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World J Gastroenterol. Oct 14, 2014; 20(38): 13804-13819
Published online Oct 14, 2014. doi: 10.3748/wjg.v20.i38.13804
Pathogenetic mechanisms in gastric cancer
Jing Shi, Yi-Ping Qu, Peng Hou
Jing Shi, Yi-Ping Qu, Peng Hou, Department of Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University School of Medicine, Xi’an 710061, Shaanxi Province, China
Author contributions: Shi J and Qu YQ collected and analyzed the literature; Hou P wrote the manuscript.
Supported by National Key Program for Developing Basic Research, No. 2010CB933903; the National Natural Science Foundation of China, No. 81171969, No. 81272933 and No. 81372217; and the Fundamental Research Funds for the Central Universities
Correspondence to: Peng Hou, PhD, Department of Endocrinology, The First Affiliated Hospital of Xi’an Jiaotong University School of Medicine, No. 277 of Yanta West Road, Xi’an 710061, Shaanxi Province, China. phou@mail.xjtu.edu.cn
Telephone: +86-298-5324039 Fax: +86-298-5324039
Received: October 24, 2013
Revised: April 30, 2014
Accepted: May 28, 2014
Published online: October 14, 2014

Abstract

Gastric cancer (GC) is a major public health issue as the fourth most common cancer and the second leading cause of cancer-related death. Recent advances have improved our understanding of its molecular pathogenesis, as best exemplified by elucidating the fundamental role of several major signaling pathways and related molecular derangements. Central to these mechanisms are the genetic and epigenetic alterations in these signaling pathways, such as gene mutations, copy number variants, aberrant gene methylation and histone modification, nucleosome positioning, and microRNAs. Some of these genetic/epigenetic alterations represent effective diagnostic and prognostic biomarkers and therapeutic targets for GC. This information has now opened unprecedented opportunities for better understanding of the molecular mechanisms of gastric carcinogenesis and the development of novel therapeutic strategies for this cancer. The pathogenetic mechanisms of GC are the focus of this review.

Key Words: Gastric cancer, Risk factors, Genetic alterations, Epigenetic alterations, Signaling pathways

Core tip: Gastric cancer (GC) is a complex, multistep process involving environmental factors and deregulation of canonical oncogenic pathways. Central to these mechanisms are the genetic and epigenetic alterations in these oncogenic signaling pathways. We discuss the recent remarkable progress in understanding the molecular mechanisms and the opening of unprecedented opportunities for the development of novel therapeutic strategies for GC.



INTRODUCTION

Gastric cancer (GC) is one of the most common cancers in the world, particularly in developing countries, and the mortality of GC is the second leading cause of cancer-related deaths[1-3]. It is often not detected until an advanced stage; consequently, the 5-year survival rate is low (10%-20%)[4]. About 95% of gastric tumors are adenocarcinomas, which can be classified into well-differentiated (intestinal), undifferentiated (diffuse), and ‘mixed’ types[5]. Although the incidence is declining, its prognosis remains poor. Epidemiological evidence indicates that environmental factors play a major role in the carcinogenesis. Among the environmental factors, diet and infection with Helicobacter pylori (H. pylori) are the most common suspects in gastric tumorigenesis[6,7]. In addition to environmental factors, GC is a complex, multistep process involving deregulation of canonical oncogenic pathways. These oncogenic signaling pathways can be overactivated by some genetic and epigenetic alterations[8,9]. Genetic alterations, such as gene mutations, gene amplification, deletions or allelic loss and chromosomal translocations, can cause gain-of-function in oncogenes and loss-of-function in tumor suppressor genes, ultimately contributing to gastric carcinogenesis[9,10]. Moreover, like other human cancers, gastric tumorigenesis can also be profoundly influenced by epigenetic abnormalities, such as aberrant gene methylation, histone modification and microRNAs[10,11]. For example, promoter hypermethylation as an important hallmark of cancer cells is one of the major mechanisms to inactivate tumor suppressor genes in gastric tumorigenesis[11,12]. Increasing evidence indicates that most cancer phenotypes are largely governed by complex interactions between multiple pro- and anti-oncogenic signaling circuits[13]. This review discusses the recent remarkable progress in understanding the molecular pathogenesis and mechanisms of GC.

ENVIRONMENTAL RISK FACTORS

GC, like other cancers, is the end result of the interplay of many risk factors as well as protective factors. Environmental and genetic factors are also likely to play a role in the etiology of this disease. Among the environmental factors, it is clear that H. pylori infection and diet are strong and established risk factors of GC[6,7].

H. pylori infection is an important and established risk factor of GC. About 50% of the world’s population are infected by H. pylori; most of the infected individuals remain asymptomatic and fewer than 0.5% of infected individuals will develop GC. Although H. pylori infection is thus not a sufficient cause for the development of GC[14], H. pylori infection has been associated with high prevalence of GC and can also be found in the gastric mucosa of patients with chronic gastric inflammation[15,16]. The connection between H. pylori and GC is not only based on epidemiologic data and animal models[17-19], but data from clinical trials have also suggested that H. pylori eradication therapy can effectively reduce the development of precancerous lesions and GC[20]. H. pylori infection causes chronic inflammation, accumulation of reactive oxygen species (ROS) and oxidative DNA damage in the gastric mucosa, and promotes the sequential progression of normal gastric epithelium through atrophic gastritis, intestinal metaplasia, and dysplasia to carcinoma[21]. Intestinal metaplasia is a preneoplastic lesion and confers increased risk for GC development. However, the molecular networks connecting infection to lesion formation and the cellular origin of this lesion remain largely unknown[22]. Although the intestinal-type GC are more related to atrophic gastritis, intestinal metaplasia and dysplasia, H. pylori infection also can increase the risk of diffuse-type GC. Moreover, H. pylori infection enhances aberrant promoter methylation in gastric mucosa, contributing to gastric tumorigenesis by silencing tumor suppressor genes[23-25]. However, H. pylori infection cannot affect mRNA and protein expression of DNA methyltransferases (DNMTs)[23,26]. Until now, the molecular mechanism of H. pylori-induced aberrant gene methylation in GC remains poorly understood.

In addition to H. pylori infection, dietary and lifestyle factors also increase the risk of gastric carcinogenesis. An excessive intake of starch, fat, meat, salt and N-nitroso compounds poor in protein quality increases the risk of GC, especially preserved food rich in salt, salt per se and N-nitroso compounds; whereas a diet rich in fresh fruits, vegetables and dietary fiber can decrease the risk of GC[14,27]. N-methyl-N-nitro-N-nitrosoguanidine (MNNG) is one of the known gastric carcinogens, which enhance the carcinogenic effects[28,29]. N-nitroso compounds can be formed by the reaction of nitrate or nitrite during the process of preservation and during digestion in the stomach, and they may be present in some foods including cured meats, dried milk, instant soups, and coffee dried on direct flame[30-32]. Ingestion of salt-preserved food can induce direct damage to the gastric mucosa resulting in gastritis and can increase the risk of persistent H. pylori infection; examples are salted fish, soy sauce, pickled vegetables, cured meat[33,34]. Moreover, high starch and low protein diets may favor acid-catalyzed nitrosation in the stomach and cause mechanical damage to the gastric mucosa[14,35]. Fruits and vegetables are rich sources of carotenoids, vitamin C, folate and phytochemicals, and may modestly reduce risk in the process of carcinogenesis[14,34,35]. It has been reported that epigallocatechin gallate (EGCG) is the most abundant polyphenol in green tea and it possesses a significant protective effect against H. pylori-induced cytotoxicity in gastric epithelial cells[36].

Other established lifestyle factors, including cigarette smoking and alcohol consumption, may affect the risk of GC[37,38]. Alcohol, a gastric irritant, is an important risk factor for GC. Tobacco has been reported to induce the development of precursor gastric lesions and increase the incidence of H. pylori infection. Accumulated evidence has shown an association between gastroesophageal reflux disease (GE reflux) and elevated risk for diffuse-type GC[39-41]. In addition, Epstein-Barr virus (EBV) infection is also closely associated with gastric carcinogenesis[38].

ALTERED SIGNALING PATHWAYS IN GC

GC is a complex and molecularly heterogeneous disease involving deregulation of canonical oncogenic pathways, such as p53[42], wnt/β-catenin[43], nuclear factor (NF)-κB[44] and PI3K/Akt[45] pathways. Central to these mechanisms are the genetic and epigenetic alterations in these oncogenic signaling pathways[8,9]. Of them, some molecular alterations are closely associated with poor clinical outcomes of GC patients and are summarized in Tables 1 and 2.

