Hyper-Methylated Loci Persisting from Sessile Serrated Polyps to Serrated Cancers

Abstract

Although serrated polyps were historically considered to pose little risk, it is now understood that progression down the serrated pathway could account for as many as 15%–35% of colorectal cancers. The sessile serrated adenoma/polyp (SSA/P) is the most prevalent pre-invasive serrated lesion. Our objective was to identify the CpG loci that are persistently hyper-methylated during serrated carcinogenesis, from the early SSA/P lesion through the later cancer phases of neoplasia development. We queried the loci hyper-methylated in serrated cancers within our right-sided SSA/Ps from the New Hampshire Colonoscopy Registry, using the Illumina Infinium Human Methylation 450 k panel to comprehensively assess the DNA methylation status. We identified CpG loci and regions consistently hyper-methylated throughout the serrated carcinogenesis spectrum, in both our SSA/P specimens and in serrated cancers. Hyper-methylated CpG loci included the known the tumor suppressor gene RET (p = 5.72 × 10−10), as well as loci in differentially methylated regions for GSG1L, MIR4493, NTNG1, MCIDAS, ZNF568, and RERG. The hyper-methylated loci that we identified help characterize the biology of SSA/P development, and could be useful as therapeutic targets, or for future identification of patients who may benefit from shorter surveillance intervals.

Genome‐wide DNA methylation analysis of colorectal adenomas with and without recurrence reveals an association between cytosine‐phosphate‐guanine methylation and histological subtypes

“…Several of the observed targets of differential methylation, for example, AXIN2, DKK3, GRIA4, MLH1, SEPT9, SFRP1, SLC8A1, and SYN3, were also reported in recent studies. 21,42,43 Additionally, our study confirmed earlier publications that DMPs are not randomly distributed within the genome 13,22,34 : DMPs in CGIs were frequently hypermethylated while open sea and shelf regions were hypomethylated;…”

“…B, Quantitative GREM2 gene body methylation analysis of four CpG dinucleotides (FOR-assay) in primary adenomas with and without recurrence, and recurrent adenomas. Additionally, our study confirmed earlier publications that DMPs are not randomly distributed within the genome13,22,34 : DMPs in CGIs were frequently hypermethylated while open sea and shelf regions were hypomethylated; C, Quantitative GREM2 gene body methylation analysis of four CpG dinucleotides (REV-assay) in primary adenomas with and without recurrence and recurrent adenomas.…”

“…33 Many tumor suppressor genes are hypermethylated at CpG-dense promoters, which are, therefore, silenced in colorectal tumors. 16,34 It is also now accepted that methylation assays can be applied for CRC screening. The FDA approved a SEPT9 gene methylation assay in 2016 as an additional CRC screening option to be considered for patients who have a history of an intermittent completion of colonoscopy and fecal occult blood tests.…”

Impact of a diet and activity health promotion intervention on regional patterns of DNA methylation

“…We also observed that methylation increased in this region following MBC2, which may indicate that a healthier lifestyle downregulates the protein in immune cells. In contrast, a small study by Andrew et al found that ZNF568, a zinc finger transcription factor, was hypermethylated in sessile serrated colon polyps (n = 34) compared to normal adjacent mucosal tissue (n = 15) [48]. We also observed an increase in ZNF568 methylation following improved health behaviors at only 9 months.…”

Germ Cell-Specific Gene 1-Like Protein Regulated by Splicing Factor CUGBP Elav-Like Family Member 5 and Primary Bile Acid Biosynthesis are Prognostic in Glioblastoma Multiforme

“…GSG1L was inactive in the AMPA-type glutamate receptors (AMPARs) in cancer (Gu et al, 2016;Andrew et al, 2017). In addition, GBM could secrete glutamate and trigger the AMPARs, leading to cell death in neurons surrounding the tumor (Van Vuurden et al, 2009).…”