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Genome-wide DNA methylation profiling of primary colorectal laterally spreading tumors identifies disease-specific epi-mutations on common pathways

ABSTRACT: Colorectal laterally spreading tumors (LSTs) are rare comparing to adenomas but are becoming more prevalent. Unlike many neoplasms in colons, LST grows to extremely large size, usually greater than 10mm in diameter while rarely invades deeply. Also, there is a low tendency for LSTs to become cancerous. The epigenetic landscape of LST has not been defined. In this study, we used a genome-wide methylation profiling technology, i.e. the Illumina Human Methylation 450K array, to query the main epigenetic difference between LST and para-cancerous samples. Our results suggest that LST displays significant decrease in DNA methylation, especially in some intergenic regions (IGR). By integration of public data for adenomas and colorectal cancers, we defined the commonality and specific epigenetic signatures for these three types of neoplasms in colon, in particular LST and adenomas which represent precancerous conditions. These three diseases shared little specific DNA methylation abnormalities. However, our pathway-level analysis revealed that certain pathways were common targets of epimutation. More interestingly, different diseases seem to employ distinct epigenetic insult to disturb these pathways. Between LST and adenoma, we found eight pathways were commonly targeted but the epi-mutation patterns were opposite between the two diseases. Comparison between precancerous conditions and invasive states revealed the key pathways governing the progression to malignancy, including CAMs and PI3K-Akt pathways.

ORGANISM(S): Homo sapiens

PROVIDER: GSE106556 | GEO | 2019/01/01

REPOSITORIES: GEO

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Project description:BACKGROUND & AIM: Sessile serrated adenoma/polyps (SSA/Ps) are the likely culprit of ~20% colon cancers but they are molecularly poorly understood. We investigated their epigenetic phenotype using high-throughput analysis of DNA methylation and gene expression. METHODS: 17 SSA/Ps and, as a comparative group, 15 conventional adenomas (all with matched samples of normal mucosa) were prospectively collected during colonoscopy. DNA from the 64 tissues was analyzed, via bisulfite next generation sequencing, for methylation at ~2.7 million CpG sites located prevalently in gene regulatory regions spanning 80.5Mb (~2.5% of the genome). The transcriptome of these samples was also investigated using RNA sequencing. An independent series of 61 archival lesions was used for targeted verification of DNA methylation. RESULTS: Both SSA/Ps and conventional adenomas showed a profound remodelling of their methylome. Cytosine hypermethylation was more pervasive in SSA/Ps than adenomas, in terms of number of hypermethylated regions (22,147 vs 15,965, respectively) and genes (4938 vs 3443, respectively). In addition, the extent of hypermethylation in a given region was higher in SSA/Ps than adenomas. This methylation pattern of SSA/Ps was reminiscent of the CpG island methylator phenotype (CIMP) of their descendant cancers. We have called this phenotype proto-CIMP since most of the hypermethylation occurred in CpG islands and shores. SSA/Ps were also protected from a wave of demethylation that instead occurred in adenomas outside of CpG islands/shores (4288 vs 18,417 hypomethylated regions in SSAPs vs adenomas). Verification studies of six hypermethylated regions demonstrated the high potential of DNA methylation markers for predicting the diagnosis of SSA/Ps and/or adenomas. Proto-CIMP of SSA/Ps was surprisingly associated with a higher number of up- (618) than downregulated (349) genes, while adenomas showed the opposite trend (516 up- vs 712 downregulated genes). CONCLUSIONS: The epigenetic landscape of SSA/Ps differs substantially from that of conventional adenomas. This huge amount of epigenetic variation represents a rich source of promising diagnostic tools, such as novel DNA markers or histologic stainings, for the tailored management of the two most frequent colon cancer precursors.

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Genome-wide DNA methylation profiling of primary colorectal laterally spreading tumors identifies disease-specific epi-mutations on common pathways

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