Table 1 Genetic alterations in gastric cancer.
GenesAlterationsFunctionPathologyPrognosisRef.
Tumor suppressor genes
TP53Mutation/LOHTranscription factorBothAssociation with poor survival[42,46,48,182]
APCMutation/ LOHSignal transductionIntestinalAssociation with poor survival[48,98,99]
CDHIMutations/LOHAdhesionDiffuseAssociation with poor survival[48,102,106,183,184]
hMLH1/hMSH2MutationsDNA mismatch repairBothAssociation with poor survival and microsatellite instability[10,140,185]
p16Mutations/LOHCell cycleBothLOH of p16 association with lymph metastasis[48,136,186,187]
RIZMutations/LOHNuclear histone/protein methyltransferase-Association with microsatellite instability[188-190]
hMSH3MutationsDNA mismatch repair-Association with microsatellite instability[191,192]
hMSH6MutationsDNA mismatch repair-Association with microsatellite instability[191,192]
PTENMutations/LOHprotein tyrosine phosphatasesBothAssociation with TNM stage, lymph node metastasis and poor survival[65,66,193,194]
bcl-2LOHApoptosis inhibitorIntestinalAssociation with invasion depth and lymph node metastasis[182,195]
DCCLOHCell adhesionIntestinalAssociation with poor survival[48,196]
NM23LOHNucleoside diphosphate kinaseBothAssociation with metastasis and poor survival[197-199]
p21LossCell cycleBothAssociation with poor survival[51]
FHITLOHPurine metabolismBothAssociation with invasive depth and microsatellite instability[200]
BRCA1LOHGenetic instabilityBothAssociation with poor survival[201,202]
Oncogenes
β-CateninMutationsAdhesion,IntestinalAssociation with poor survival and EBV-associated GC[10,58,97]
Signal transduction
BRAFMutationsSignal transductionBothAssociation with microsatellite instability[71,203]
K-RasMutationsSignal transductionIntestinalAssociation with poor prognosis and microsatellite instability[57,71-73,204]
PIK3CAAmplificationSignal transductionBothAssociation with poor survival[55-58]
Mutations
EGFRAmplificationGrowth factor receptorBothAssociation with poor survival[57,81,205]
Tyrosine kinases
ERBB2AmplificationGrowth factor ReceptorIntestinalAssociation with poor survival[68,81-85,205]
MutationsTyrosine kinases
ERBB3OverexpressionGrowth factor receptorDiffuseAssociation with poor survival[68,81,85]
Tyrosine kinases
ERBB4AmplificationGrowth factor receptorBothAssociation with poor survival[86]
Tyrosine kinases
c-MetAmplificationGrowth factor receptorDiffuseAssociation with poor survival[86,206]
KSAMAmplificationGrowth factor receptorDiffuseAssociation with poor survival[207]
VEGFOverexpressionGrowth factorIntestinalAssociation with metastasis and poor survival[153,154,208]
CD44AmplificationCell adhesionBothAssociation with metastasis and poor survival[86,209]
PRL3AmplificationCell signaling moleculesBothAssociation with metastasis and poor survival[210,211]
c-MycAmplificationTranscription factorIntestinalAssociation with poor survival[212,213]
Cyclin EAmplificationCell cycle regulatorBothAssociation with poor survival[208,214]
Table 2 Epigenetic alterations in gastric cancer.
GenesFunctionPrognosisDetected in serumRef.
DNA methylation
BRCA1DNA repairAssociation with age-[215]
hMLH1DNA repairAssociation with poor survivalYes[75,216]
MGMTDNA repairAssociation with poor survival-[75]
RASSF1ADNA repair/Cell cycleAssociation with poor survivalYes[74,76,77]
CDH1Cell invasion/MetastasisAssociation with poor survivalYes[105,106,138,139,216,217]
RASSF2DNA repair/Cell cycleAssociation with poor survival-[75]
P16Cell cycleAssociation with poor survivalYes[75,137-139,218]
IGFBP3Cell cycleAssociation with lymph node metastasis-[219]
CHFRCell cycleAssociation with invasion depth, differentiation and lymph node metastasis-[218,220]
P15Cell cycle-Yes[139,221]
ADAM23Cell invasion/metastasis--[222,223]
APCCell invasion, Metastasis,Association with poor survivalYes[216]
Signal transduction
LOXCell invasion and metastasisAssociation with Helicobacter pylori-positive individuals-[22]
TIMP3Cell invasion and metastasisAssociation with poor survivalYes[74,216]
HAND1Cell differentiationAssociation with poor survival-[22,75]
MLF1Cell differentiationAssociation with lymph node metastasis-[75,223]
PRDM5Cell differentiation--[223,224]
RORACell differentiation--[223]
NDRG2Cell differentiationAssociation with lymph node metastasis-[225]
BNIP3ApoptosisAssociation with poor survival-[226,227]
DAPKApoptosisAssociation with poor survivalYes[74,139,218,227,228]
TMSApoptosisAssociation with poor survival-[228]
FHITApoptosisAssociation with lymph node metastasis-[105]
GSTP1ApoptosisAssociation with EBV-related gastric cancerYes[139,229]
FLNcCell morphologyAssociation with poor survival-[75]
RUNX3Transcriptional factor, Signal transductionAssociation with poor survivalYes[120,122,123,218,220]
ZNF545Transcriptional factorAssociation with poor survival-[230]
RARβSignal transductionAssociation with poor survivalYes[74,138]
HRASLSSignal transduction--[75]
SFRP2Signal transduction--[108,231]
SFRP1Signal transductionAssociation with lymph node metastasis-[231]
MicroRNAs
let-7gTumor suppressorAssociation with invasion depth, lymph node metastasis-[232]
miR-433Tumor suppressorAssociation with invasion depth, lymph node metastasisGRB2[147,232]
miR-1Tumor suppressorAssociation with tumor stage-[233]
miR-20aTumor suppressorAssociation with tumor stage-[233]
miR-27aTumor suppressorAssociation with tumor stage-[233]
miR-34Tumor suppressorAssociation with tumor stageBcl-2, Notch, and HMGA2[233,234]
miR-423-5pTumor suppressorAssociation with tumor stage-[233]
miR-125a-5pTumor suppressorAssociation with tumor size, invasion,ERBB2[87]
liver metastasis, and poor survival
miR-146aTumor suppressorAssociation with lymph node metastasis, venous invasion, and poor survivalEGFR, IRAK1[87]
miR-9Tumor suppressor-RAB34, CDX2, and NF-κB1[147,234,235]
miR-375Tumor suppressor-PDK1, 14-3-3zeta[236]
miR-433Tumor suppressor-GRB2[147]
miR-214OncogenesisAssociation with invasion depth and lymph node metastasis-[232]
miR-130bOncogenesis-RUNX3[121]
p53 pathway

Gene mutations play a key role in transforming normal cells into cancerous cells; they directly or indirectly suppress the normal function of tumor suppressor genes, or enhance transforming activity of oncogenes. So far, numerous gene mutations have been identified in GCs. One of the most commonly mutated genes is TP53 in GC, which encodes p53 protein[46]. Tumor suppressor p53 plays a fundamental role in the regulation of the cell cycle and apoptosis, and its inactivation is central to the pathogenesis of many human cancers, including GC[46]. Numerous reports have demonstrated that the function of TP53 is more frequently inactivated in GCs by mutations and loss of heterozygosity (LOH) than by DNA methylation. TP53 mutation pattern is characterized by frequent G:C→A:T mutations at CpG sites. There are about 30%-70% of GCs containing TP53 point mutations. TP53 mutations are an early event in GC and show a different pattern in diffuse- or intestinal-type GC. Mutations of TP53 seem to be an early event and not related to tumor stage in intestinal-type GC, but their frequency increases with stage progression and they are common in diffuse-type GC[42,46-48]. It has been reported that there is significant correlation between LOH of TP53 with gastric precancerous lesions, suggesting that loss of TP53 may be an early event in gastric carcinogenesis[49]. Cyclin-dependent kinase (CDK) inhibitor p21 gene is directly involved in human carcinogenesis through directly inhibiting DNA replication[50]. It has been reported that the expression of p21 is usually assessed in combination with TP53 status, and GC patients with loss of p21 have worse survival[51]. Thus, aberrant p53 pathway may play an important role in gastric carcinogenesis.

