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In EAC, methylation patterns of promoter CpG widely in molecular pathogeneses. Nonetheless,
[34]
islands in several genes, such as tumor suppressor epigenetic alterations play important roles in the
genes (APC, TIMP3, SFRP1, SFRP2, WIF1, AKAP12, development of both gastric carcinoma types. Gene
RUNX3, SOCS1 and SOCS3) and DNA repair promoter methylation has been reported to associate with
[29]
genes (MGMT), have been reported previously. In gastric cancer development, such as CDKN2A, CDK2AP2,
Barrett’s esophagus, a pre-malignant condition that can CDH1, MGMT, RASSF1, RUNX3, DLC1, ITGA4, ZIC1,
lead to EAC development, aberrant DNA methylation PRDM5, PCDH10, TFPI2, RUNX3, SPINT2, BTG4,
has also been shown to occur in promoters of tumor SFRP2, hMLH1, DKK-3, TCF4, GRIK2, RAR, CHFR,
suppressor genes, adhesion molecules and DNA repair BNIP3, RASSF1A, LRP1B and SFRP5, promoter of
genes (AKAP12, APC, CDH13, DAPK1, GPX, GST, which was more frequently methylated in gastric cancer
MGMT, NELL1, REPRIMO/RPRM, p16, SFRP, tissues than those of the corresponding normal gastric
SOCS, SST, TAC1, TIMP3 and WIF1). Jin et al. tissue. [35,36] Furthermore, promoter methylation of many
[30]
reported that promoter hypermethylation of eight genes genes with different biological functions has been
(p16, RUNX3, HPP1, NELL1, TAC1, SST, AKAP12 and associated with the clinicopathological characteristics
[37]
CDH13) could predict neoplastic progression risk in and prognosis of gastric cancer [Table 2]. Of these
[38]
[31]
Barrett’s esophagus. However, in the study of DNA genes, promoter hypermethylation of CDH1 and
hypo-methylation in Barrett’s EAC (BAC), Alvarez et al. MGMT [39,40] was associated with worse outcomes of
reported a predominance of DNA hypo-methylation gastric cancer patients after surgery. However, patients
rather than DNA hyper-methylation in early-stage with hypermethylated IGF2 in blood leukocyte DNA
of BAC carcinogenesis. They also detected DNA reportedly had a signifi cantly better survival rate than
[41]
hypo-methylation in a series of genes associated with those with hypo-methylated IGF2. Additionally,
the immune system such as chemokines (CXCL1 and DNA methylation of detected in body fl uids that can
CXCL3). [32] be obtained non-invasively, such as serum and gastric
washes, may have a clinical application for gastric cancer;
Altered DNA Methylation in Gastric Cancer for example, detection of aberrant DNA methylation
of CDH1, DAPK, GSTP1, p15, p16, RARβ, RASSF1A,
Gastric cancer is the fourth most frequently diagnosed
cancer and the second leading cause of cancer-related RUNX3 and TFPI2 in serum may be a useful biomarker
[42]
deaths in the world. Gastric adenocarcinoma accounts for gastric cancer.
[33]
for 90-95% of gastric cancer and has two histological Environmental factors also signifi cantly affect
subtypes (intestinal and diffuse) based on microscopic DNA methylation. Etiological studies have closely
observation and tumor growth patterns, which differ associated two distinct infectious agents, Helicobacter

Table 2: Association of gene promoter methylation with clinical outcomes of gastric cancer
Gene Correlation with clinical outcomes References
DNA hypermethylation
BNIP3 Association with poor prognosis [100,101]
CACNA2D3 Correlation with lymph node metastasis [102]
CDH1 Association with poor prognosis, H. pylori infection, and EBV infection [38,46,49-51]
DAPK Correlation with cell differentiation, lymph node metastasis [100,103]
FLNc Association with poor prognosis [104]
GPX3 Correlation with lymph node metastasis [105,106]
HAI-2/SPINT2 Correlation with cell differentiation, lymph node metastasis [107]
HoxD10 Association with poor prognosis [108]
LOX Association with poor prognosis and H. pylori infection [45]
MGMT Association with poor prognosis [103,104,109]
MLH1 Association with poor prognosis [104]
p15 Association with EBV infection [49-51]
p16 Association with poor prognosis, H. pylori infection and EBV infection [38,46,49-51,102,104]
p73 Association with EBV infection [52]
PAX6 Association with poor prognosis [100]
RASSF1A Association with poor prognosis [100,103]
RASSF2 Association with poor prognosis [104]
RUNX3 Correlation with TNM stage and H. pylori infection [110,111]
DNA hypormetylation
LINE-1 Association with poor prognosis and H. pylori infection [55,56]
SURF Association with poor prognosis [57]
H. pylori: Helicobacter pylori; EBV: Epstein-Barr virus

Journal of Cancer Metastasis and Treatment ¦ Volume 1 ¦ Issue 3 ¦ October 15, 2015 ¦ 115