Genome‐wide DNA methylation profiling of primary colorectal laterally spreading tumors identifies disease‐specific epimutations on common pathways

Abstract

Colorectal laterally spreading tumors (LSTs) grow to extremely large size while rarely invade deeply. Also, there is a low tendency to become cancerous. We used the Illumina Human Methylation 450K array to query the main epigenetic difference of LSTs. We built a discovery cohort with 10 matched cases, and a validation cohort with 9 additional matched cases. Our results suggest that LST displays significant decrease in DNA methylation, highlighted by the discovery of 1,018 hypomethylated intergenic regions (IGRs). Comparing to classic differentially methylated probes and regions that overlap transcription starting site and CpG island, IGR-regions were associated more closely with genes involved in functional biological processes and correlated with specific histone modifications. Hypomethylated IGR regions were often annotated as tissue-specific regulatory elements for noncolon tissues and were typically epigenetically silenced in normal colon mucosa. By integration of public data, we defined the commonality and specific epigenetic signatures for adenomas, LSTs and colon adenocarcinomas. Only 435 hypermethylated differentially methylated probes (DMPs) and differentially methylated regions (DMRs) and 517 hypomethylated DMPs and DMRs were shared by the three diseases. However, our pathway-level analysis discovered that genes in four pathways were common target of epimutations in LSTs, adenomas and CRCs. More interestingly, different diseases seem to employ distinct epigenetic insult to disturb specific pathways. Between LST and adenoma, we found eight pathways including Ras signaling and Rap1 signaling pathway were commonly targeted but the epimutation patterns were opposite. Comparison between precancerous conditions and invasive states revealed the key pathways governing the progression to malignancy, including PI3K-Akt pathways.

Epigenome-wide DNA methylation profiling of portal vein tumor thrombosis (PVTT) tissues in hepatocellular carcinoma patients

“…Aberrant DNA methylation status has emerged as an important hallmark in various cancers [4] . Abnormal methylation of tumor suppressor genes and oncogenes has been proven to play an important role in many malignancies, such as liver cancer [5] , [6] , [7] , [8] , [9] , gastric cancer [10] and colorectal cancer [11] , [12] . DNA methylation is a dynamic epigenetic marker accompanied with occurrence and development of cancer, which has widely effects on the prevention, diagnosis, prediction and therapy of the disease [13] .…”

A panel of DNA methylation signature from peripheral blood may predict colorectal cancer susceptibility

“…The biological processes involve cellular component organization or biogenesis, and cellular localization. The Rap1 signaling pathway has been implicated in the previous genome-wide profile of colorectal cancer [ 48 ] and has been known to play several important roles in tumor cell invasion and metastasis [ 49 ]. The pathway and biological processes put together demonstrate that multiple pathways, which were affected by aberrant methylation were involved in CRC tumorigenesis.…”

Genome-wide analysis of the hypoxia-related DNA methylation-driven genes in lung adenocarcinoma progression

“…The pheatmap package of R software was used to generate heat map. Distribution analysis of differentially methylated probes (DMPs) was performed according to the previous reference [19].…”