PI3 kinase/Akt pathway

The PI3 kinase (PI3K)/Akt signaling pathway regulates cellular metabolism and growth by acting as a cellular sensor for nutrients and growth factors and plays an important role in tumorigenesis[52-54]. PI3K is a lipid kinase, which is mainly activated by tyrosine kinases. PIK3CA is a catalytic 110-kDa subunit of PI3 kinase and an activator of the PI3K/Akt pathway. It is frequently activated by genomic amplification[55] or mutation[56-58]. Gene amplification is one of the most frequent genomic alterations found in human cancers[59-62]. Increased gene dosage by this genetic event is a common mechanism for oncogene overexpression during tumorigenesis[63], and also reflects the genetic instability of the tumor cells like other types of genetic alterations[64]. Our recent study has demonstrated that PIK3CA mutations are not common, but its amplification is very common in GC[55]. Notably, PIK3CA amplification is associated with elevated p-Akt, suggesting that this genetic alteration may be a major mechanism in activating the PI3K/Akt signaling pathway, further contributing to gastric tumorigenesis[55].

PTEN encodes a multifunctional phosphatase that negatively regulates cell growth, migration and survival via the PI3K/Akt signaling pathway. Mutations, LOH and promoter methylation in the PTEN gene have been frequently identified in GC[48,65,66]. These genetic/epigenetic alterations ultimately contribute to overactivation of the PI3K/Akt signaling pathway during gastric tumorigenesis.

ERBB3 is a member of the epidermal growth factor receptor (EGFR) family or ERBB tyrosine kinase (TK) receptor family, and plays important roles in animal development; deregulation has been linked to several pathologies, including cancer. This receptor family mediates cell proliferation and survival by the MAPK and PI3K/Akt signaling pathways[67]. ERBB3 overexpression is frequently found in GC, particularly in the diffuse-type tumors, contributing to the overactivation of the PI3K/Akt pathway[68]. Thus, aberrations of the ErbB3/PI3 kinase pathway may play an important role in diffuse-type GC. Collectively, specific genotype-based targeting against the PI3K/Akt signaling pathway may be an effective therapeutic strategy for GC.

MAPK pathway

The MAPK (Ras/Raf/Mek/Erk) signaling pathway regulates a series of cell activities such as angiogenesis, proliferation, differentiation, apoptosis and migration. The MAPK pathway consists of several kinases, including Ras, Raf, and Mek, and is often deregulated in GC[69]. Ras (H-, K-, N-isotypes), which encode small G proteins, belong to a commonly mutated oncogene family and function as molecular switches of numerous signaling cascades, including MAPK pathway[70]. Mutations of KRAS and BRAF are common in GC[71-73]. ERK1/2, the final effectors of this pathway, are also found to be activated in GC[74]. In addition, tumor suppressor gene RASSF1A (ras-association domain family 1A), RASSF2, and HRASLS are usually silenced by promoter hypermethylation in various human cancers, including GC[12,75-78]. Especially, RASSF1A contains a ras-association (RA) and a Sav/RASSF/Hpo (SARAH) domain. Its inactivation by promoter methylation can activate the MAPK signaling pathway, and effectively block cancer cell apoptosis, ultimately contributing to tumorigenesis, including GC[48,79].

EGFR is a member of the EGFR family, and works as a cell surface receptor of extracellular ligands, including epidermal growth factor (EGF) and transforming growth factor alpha. Ligand binding to EGFR extracellular domain leads to the phosphorylation of its intracellular tyrosine kinase domain. This will initiate a series of intracellular signals, such as activation of the MAPK signaling pathway[80]. EGFR overexpression is frequently found in GC and is associated with the depth of invasion and poor survival of GC patients[81]. ERBB2, a member of the EGFR family, does not have any specific ligands that it binds directly and may be regulated by ligands in the same way as EGFR. Amplification or overexpression of ERBB2 is very common in intestinal-type GC, but not in diffuse-type GC[68,82,83]. Activated ERBB2 oncogenic pathway may play an important role in intestinal-type GC. ERBB2 mutations occasionally occur in metastatic gastric carcinoma, suggesting that these mutations play a role in the metastatic process of some GCs[82]. However, as compared with mutations, overexpression of ERBB2 caused by copy number gain is more commonly found in human cancers, including GC[84]. Strikingly, ERBB2 amplification may serve as a prognostic marker for tumor invasion, lymph node metastasis and poor prognosis[68,83,85]. Our recent study has demonstrated frequent ERBB4 amplification in GC and is strongly associated with poor survival of GC patients[86]. In addition, MiR-125a-5p, which targets ERBB2[87], and miR-146a, which targets both EGFR and IRAK1[88], are related to survival and may be prognostic factors in GC.

Taken together, these findings suggest that the MAPK pathway plays an important role in gastric tumorigenesis, and may be an effective therapeutic target for GC.

Wnt pathway

Wnt signaling regulates several biological processes, such as determination of cell fate, morphology, polarity, adhesion and growth[89,90] and is divided into canonical and non-canonical pathways. In the former, wnt signals stabilize β-catenin (or CTNNB1), hereby activating gene transcription through interaction of β-catenin with transcriptional factors[89]. Numerous reports have demonstrated that this pathway plays an important role in the invasion and metastasis of GC and may be a good indicator for evaluating the biological behavior of GC[91,92]. The non-canonical pathway is not related to β-catenin and is involved in embryonic development and cell polarity, as well as being also linked to the development of GC[93,94].

APC (adenomatous polyposis coli) is involved in chromosomal segregation, and its inactivation causes aneuploidy and perturbed structure of the chromosomes[95,96]. β-catenin mutations or APC inactivation can cause accumulation and high intranuclear levels of β-catenin, which regulate the wnt signaling pathway and play an important role in early tumor growth, including GC[10,48]. Mutation of the β-catenin gene may function in initiation of invasive processes in intestinal-type GC[97]. The APC gene product binds to the multifunctional protein β-catenin, whose free concentration within the cell is strictly regulated and kept at a low level. Inactivation of the APC gene is more frequently caused by mutations and LOH than DNA methylation. APC mutations are frequently associated with moderately well differentiated intestinal-type tumors[98,99]. There are about 30%-40% of GCs that show LOH in the APC gene[48]. E-cadherin, a calcium dependent cell-to-cell adhesion glycoprotein, is encoded by the CDH1 gene and plays a critical role in maintaining the normal epithelium architecture[100]. The cytoplasmic domain of this molecule interacts with β-catenin, forming strong cohesive nets between the actin cytoskeleton[101], essential for processes of cell-cell adhesion and cell shape, polarity, migration and invasion. Inactivation of CDH1 induced by mutation, LOH or aberrant promoter methylation markedly reduces cell adhesion, alters morphology and enhances cellular motility[10,11,48,102], resulting in tumor dedifferentiation, invasiveness, metastasis and prognosis[103-105]. It has been reported that approximately 50% of diffuse GC is associated with loss of CDH1 function caused by mutations, LOH and promoter methylation[105,106].

In addition, several antagonists of wnt signaling have been identified with two functional classes: the secreted frizzled-related protein (sFRP) class and the dickkopf (Dkk) class[107]. Recent studies on GC have described aberrant methylation for several regulators of the wnt pathway, including SFRP1, SFRP2, SFRP4, SFRP5, Dkk-3 genes[107-109], further implicating the role of the wnt pathway in gastric tumorigenesis.

NF-κB pathway

NF-κB is a critical regulator of genes involved in cell survival and proliferation, cellular stress response and inflammation[110,111]. It is well documented that chronic infections and inflammation serve as major risk factors for various types of cancer, including GC[9]. NF-κB can activate the genes in response to certain stimuli, including ROS, tumor necrosis factor alpha (TNFα), interleukin 1 beta (IL-1β), and bacterial lipopolysaccharides (LPS)[112]. Activation of NF-κB is by the canonical/classical and non-canonical/alternative pathways. The canonical pathway can be activated by several stimuli, such as inflammation cytokines and antigens[113]. The non-canonical pathway is induced by certain receptor signals like B-cell activating factor (BAFF), lymphotoxin β (LTβ), CD40 ligand, TNF-like weak inducer of apoptosis (TWEAK) and receptor activator of NF-κB ligand (RANKL)[114]. There is evidence that NF-κB is constitutively activated in GC tissues, with high levels in GC cell lines as compared with normal adjacent epithelial cells[115]. More importantly, GC patients with high NF-κB levels in cancer cells have a lower survival time than those with low NF-κB activation[116].

