Colorectal cancer early methylation alterations affect the crosstalk between cell and surrounding environment, tracing a biomarker signature specific for this tumor

Abstract

Colorectal cancer (CRC) develops through the accumulation of both genetic and epigenetic alterations. However, while the former are already used as prognostic and predictive biomarkers, the latter are less well characterized. Here, performing global methylation analysis on both CRCs and adenomas by Illumina Infinium HumanMethylation450 Bead Chips, we identified a panel of 74 altered CpG islands, demonstrating that the earliest methylation alterations affect genes coding for proteins involved in the crosstalk between cell and surrounding environment. The panel discriminates CRCs and adenomas from peritumoral and normal mucosa with very high specificity (100%) and sensitivity (99.9%). Interestingly, over 70% of the hypermethylated islands resulted in downregulation of gene expression. To establish the possible usefulness of these non-invasive markers for detection of colon cancer, we selected three biomarkers and identified the presence of altered methylation in stool DNA and plasma cell-free circulating DNA from CRC patients.

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;…”

“…Not determined (N.D.) methylation levels of REV-assay CpG sites are shown as straight lines. 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. Data points represent the mean methylation frequency per CpG and subgroup.…”

“…19 Consequently, multiple studies have shed light on the methylome landscapes of CRCs and determined the contribution of altered methylation to the development and progression of CRC. 13,20,21 The aberrant methylation of DNA also affects adenomas. 22 However, differential epigenetic alterations of recurring and nonrecurring colorectal adenomas have not yet been systematically and comprehensively investigated.…”

“…17,18 Recent advances in analytical technologies have permitted the assessment of genome-wide methylation patterns. 13,20,21 The aberrant methylation of DNA also affects adenomas. 13,20,21 The aberrant methylation of DNA also affects adenomas.…”

Reduced aquaporin-1 transcript expression in colorectal carcinoma is associated with promoter hypermethylation

“…Promoter methylation plays a role in mediating gene expression, as evidenced by studies showing that methylation of gene promoter regions varies considerably depending on the cell type, with more methylation correlating with low or no transcription [12]. This has been highlighted in cancer, as experimentally shown by some research groups, which show that hypermethylation occurs in cancer at promoters of genes already transcriptionally repressed [13,14]. However, studies on the association between AQP1 promoter methylation and gene expression are currently limited to glioblastoma multiform, normal salivary gland and salivary gland adenoid cystic carcinoma [15][16][17], and have not been reported for other carcinomas including CRC.…”