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pylori and Epstein-Barr virus (EBV) with gastric profi les, primary colorectal cancer is divided into
carcinogenesis. [43,44] Previous prospective studies showed three distinct subclasses, that is, CIMP1, CIMP2 and
that H. pylori infection had an essential role in gastric CIMP-negative. CIMP1 tumor often shows mutations of
carcinogenesis and the mechanisms, underlying MSI (80%) and BRAF (53%) while CIMP2 tumor often
[43]
gastric carcinogenesis due to H. pylori-induced shows K-RAS mutation (92%) but rarely shows MSI or
DNA methylation, had been indicated. H. pylori BRAF or TP53 mutations. Non-CIMP tumor has a high
infection induced aberrant promoter methylation in frequency of TP53 mutations (71%). CIMP1 has a
[60]
tumor-suppressor genes, such as RUNX3, p16, LOX favorable prognosis, whereas CIMP2 is associated with
and CDH1. [45,46] Furthermore, IL-1β is thought to be poor prognosis. Cancer CIMP status has been assessed
[60]
especially signifi cant as a specifi c single-nucleotide as a predictive marker for 5-FU responsiveness. [61]
polymorphism of IL-1β in association with increases in
both gastric cancer risk and incidence. [47,48] EBV infection Colorectal cancer with CIMP is distinct from those with
occurs at a very early-stage in cancer development chromosomal instability, and there are two forms of
and plays an important role in gastric carcinogenesis. nuclear derangement represented alternative pathways
[62,63]
Aberrant methylation of tumor suppressor genes, such for colorectal cancer development, which overlap
as CDH1, p15, p16 and p73, is frequently observed somewhat as hypermethylation can occur in APC and
[64]
in EBV-associated gastric cancer but is less frequently is part of the chromosomal instability pathway, or
[65]
detected in adjacent non-neoplastic mucosa, [49-52] in the MLH1 gene, triggering MSI. MLH1 accounts
which suggests that aberrant methylation is a critical for approximately 40% of the cases of the hereditary
[66]
mechanism of EBV-related gastric tumorigenesis. colorectal cancer and Lynch syndrome. Detection
Regarding the molecular mechanisms underlying host of MLH1 methylation is currently used to discriminate
DNA methylation during early-stage EBV infection in between sporadic colorectal cancer with MSI and familial
[67]
gastric epithelium, LMP2A expression was upregulated forms (Lynch syndrome). Methylation of MGMT
through STAT3 phosphorylation, which further induced promoter also occurs during colorectal cancer progression
DNA methyltransferases during EBV infection. [53] in either pathway and may facilitate the accumulation of
point mutations as tumors evolve. [65]
However, few studies addressed or detected DNA
hypo-methylation in gastric cancer. In gastric cancer, The CpG island methylation affects a number of genes
global genomic hypo-methylation has been found in in colon cancer, and signifi cance of these epigenetic
premalignant stages of the disease. In our previous alterations in colon cancer pathogenesis has been
[54]
[68,69]
study that assessed 203 resected gastric cancer specimens, widely reported. Hundreds of gene promoters
we found gastric cancer tissues had signifi cantly lower have been found to be aberrantly methylated in the
LINE-1 methylation levels than that of their matched average colorectal cancer genome and their number
normal gastric mucosa. LINE-1 hypo-methylation in is ever-growing, including genes of the Wnt signaling
gastric cancer was also associated with shorter survival pathway such as APC, AXIN2, DKK1, SFRP1, SFRP2
of patients. Moreover, LINE-1 hypo-methylation and WNT5A, the DNA repair genes MGMT, hMLH1 and
[55]
of non-cancerous gastric mucosae in gastric cancer hMLH2, cell cycle-related genes such as p14, p15 and
patients signifi cantly correlated with H. pylori p16, RAS signaling genes RASSF1A and RASSF1B and
[56]
infection. Hur et al. reported that gastric cancer tissues many more. [70,71]
had conspicuously higher expression of SULF1 regulated Several DNA methylation markers have been proposed
by promoter hypo-methylation than that of the normal as useful early biomarkers for colorectal cancer early
mucosa. SULF1 is also an independent prognostic factor, detection and prediction of prognosis. For instance,
and LN is a metastasis predictive factor in gastric cancer methylation of MLH1 can be detected in colorectal
patients. [57] cancer tissue samples or blood to help interpret
[72]
[73]
MSI because its presence helps to exclude diagnosis of
Altered DNA Methylation in Colorectal Cancer
Lynch syndrome. The presence of aberrantly methylated
Aberrant DNA methylation was reported as an important SEPT9 (which encodes a GTPase that is involved in
hallmark of colorectal cancer. Colorectal cancer is dysfunctional cytoskeletal organization) in plasma is a
a heterogeneous disease and molecularly, it can be valuable and minimally invasive blood-based polymerase
classifi ed into three major molecular subtypes, that is, chain reaction test with a sensitivity of almost 70% and
microsatellite instability (MSI), chromosomal instability a specifi city of 90% in colorectal cancer detection. [74-78]
and CpG island methylator phenotype (CIMP). In In fact, an assay that detects hypermethylated SEPT9
[58]
1999, Baylin and Issa et al. coined the term “CpG island is now being commercialized and offered in some
methylator phenotype” or CIMP, in which promoter of parts of Europe to screen colorectal cancer. Moreover,
tumor suppressor genes was methylated to contribute detection of aberrant methylation of vimentin in fecal
to tumorigenesis at least in theory through progressive DNA was reported in colorectal cancer when compared
genetic silence, possibly even in the absence of any with normal control; the sensitivity and specifi city
[79]
genetic mutations. According to epigenetic and clinical of methylated vimentin for colorectal cancer were 88%
[59]
116 Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 3 ¦ October 15, 2015 ¦