Transforming growth factor-β signaling

Transforming growth factor beta (TGF-β) is a multifunctional cytokine that controls differentiation, apoptosis, cell growth and immune reactions. The TGF-β family mainly includes three isoforms, TGF-β1, TGF-β2, TGF-β3, in mammals[117,118]. In early stages of GC, TGF-β signaling is considered to be a tumor suppressor pathway, whereas in the late stage it promotes invasion and metastasis[119]. The TGF-β signaling pathway is composed of two distinct receptors with intrinsic serine/threonine kinase activity, TGF-β receptor type I, type II (TGFBR1 and TGFBR2) and Smad proteins. The loss of TGF-β response due to the dysregulation of TGFBR1, TGFBR2 and Smad4 is well known for its contribution to oncogenesis. Moreover, methylation of TGFBR1, TGFBR2 and Smad4 may exist in the gastric cardia dysplasia stages and plays a key role in these genes silencing with subsequent effects on the TGF-β/Smad signaling pathway[120]. TGF-β induces RUNX3, a transcription factor that is an inhibitor of the wnt signaling pathway and has been involved in gastric tumorigenesis. Reduced expression of RUNX3 in GC has been attributed to aberrant promoter methylation. In addition, MiR-130b is identified as the top candidate miRNA for RUNX3 binding. Its overexpression can downregulate RUNX3 expression[121]. Importantly, loss of RUNX3 expression is closely associated with the progression, differentiation, metastasis and poor prognosis of GC[122-124].

Cyclooxygenase -2/Prostaglandin E2 pathway

Cyclooxygenase-2 (COX-2) is a rate-limiting enzyme responsible for the conversion of arachidonic acid to prostaglandins (PGs)[125]. Its overexpression has been reported in various human cancers, including GC[126,127]. Moreover, several studies have shown that treatment with COX-2 selective inhibitors suppresses chemically induced tumor formation and xenografted tumor growth[128]. These findings suggest that the COX-2 pathway plays an essential role in GC development. COX-2 is responsible for catalyzing the biosynthesis of PG-H2, which is further converted to prostaglandin E2 (PGE2) by microsomal PGE synthase-1 (mPGES-1)[129]. COX-2-derived PGE2 can promote cell growth, inhibit apoptosis and enhance cellular invasiveness, facilitating cancer progression[130]. Up-regulation of PGE2 is found in most of the gastrointestinal cancers[131], indicating that an increased level of PGE2 through induction of COX-2 and mPGES-1 is crucial for gastric tumorigenesis.

Retinoblastoma pathway

The retinoblastoma (Rb) family is involved in cell cycle regulation and their function and/or expression is often lost in various kinds of tumors[132]. In normal cells, the cell cycle is controlled by a complex series of signaling pathways by which a cell grows, replicates its DNA and divides. Dysregulation of cell cycle components can cause tumor formation[133]. Tumor suppressor gene p16 is a CDK inhibitor that slows down the progression of the cell cycle by inactivating the cyclin dependent kinase that phosphorylates Rb protein[134,135]. Thus, p16 contributes to the maintenance of Rb in an unphosphorylated state and inhibits cell cycle progression. Mutations in p16 gene are frequently found in human cancers, including GC[10,48,136]. Our previous studies have shown that there is close association of hypermethylation of p16 with poor survival of GC patients[12,75] and methylation status of p16 can predict response to 5-FU[137]. Strikingly, p16 methylation can be detected in 19%-51.9% and 25%-57.4% of serum extracted from GC patients[138,139], implicating its significance in the diagnosis and prognosis of GC.

Others

Many other molecular events are also found in gastric carcinogenesis (Tables 1 and 2). For example, the majority of GC is characterized by genetic instability, which is generally classified into two major types: microsatellite instability (MSI) and chromosomal instability (CIN)[140,141]. MSI is characteristic for the hereditary type of GC and results from errors in DNA replication. These replication errors are detected and repaired by a complex of mismatch repair (MMR) proteins[140], including hMLH1 and hMSH2. Functional inactivation of MMR can be caused by gene mutations and CpG island methylation. Inactivation or deficiency of MMR genes often leads to inactivation of tumor suppressor genes, LOH and mutations in critical genes. CIN is characterized by gross chromosomal abnormalities[141], resulting in major modifications of chromosomal quantity or quality, including genomic amplifications of oncogenes and/or LOH, deletions or allelic loss, chromosomal translocations. Of them, chromosomal translocations lead to the formation of protein coding genes with oncogenic functions and rearrangements of chromosomes. A recent study has shown that CD44-SLC1A2 gene fusions are detected in 1% to 2% of GCs, but not in adjacent matched normal gastric tissues. Fusion of the SLC1A2 gene coding region to CD44 regulatory elements likely causes SLC1A2 transcriptional dysregulation[142]. Thus, the genomics of GC display high instability and all these abnormalities may lead to oncogene activation and/or tumor suppressor gene inactivation.

In addition to DNA methylation, microRNAs (miRNAs) and histone modifications are important epigenetic modifications, which play critical roles in gastric tumorigenesis[143-145]. MiRNAs can function as either tumor suppressors or oncogenes depending upon their target genes. Many tumor suppressor miRNAs that target growth-promoting genes are downregulated in human cancers, whereas oncogenic miRNAs that target growth inhibitory pathways are often upregulated in cancer cells[146]. For example, miR-9 and miR-433, which target tumor-associated genes GRB2 and RAB34 respectively, are significantly down-regulated in GC as compared with adjacent normal tissues[147]. MiR-146a, which targets both EGFR and IRAK1, is related to survival and may be a prognostic factor in GC[88]. Histones are structural proteins of chromatin and are composed of five basic proteins: H1, H2A, H2B, H3 and H4. The N-terminal tails of histones are subject to posttranslational covalent modifications, including methylation, acetylation, ubiquitination, sumoylation, phosphorylation, proline isomerization and ADP ribosylation. These modifications can alter chromatin remodeling, and histone acetylation and methylation are associated with pathological epigenetic disruption in cancer cells[148,149]. High levels of H3K4me3 (trimethylation of lysine 4 on histone H3), H3K36me3, H3K79me3, H4K20me1, H3K27ac, H2BK5ac are associated with actively transcribed genes. In contrast, low levels of acetylation and high levels of methylation of H3K27, H3K9 and H4K20 are associated with transcriptional repression[144]. For example, H3K9me3 is positively correlated with tumor stage, lymphovascular invasion, tumor recurrence and poor survival, indicating that histone modification may be a useful predictor for poor prognosis of GC patients[150]. Collectively, these observations suggest that miRNAs and histone modification may play a key role in gastric carcinogenesis and are closely associated with worse prognosis of cancer patients.

TRANSLATIONAL PROMISES IN GC

GC is a complex disease that involves multiple risk factors and multiple genetic/epigenetic alterations. Currently, surgical resection and chemotherapy are important strategies for GC treatment. However, despite recent advances in perioperative and adjuvant chemotherapy, most patients with advanced GC still have a poor prognosis. Thus, a better understanding of the pathogenetic mechanisms of GC may lead to new diagnostic, therapeutic and preventive approaches to this disease. Screening and treatment of H. pylori infection, restriction of dietary salt, and a diet rich in fresh fruits and vegetables can decrease the risk of GC and prevent GC[20]. In addition, identification of genetic and epigenetic markers in GC patients may be an encouraging factor to advance individualized and targeted therapies.

In recent years, in the ToGA study, trastuzumab, which is a specific antibody for ERBB2, has been approved as a current standard of chemotherapy in ERBB2-positive GC patients[151,152]. Given that VEGF overexpression is often found in GC, and is related to tumor aggressiveness, VEGF may thus become a valid target for antiangiogenic therapy[153,154]. Anti-VEGF agents have recently been developed, including mAbs and TKIs (the tyrosine kinase inhibitors). Bevacizumab, the VEGF monoclonal antibody, is currently being investigated for GC treatment in combination with different chemotherapeutic compounds in a phase III (AVAGAST) study. Strikingly, adding bevacizumab to chemotherapy is associated with significant increases in PFS (progression-free survival) and overall response rate in the first-line treatment of advanced GC[155]. Apatinib, a TKI that selectively targets VEGFR-2 (a type III receptor tyrosine kinase), has been investigated in a phase II clinical trial that shows that apatinib improved PFS and OS (overall survival) in heavily pretreated patients with metastatic GC[156]. Other anti-VEGF agents, such as ramucirumab, sunitinib, sorafenib and cediranib, have also been investigated for GC treatment[157].

Specific inhibitors against molecular target EGFR have been developed in GC treatment although not completely effective and they need further investigation. Anti-EGFR mAbs and TKIs are currently undergoing clinical trials for GC patients. Cetuximab has shown some encouraging results when combined with other chemotherapeutic agents in phase II trials, whereas the phase III trial (EXPAND) demonstrates that addition of cetuximab to capecitabine-cisplatin provided no additional benefit to chemotherapy alone in the first-line treatment of advanced GC[158]. Lapatinib, a TKI, inhibits both EGFR and ERBB2 kinases. Although a poor objective response rate has been observed in the phase II studies[159,160], phase III studies are evaluating the role of lapatinib in conjunction with chemotherapy[161]. Compounds against other novel targets, such as mechanistic target of rapamycin mTOR (everolimus)[162,163], hepatocyte growth factor receptor c-Met (foretinib[163] and rilotumumab[152]), KSAM (AZD4547)[152], MMP (marimastat)[164], and protein kinase C (bryostatin-1)[165], have also been investigated in GC.

Epigenetic changes in DNA are reversible, different from genetic changes, and they represent very attractive targets for new therapeutic approaches. Several epigenetic drugs targeting DNA methylation and histone deacetylation enzymes have been investigated in clinical trials. Treatments targeting cancer are designed to inhibit either the function of DNMTs or histone deacetylase (HDAC). DNMT inhibitors are divided into two families: the nucleoside analogs and the non-nucleoside inhibitors. The three most commonly used catalytic inhibitors of DNMTs are the nucleoside analogs 5-azacytidine, 5-aza-2-deoxycytidine, and zebularine. The first DNA methylation inhibitor 5-azacytidine (azacitidine) and 5-aza-2-deoxycytidine (decitabine) have been recently approved by the FDA for treatment of myelodysplastic syndromes (MDS) and primary cutaneous T-cell lymphoma (CTCL)[166-168]. However, 5-azacytidine and 5-aza-2-deoxycytidine have a weak response in solid tumors[169]. SGI-110, a second generation DNMT inhibitor, is being investigated in phase II clinical trials for the treatment of MDS and acute myeloid leukemia(AML)[170,171]. Zebularine and 5-azacytidine need to be incorporated into DNA to trap DNMTs; they may have additional nonspecific toxicities, whereas non-nucleoside molecules, such as EGCG and genistein, do not rely on DNA incorporation. EGCG, the main polyphenol of green tea, and genistein have been characterized as enzymatic and cellular DNMT inhibitors[172,173]. Other commonly used drugs have been shown to bring about DNA demethylation, such as procainamide and hydralazine[174]. HDAC inhibitors (HDACis) now also are considered as potential therapeutics. Trichostatin A (TSA) and suberoylanilide hydroxamic acid (SAHA) are the classic HDACis. HDAC inhibitors can induce cell differentiation, apoptosis, and growth suppression and may be an innovative approach in GC treatment[175]. Vorinostat (SAHA), also known as suberoylanilide hydroxamic acid, is the first clinically approved HDACi, which has been recently approved for clinical use in CTCL[176]. Preclinical studies have shown that vorinostat has potential antitumor activity, including in GC, and may improve clinical outcomes for GC patients[177]. A phase I study of vorinostat combined with capecitabine and cisplatin has been performed to assess the recommended phase II trial dose in patients with advanced GC[178]. These findings suggest that a new area of potential interest is the development of histone methyltransferase (HMTase) inhibitors. HMTase inhibitors may be used therapeutically to activate silenced tumor suppressor genes.

CONCLUSION

In addition to environmental factors, gastric carcinogenesis involves complex genetic and epigenetic alterations. It is now well established that genetic/epigenetic alterations can be driver events in the progression of normal gastric mucosa to cancer. Moreover, these alterations also contribute to the molecular heterogeneity of GC, as illustrated by the identification of molecular subtypes of GCs that can be identified by their unique genetic/epigenetic signatures. Given the role of these molecular events in directing the pathogenesis of GC, studying their signatures and developing them as biomarkers for diagnosis, prognosis and direction of therapy is likely to yield clinically useful assays that will be used to direct patient care.

In recent years, a large number of biomarkers have been developed for the early detection and prognostic evaluation of GC, as well as for predicting response to relevant therapies. However, in many important diagnostic scenarios, DNA from the cancer cells represents only a small fraction of the total DNA in the clinical sample, such as plasma, serum, urine, feces, or sputum. An exciting evolution of the development of biomarkers is the improvement of the biotechnology, such as next generation sequencing or deep sequencing, which now allows us to profile genetic/epigenetic alterations at a much higher sensitivity and genomic scale previously not possible[179,180].

Although recent diagnostic and therapeutic advances have provided excellent survival for patients with early GC, patients are usually diagnosed at an advanced stage and the prognosis is still dismal[181]. Thus, there is a pressing need to develop effective therapeutic strategies for this disease. Increasing evidence has demonstrated that combinations of various targeted agents with chemotherapies will be an effective strategy for GC treatment. In addition, continued efforts to investigate these molecular events will allow for a better understanding of the pathogenesis of GC and will lead to the translation of these insights into the clinical arena.

Footnotes

P- Reviewer: Beltran MA, Caboclo JLF, Fassan M, Ierardi E, Kakushima N, KatoJ, Lee TY, Shi C S- Editor: Ma YJ L- Editor: Logan S E- Editor: Ma S

References
1.  Yang L. Incidence and mortality of gastric cancer in China. World J Gastroenterol. 2006;12:17-20.  [PubMed]  [DOI]
2.  Dicken BJ, Bigam DL, Cass C, Mackey JR, Joy AA, Hamilton SM. Gastric adenocarcinoma: review and considerations for future directions. Ann Surg. 2005;241:27-39.  [PubMed]  [DOI]
3.  Crew KD, Neugut AI. Epidemiology of gastric cancer. World J Gastroenterol. 2006;12:354-362.  [PubMed]  [DOI]
4.  Zou XM, Li YL, Wang H, Cui W, Li XL, Fu SB, Jiang HC. Gastric cancer cell lines induced by trichostatin A. World J Gastroenterol. 2008;14:4810-4815.  [PubMed]  [DOI]
5.  Stelzner S, Emmrich P. The mixed type in Laurén’s classification of gastric carcinoma. Histologic description and biologic behavior. Gen Diagn Pathol. 1997;143:39-48.  [PubMed]  [DOI]
6.  Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M, Taniyama K, Sasaki N, Schlemper RJ. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001;345:784-789.  [PubMed]  [DOI]
7.  Kato M, Asaka M. Recent development of gastric cancer prevention. Jpn J Clin Oncol. 2012;42:987-994.  [PubMed]  [DOI]
8.  Zabaleta J. Multifactorial etiology of gastric cancer. Methods Mol Biol. 2012;863:411-435.  [PubMed]  [DOI]
9.  Figueiredo C, Garcia-Gonzalez MA, Machado JC. Molecular pathogenesis of gastric cancer. Helicobacter. 2013;18 Suppl 1:28-33.  [PubMed]  [DOI]
10.  Resende C, Ristimäki A, Machado JC. Genetic and epigenetic alteration in gastric carcinogenesis. Helicobacter. 2010;15 Suppl 1:34-39.  [PubMed]  [DOI]
11.  Calcagno DQ, Gigek CO, Chen ES, Burbano RR, Smith Mde A. DNA and histone methylation in gastric carcinogenesis. World J Gastroenterol. 2013;19:1182-1192.  [PubMed]  [DOI]
12.  Qu Y, Dang S, Hou P. Gene methylation in gastric cancer. Clin Chim Acta. 2013;424:53-65.  [PubMed]  [DOI]
13.  Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144:646-674.  [PubMed]  [DOI]
14.  Tsugane S, Sasazuki S. Diet and the risk of gastric cancer: review of epidemiological evidence. Gastric Cancer. 2007;10:75-83.  [PubMed]  [DOI]
15.  Catalano V, Labianca R, Beretta GD, Gatta G, de Braud F, Van Cutsem E. Gastric cancer. Crit Rev Oncol Hematol. 2009;71:127-164.  [PubMed]  [DOI]
16.  Houghton J, Wang TC. Helicobacter pylori and gastric cancer: a new paradigm for inflammation-associated epithelial cancers. Gastroenterology. 2005;128:1567-1578.  [PubMed]  [DOI]
17.  Fock KM, Ang TL. Epidemiology of Helicobacter pylori infection and gastric cancer in Asia. J Gastroenterol Hepatol. 2010;25:479-486.  [PubMed]  [DOI]
18.  Compare D, Rocco A, Nardone G. Risk factors in gastric cancer. Eur Rev Med Pharmacol Sci. 2010;14:302-308.  [PubMed]  [DOI]
19.  Pandey R, Misra V, Misra SP, Dwivedi M, Kumar A, Tiwari BK. Helicobacter pylori and gastric cancer. Asian Pac J Cancer Prev. 2010;11:583-588.  [PubMed]  [DOI]
20.  Correa P, Piazuelo MB, Camargo MC. The future of gastric cancer prevention. Gastric Cancer. 2004;7:9-16.  [PubMed]  [DOI]
21.  Augusto AC, Miguel F, Mendonça S, Pedrazzoli J, Gurgueira SA. Oxidative stress expression status associated to Helicobacter pylori virulence in gastric diseases. Clin Biochem. 2007;40:615-622.  [PubMed]  [DOI]
22.  Barros R, Freund JN, David L, Almeida R. Gastric intestinal metaplasia revisited: function and regulation of CDX2. Trends Mol Med. 2012;18:555-563.  [PubMed]  [DOI]
23.  Nakajima T, Yamashita S, Maekita T, Niwa T, Nakazawa K, Ushijima T. The presence of a methylation fingerprint of Helicobacter pylori infection in human gastric mucosae. Int J Cancer. 2009;124:905-910.  [PubMed]  [DOI]
24.  Niwa T, Tsukamoto T, Toyoda T, Mori A, Tanaka H, Maekita T, Ichinose M, Tatematsu M, Ushijima T. Inflammatory processes triggered by Helicobacter pylori infection cause aberrant DNA methylation in gastric epithelial cells. Cancer Res. 2010;70:1430-1440.  [PubMed]  [DOI]
25.  Shin CM, Kim N, Jung Y, Park JH, Kang GH, Kim JS, Jung HC, Song IS. Role of Helicobacter pylori infection in aberrant DNA methylation along multistep gastric carcinogenesis. Cancer Sci. 2010;101:1337-1346.  [PubMed]  [DOI]
26.  Hur K, Niwa T, Toyoda T, Tsukamoto T, Tatematsu M, Yang HK, Ushijima T. Insufficient role of cell proliferation in aberrant DNA methylation induction and involvement of specific types of inflammation. Carcinogenesis. 2011;32:35-41.  [PubMed]  [DOI]
27.  Tsugane S. Salt, salted food intake, and risk of gastric cancer: epidemiologic evidence. Cancer Sci. 2005;96:1-6.  [PubMed]  [DOI]
28.  Tatematsu M, Takahashi M, Fukushima S, Hananouchi M, Shirai T. Effects in rats of sodium chloride on experimental gastric cancers induced by N-methyl-N-nitro-N-nitrosoguanidine or 4-nitroquinoline-1-oxide. J Natl Cancer Inst. 1975;55:101-106.  [PubMed]  [DOI]
29.  Bilici M, Cayir K, Tekin SB, Gundogdu C, Albayrak A, Suleyman B, Ozogul B, Erdemci B, Suleyman H. Effect of mirtazapine on MNNG-induced gastric adenocarcinoma in rats. Asian Pac J Cancer Prev. 2012;13:4897-4900.  [PubMed]  [DOI]
30.  Suzuki H, Iijima K, Scobie G, Fyfe V, McColl KE. Nitrate and nitrosative chemistry within Barrett’s oesophagus during acid reflux. Gut. 2005;54:1527-1535.  [PubMed]  [DOI]
31.  Mitacek EJ, Brunnemann KD, Suttajit M, Caplan LS, Gagna CE, Bhothisuwan K, Siriamornpun S, Hummel CF, Ohshima H, Roy R. Geographic distribution of liver and stomach cancers in Thailand in relation to estimated dietary intake of nitrate, nitrite, and nitrosodimethylamine. Nutr Cancer. 2008;60:196-203.  [PubMed]  [DOI]
32.  Liu C, Russell RM. Nutrition and gastric cancer risk: an update. Nutr Rev. 2008;66:237-249.  [PubMed]  [DOI]
33.  Tsugane S, Sasazuki S, Kobayashi M, Sasaki S. Salt and salted food intake and subsequent risk of gastric cancer among middle-aged Japanese men and women. Br J Cancer. 2004;90:128-134.  [PubMed]  [DOI]
34.  Wang XQ, Terry PD, Yan H. Review of salt consumption and stomach cancer risk: epidemiological and biological evidence. World J Gastroenterol. 2009;15:2204-2213.  [PubMed]  [DOI]
35.  Krejs GJ. Gastric cancer: epidemiology and risk factors. Dig Dis. 2010;28:600-603.  [PubMed]  [DOI]
36.  Hou IC, Amarnani S, Chong MT, Bishayee A. Green tea and the risk of gastric cancer: epidemiological evidence. World J Gastroenterol. 2013;19:3713-3722.  [PubMed]  [DOI]
37.  Trédaniel J, Boffetta P, Buiatti E, Saracci R, Hirsch A. Tobacco smoking and gastric cancer: review and meta-analysis. Int J Cancer. 1997;72:565-573.  [PubMed]  [DOI]
38.  Guggenheim DE, Shah MA. Gastric cancer epidemiology and risk factors. J Surg Oncol. 2013;107:230-236.  [PubMed]  [DOI]
39.  Buas MF, Vaughan TL. Epidemiology and risk factors for gastroesophageal junction tumors: understanding the rising incidence of this disease. Semin Radiat Oncol. 2013;23:3-9.  [PubMed]  [DOI]
40.  Chow WH, Finkle WD, McLaughlin JK, Frankl H, Ziel HK, Fraumeni JF. The relation of gastroesophageal reflux disease and its treatment to adenocarcinomas of the esophagus and gastric cardia. JAMA. 1995;274:474-477.  [PubMed]  [DOI]
41.  Crane SJ, Locke GR, Harmsen WS, Diehl NN, Zinsmeister AR, Melton LJ, Romero Y, Talley NJ. Subsite-specific risk factors for esophageal and gastric adenocarcinoma. Am J Gastroenterol. 2007;102:1596-1602.  [PubMed]  [DOI]
42.  Bellini MF, Cadamuro AC, Succi M, Proença MA, Silva AE. Alterations of the TP53 gene in gastric and esophageal carcinogenesis. J Biomed Biotechnol. 2012;2012:891961.  [PubMed]  [DOI]
43.  Cheng XX, Wang ZC, Chen XY, Sun Y, Kong QY, Liu J, Li H. Correlation of Wnt-2 expression and beta-catenin intracellular accumulation in Chinese gastric cancers: relevance with tumour dissemination. Cancer Lett. 2005;223:339-347.  [PubMed]  [DOI]
44.  Cao HJ, Fang Y, Zhang X, Chen WJ, Zhou WP, Wang H, Wang LB, Wu JM. Tumor metastasis and the reciprocal regulation of heparanase gene expression by nuclear factor kappa B in human gastric carcinoma tissue. World J Gastroenterol. 2005;11:903-907.  [PubMed]  [DOI]
45.  Yu HG, Ai YW, Yu LL, Zhou XD, Liu J, Li JH, Xu XM, Liu S, Chen J, Liu F. Phosphoinositide 3-kinase/Akt pathway plays an important role in chemoresistance of gastric cancer cells against etoposide and doxorubicin induced cell death. Int J Cancer. 2008;122:433-443.  [PubMed]  [DOI]
46.  Fenoglio-Preiser CM, Wang J, Stemmermann GN, Noffsinger A. TP53 and gastric carcinoma: a review. Hum Mutat. 2003;21:258-270.  [PubMed]  [DOI]
47.  Souza RF. Molecular and biologic basis of upper gastrointestinal malignancy--esophageal carcinoma. Surg Oncol Clin N Am. 2002;11:257-72, viii.  [PubMed]  [DOI]
48.  Tamura G. Alterations of tumor suppressor and tumor-related genes in the development and progression of gastric cancer. World J Gastroenterol. 2006;12:192-198.  [PubMed]  [DOI]
49.  Karaman A, Kabalar ME, Binici DN, Oztürk C, Pirim I. Genetic alterations in gastric precancerous lesions. Genet Couns. 2010;21:439-450.  [PubMed]  [DOI]
50.  Warfel NA, El-Deiry WS. p21WAF1 and tumourigenesis: 20 years after. Curr Opin Oncol. 2013;25:52-58.  [PubMed]  [DOI]
51.  Kouraklis G, Katsoulis IE, Theocharis S, Tsourouflis G, Xipolitas N, Glinavou A, Sioka C, Kostakis A. Does the expression of cyclin E, pRb, and p21 correlate with prognosis in gastric adenocarcinoma? Dig Dis Sci. 2009;54:1015-1020.  [PubMed]  [DOI]
52.  Michl P, Downward J. Mechanisms of disease: PI3K/AKT signaling in gastrointestinal cancers. Z Gastroenterol. 2005;43:1133-1139.  [PubMed]  [DOI]
53.  Sukawa Y, Yamamoto H, Nosho K, Kunimoto H, Suzuki H, Adachi Y, Nakazawa M, Nobuoka T, Kawayama M, Mikami M. Alterations in the human epidermal growth factor receptor 2-phosphatidylinositol 3-kinase-v-Akt pathway in gastric cancer. World J Gastroenterol. 2012;18:6577-6586.  [PubMed]  [DOI]
54.  Bartholomeusz C, Gonzalez-Angulo AM. Targeting the PI3K signaling pathway in cancer therapy. Expert Opin Ther Targets. 2012;16:121-130.  [PubMed]  [DOI]
55.  Shi J, Yao D, Liu W, Wang N, Lv H, Zhang G, Ji M, Xu L, He N, Shi B. Highly frequent PIK3CA amplification is associated with poor prognosis in gastric cancer. BMC Cancer. 2012;12:50.  [PubMed]  [DOI]
56.  Zang ZJ, Cutcutache I, Poon SL, Zhang SL, McPherson JR, Tao J, Rajasegaran V, Heng HL, Deng N, Gan A. Exome sequencing of gastric adenocarcinoma identifies recurrent somatic mutations in cell adhesion and chromatin remodeling genes. Nat Genet. 2012;44:570-574.  [PubMed]  [DOI]
57.  Corso G, Velho S, Paredes J, Pedrazzani C, Martins D, Milanezi F, Pascale V, Vindigni C, Pinheiro H, Leite M. Oncogenic mutations in gastric cancer with microsatellite instability. Eur J Cancer. 2011;47:443-451.  [PubMed]  [DOI]
58.  Lee J, van Hummelen P, Go C, Palescandolo E, Jang J, Park HY, Kang SY, Park JO, Kang WK, MacConaill L. High-throughput mutation profiling identifies frequent somatic mutations in advanced gastric adenocarcinoma. PLoS One. 2012;7:e38892.  [PubMed]  [DOI]
59.  Santarius T, Shipley J, Brewer D, Stratton MR, Cooper CS. A census of amplified and overexpressed human cancer genes. Nat Rev Cancer. 2010;10:59-64.  [PubMed]  [DOI]
60.  Peng DF, Sugihara H, Mukaisho K, Tsubosa Y, Hattori T. Alterations of chromosomal copy number during progression of diffuse-type gastric carcinomas: metaphase- and array-based comparative genomic hybridization analyses of multiple samples from individual tumours. J Pathol. 2003;201:439-450.  [PubMed]  [DOI]
61.  Buffart TE, van Grieken NC, Tijssen M, Coffa J, Ylstra B, Grabsch HI, van de Velde CJ, Carvalho B, Meijer GA. High resolution analysis of DNA copy-number aberrations of chromosomes 8, 13, and 20 in gastric cancers. Virchows Arch. 2009;455:213-223.  [PubMed]  [DOI]
62.  Zhang D, Wang Z, Luo Y, Xu Y, Liu Y, Yang W, Zhang X. Analysis of DNA copy number aberrations by multiple ligation-dependent probe amplification on 50 intestinal type gastric cancers. J Surg Oncol. 2011;103:124-132.  [PubMed]  [DOI]
63.  Schwab M. Amplification of oncogenes in human cancer cells. Bioessays. 1998;20:473-479.  [PubMed]  [DOI]
64.  Albertson DG. Gene amplification in cancer. Trends Genet. 2006;22:447-455.  [PubMed]  [DOI]
65.  Guo CY, Xu XF, Wu JY, Liu SF. PCR-SSCP-DNA sequencing method in detecting PTEN gene mutation and its significance in human gastric cancer. World J Gastroenterol. 2008;14:3804-3811.  [PubMed]  [DOI]
66.  Wen YG, Wang Q, Zhou CZ, Qiu GQ, Peng ZH, Tang HM. Mutation analysis of tumor suppressor gene PTEN in patients with gastric carcinomas and its impact on PI3K/AKT pathway. Oncol Rep. 2010;24:89-95.  [PubMed]  [DOI]
67.  Ocaña A, Pandiella A. Targeting HER receptors in cancer. Curr Pharm Des. 2013;19:808-817.  [PubMed]  [DOI]
68.  Zhang XL, Yang YS, Xu DP, Qu JH, Guo MZ, Gong Y, Huang J. Comparative study on overexpression of HER2/neu and HER3 in gastric cancer. World J Surg. 2009;33:2112-2118.  [PubMed]  [DOI]
69.  Kim EK, Choi EJ. Pathological roles of MAPK signaling pathways in human diseases. Biochim Biophys Acta. 2010;1802:396-405.  [PubMed]  [DOI]
70.  Young A, Lyons J, Miller AL, Phan VT, Alarcón IR, McCormick F. Ras signaling and therapies. Adv Cancer Res. 2009;102:1-17.  [PubMed]  [DOI]
71.  Lee SH, Lee JW, Soung YH, Kim HS, Park WS, Kim SY, Lee JH, Park JY, Cho YG, Kim CJ. BRAF and KRAS mutations in stomach cancer. Oncogene. 2003;22:6942-6945.  [PubMed]  [DOI]
72.  Yoo J, Park SY, Robinson RA, Kang SJ, Ahn WS, Kang CS. ras Gene mutations and expression of Ras signal transduction mediators in gastric adenocarcinomas. Arch Pathol Lab Med. 2002;126:1096-1100.  [PubMed]  [DOI]
73.  Chen HC, Chen HJ, Khan MA, Rao ZZ, Wan XX, Tan B, Zhang DZ. Genetic mutations of p53 and k-ras in gastric carcinoma patients from Hunan, China. Tumour Biol. 2011;32:367-373.  [PubMed]  [DOI]
74.  Liang B, Wang S, Zhu XG, Yu YX, Cui ZR, Yu YZ. Increased expression of mitogen-activated protein kinase and its upstream regulating signal in human gastric cancer. World J Gastroenterol. 2005;11:623-8.  [PubMed]  [DOI]
75.  Shi J, Zhang G, Yao D, Liu W, Wang N, Ji M, He N, Shi B, Hou P. Prognostic significance of aberrant gene methylation in gastric cancer. Am J Cancer Res. 2012;2:116-129.  [PubMed]  [DOI]
76.  Yao D, Shi J, Shi B, Wang N, Liu W, Zhang G, Ji M, Xu L, He N, Hou P. Quantitative assessment of gene methylation and their impact on clinical outcome in gastric cancer. Clin Chim Acta. 2012;413:787-794.  [PubMed]  [DOI]
77.  Wang YC, Yu ZH, Liu C, Xu LZ, Yu W, Lu J, Zhu RM, Li GL, Xia XY, Wei XW. Detection of RASSF1A promoter hypermethylation in serum from gastric and colorectal adenocarcinoma patients. World J Gastroenterol. 2008;14:3074-3080.  [PubMed]  [DOI]
78.  Endoh M, Tamura G, Honda T, Homma N, Terashima M, Nishizuka S, Motoyama T. RASSF2, a potential tumour suppressor, is silenced by CpG island hypermethylation in gastric cancer. Br J Cancer. 2005;93:1395-1399.  [PubMed]  [DOI]
79.  Dammann R, Schagdarsurengin U, Seidel C, Strunnikova M, Rastetter M, Baier K, Pfeifer GP. The tumor suppressor RASSF1A in human carcinogenesis: an update. Histol Histopathol. 2005;20:645-663.  [PubMed]  [DOI]
80.  Alvarado D, Klein DE, Lemmon MA. ErbB2 resembles an autoinhibited invertebrate epidermal growth factor receptor. Nature. 2009;461:287-291.  [PubMed]  [DOI]
81.  Slesak B, Harlozinska A, Porebska I, Bojarowski T, Lapinska J, Rzeszutko M, Wojnar A. Expression of epidermal growth factor receptor family proteins (EGFR, c-erbB-2 and c-erbB-3) in gastric cancer and chronic gastritis. Anticancer Res. 1998;18:2727-2732.  [PubMed]  [DOI]
82.  Lee JW, Soung YH, Kim SY, Park WS, Nam SW, Kim SH, Lee JY, Yoo NJ, Lee SH. ERBB2 kinase domain mutation in a gastric cancer metastasis. APMIS. 2005;113:683-687.  [PubMed]  [DOI]
83.  Tanner M, Hollmén M, Junttila TT, Kapanen AI, Tommola S, Soini Y, Helin H, Salo J, Joensuu H, Sihvo E. Amplification of HER-2 in gastric carcinoma: association with Topoisomerase IIalpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. Ann Oncol. 2005;16:273-278.  [PubMed]  [DOI]
84.  de Mello RA, Marques AM, Araújo A. HER2 therapies and gastric cancer: a step forward. World J Gastroenterol. 2013;19:6165-6169.  [PubMed]  [DOI]
85.  Begnami MD, Fukuda E, Fregnani JH, Nonogaki S, Montagnini AL, da Costa WL, Soares FA. Prognostic implications of altered human epidermal growth factor receptors (HERs) in gastric carcinomas: HER2 and HER3 are predictors of poor outcome. J Clin Oncol. 2011;29:3030-3036.  [PubMed]  [DOI]
86.  Shi J, Yao D, Liu W, Wang N, Lv H, He N, Shi B, Hou P, Ji M. Frequent gene amplification predicts poor prognosis in gastric cancer. Int J Mol Sci. 2012;13:4714-4726.  [PubMed]  [DOI]
87.  Nishida N, Mimori K, Fabbri M, Yokobori T, Sudo T, Tanaka F, Shibata K, Ishii H, Doki Y, Mori M. MicroRNA-125a-5p is an independent prognostic factor in gastric cancer and inhibits the proliferation of human gastric cancer cells in combination with trastuzumab. Clin Cancer Res. 2011;17:2725-2733.  [PubMed]  [DOI]
88.  Kogo R, Mimori K, Tanaka F, Komune S, Mori M. Clinical significance of miR-146a in gastric cancer cases. Clin Cancer Res. 2011;17:4277-4284.  [PubMed]  [DOI]
89.  Polakis P. Wnt signaling in cancer. Cold Spring Harb Perspect Biol. 2012;4.  [PubMed]  [DOI]
90.  Clevers H, Nusse R. Wnt/β-catenin signaling and disease. Cell. 2012;149:1192-1205.  [PubMed]  [DOI]
91.  Zhang H, Xue Y. Wnt pathway is involved in advanced gastric carcinoma. Hepatogastroenterology. 2008;55:1126-1130.  [PubMed]  [DOI]
92.  Pan KF, Liu WG, Zhang L, You WC, Lu YY. Mutations in components of the Wnt signaling pathway in gastric cancer. World J Gastroenterol. 2008;14:1570-1574.  [PubMed]  [DOI]
93.  Kurayoshi M, Oue N, Yamamoto H, Kishida M, Inoue A, Asahara T, Yasui W, Kikuchi A. Expression of Wnt-5a is correlated with aggressiveness of gastric cancer by stimulating cell migration and invasion. Cancer Res. 2006;66:10439-10448.  [PubMed]  [DOI]
94.  Gencer S, Şen G, Doğusoy G, Bellı AK, Paksoy M, Yazicioğlu MB. β-Catenin-independent noncanonical Wnt pathway might be induced in gastric cancers. Turk J Gastroenterol. 2010;21:224-230.  [PubMed]  [DOI]
95.  Perchiniak EM, Groden J. Mechanisms Regulating Microtubule Binding, DNA Replication, and Apoptosis are Controlled by the Intestinal Tumor Suppressor APC. Curr Colorectal Cancer Rep. 2011;7:145-151.  [PubMed]  [DOI]
96.  Fodde R, Kuipers J, Rosenberg C, Smits R, Kielman M, Gaspar C, van Es JH, Breukel C, Wiegant J, Giles RH. Mutations in the APC tumour suppressor gene cause chromosomal instability. Nat Cell Biol. 2001;3:433-438.  [PubMed]  [DOI]
97.  Park WS, Oh RR, Park JY, Lee SH, Shin MS, Kim YS, Kim SY, Lee HK, Kim PJ, Oh ST. Frequent somatic mutations of the beta-catenin gene in intestinal-type gastric cancer. Cancer Res. 1999;59:4257-4260.  [PubMed]  [DOI]
98.  Lee JH, Abraham SC, Kim HS, Nam JH, Choi C, Lee MC, Park CS, Juhng SW, Rashid A, Hamilton SR. Inverse relationship between APC gene mutation in gastric adenomas and development of adenocarcinoma. Am J Pathol. 2002;161:611-618.  [PubMed]  [DOI]
99.  Horii A, Nakatsuru S, Miyoshi Y, Ichii S, Nagase H, Kato Y, Yanagisawa A, Nakamura Y. The APC gene, responsible for familial adenomatous polyposis, is mutated in human gastric cancer. Cancer Res. 1992;52:3231-3233.  [PubMed]  [DOI]
100.  van Roy F, Berx G. The cell-cell adhesion molecule E-cadherin. Cell Mol Life Sci. 2008;65:3756-3788.  [PubMed]  [DOI]
101.  Leckband D, Sivasankar S. Mechanism of homophilic cadherin adhesion. Curr Opin Cell Biol. 2000;12:587-592.  [PubMed]  [DOI]
102.  Corso G, Marrelli D, Roviello F. Familial gastric cancer and germline mutations of E-cadherin. Ann Ital Chir. 2012;83:177-182.  [PubMed]  [DOI]
103.  Corso G, Seruca R, Roviello F. Gastric cancer carcinogenesis and tumor progression. Ann Ital Chir. 2012;83:172-176.  [PubMed]  [DOI]
104.  Carneiro P, Fernandes MS, Figueiredo J, Caldeira J, Carvalho J, Pinheiro H, Leite M, Melo S, Oliveira P, Simões-Correia J. E-cadherin dysfunction in gastric cancer--cellular consequences, clinical applications and open questions. FEBS Lett. 2012;586:2981-2989.  [PubMed]  [DOI]
105.  Leal M, Lima E, Silva P, Assumpção P, Calcagno D, Payão S, Burbano RR, Smith M. Promoter hypermethylation of CDH1, FHIT, MTAP and PLAGL1 in gastric adenocarcinoma in individuals from Northern Brazil. World J Gastroenterol. 2007;13:2568-2574.  [PubMed]  [DOI]
106.  Grady WM, Willis J, Guilford PJ, Dunbier AK, Toro TT, Lynch H, Wiesner G, Ferguson K, Eng C, Park JG. Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer. Nat Genet. 2000;26:16-17.  [PubMed]  [DOI]
107.  Taketo MM. Wnt signaling and gastrointestinal tumorigenesis in mouse models. Oncogene. 2006;25:7522-7530.  [PubMed]  [DOI]
108.  Kang GH, Lee S, Cho NY, Gandamihardja T, Long TI, Weisenberger DJ, Campan M, Laird PW. DNA methylation profiles of gastric carcinoma characterized by quantitative DNA methylation analysis. Lab Invest. 2008;88:161-170.  [PubMed]  [DOI]
109.  Nojima M, Suzuki H, Toyota M, Watanabe Y, Maruyama R, Sasaki S, Sasaki Y, Mita H, Nishikawa N, Yamaguchi K. Frequent epigenetic inactivation of SFRP genes and constitutive activation of Wnt signaling in gastric cancer. Oncogene. 2007;26:4699-4713.  [PubMed]  [DOI]
110.  Baud V, Karin M. Is NF-kappaB a good target for cancer therapy? Hopes and pitfalls. Nat Rev Drug Discov. 2009;8:33-40.  [PubMed]  [DOI]
111.  Pikarsky E, Porat RM, Stein I, Abramovitch R, Amit S, Kasem S, Gutkovich-Pyest E, Urieli-Shoval S, Galun E, Ben-Neriah Y. NF-kappaB functions as a tumour promoter in inflammation-associated cancer. Nature. 2004;431:461-466.  [PubMed]  [DOI]
112.  Thanos D, Maniatis T. NF-kappa B: a lesson in family values. Cell. 1995;80:529-532.  [PubMed]  [DOI]
113.  Nelson DE, Ihekwaba AE, Elliott M, Johnson JR, Gibney CA, Foreman BE, Nelson G, See V, Horton CA, Spiller DG. Oscillations in NF-kappaB signaling control the dynamics of gene expression. Science. 2004;306:704-708.  [PubMed]  [DOI]
114.  Xiao G, Rabson AB, Young W, Qing G, Qu Z. Alternative pathways of NF-kappaB activation: a double-edged sword in health and disease. Cytokine Growth Factor Rev. 2006;17:281-293.  [PubMed]  [DOI]
115.  Sasaki N, Morisaki T, Hashizume K, Yao T, Tsuneyoshi M, Noshiro H, