cancer model describes a progressive accumulation of genetic mutations, transforming glandular epithelial cells to form tubular adenomas (TAs), advanced adenomas, and colon. Noreen et al Clinical Epigenetics (2019) 11:196 elderly females, harbor a BRAFV600E mutation and often show microsatellite instability (MSI) due to silencing of the mismatch repair gene hMLH1 [8]. Despite the strong association between BRAFV600E and CIMP-CC, a molecular mechanism underlying the formation of this cancer-subtype has not been identified. In CC, TET1 silencing was shown to be associated with BRAFV600E and with CIMP-CC and its precursors [13], but mutations in TET genes are very rare in CC [14]
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