DNA methylation as an epigenetic biomarker in colorectal cancer

Abstract

Sporadic colorectal cancer (CRC) is a consequence of the accumulation of genetic and epigenetic alterations that result in the transformation of normal colonic epithelial cells to adenocarcinomas. Studies have indicated that a common event in the tumorigenesis of CRC is the association of global hypomethylation with discrete hypermethylation at the promoter regions of specific genes that are involved in cell cycle regulation, DNA repair, apoptosis, angiogenesis, adhesion and invasion. The present study aimed to investigate the epigenetic changes (DNA methylation) in 24 candidate genes in CRC. A total of 10 candidate hypermethylated (HM) and unmethylated (UM) genes were identified that may be useful epigenetic markers for non-invasive CRC screening. The five genes that had the highest average UM percentages in the control group were MLH1 (71.7%), DKK2 (69.6%), CDKN2A (68.4%), APC (67.5%) and hsa-mir-342 (67.4%). RUNX3 (58.9%), PCDH10 (55.5%), SFRP5 (52.1%), IGF2 (50.4%) and Hnf1b (50.0%) were the five genes with the highest average HM percentages in the test group. In summary, the present preliminary study identified the methylation profiles of normal and cancerous colonic epithelial tissues, and provided the groundwork for future large-scale methylation studies.

Aberrant DNA methylation of WNT pathway genes in the development and progression of CIMP-negative colorectal cancer

“…APC hypermethylation has been already described in adenoma and CRC tissue and CRC plasma samples. 19,47,48 In accordance with findings of Judson et al, 48 hypermethylation in the active promoter of the APC gene in adenoma samples was detected in our study as well (Table 6). Similar alteration appeared in CRC samples, but in a different Log FC values are indicated only in cases of P < 0.05.…”

“…Correspondingly to the previous findings, 11,17,[19][20] we found that another known inhibitor of canonical WNT pathway, DKK2, was significantly hypermethylated in CRC vs. NAT and AD vs. NAT comparisons. However, our promoter estimation considering the sequence in the region between 2000 bp upstream and 1000 bp downstream from the transcription start site (if the positive DNA strand was the coding strand) identified 'active promoter' in at least one of the 9 analyzed cell lines, according to the ENCODE ChromHMM results.…”

“…The most known WNT pathway alterations, such as APC and AXIN2 inactivation by mutations or loss of heterozygosity, affect the APC-GSK3-Axin complex leading to b-catenin stabilization, thereby resulting in the constitutive activation of canonical WNT signaling in CRC. 10 Promoter hypermethylation of negative regulators of canonical WNT pathway like secreted frizzledrelated proteins (SFRPs), [11][12][13][14][15][16][17][18] dickkopf family proteins (DKKs), 11,17,[19][20][21] and WIF1 WNT inhibitory factor 11,17,21 has also been described in malignancies, including CRC. Methylation patterns of CRC and normal adjacent tissue samples were compared in most of the previous global methylation studies focusing on WNT signaling pathway.…”

Downregulation of HNF1 homeobox B is associated with drug resistance in ovarian cancer

“…However, another study indicated that HNF1B may function as a tumor suppressor gene in chromophobe renal cell carcinogenesis through control of PKHD1 expression (15). It has been proven that HNF1B is downregulated in ovarian, gastric, pancreatic and colorectal cells (16,17), and its suppression influences cellular phenotypes associated with tumor-related properties in prostate cancer cells (18). The associations of HNF1B with cancer focus mainly on the single nucleotide polymorphisms (SNPs).…”

Epigenetic silencing of protocadherin 10 in colorectal cancer

“…Ying et al (18) demonstrated that the transcriptional silencing of PCDH10 may be reversed by pharmacologic demethylation with 5-aza-2'-deoxycytidine or genetic demethylation with double knockout of DNA methyltransferase (DNMT)1 and DNMT3B in the colorectal cancer HCT116 cell line, suggesting a direct epigenetic mechanism (18). The aberrant methylation of the PCDH10 promoter was also observed in 43-85% of colorectal cancer tissues in several studies, indicating that PCDH10 methylation is a frequent event in colorectal carcinogenesis (11,35,39). In the present study, PCDH10 methylation was detected in colorectal cancer samples, but not in paired adjacent colorectal tissues, in accordance with the study by Yu et al (35), suggesting that the aberrant promoter methylation of PCDH10 is specific to colorectal cancer cells.…”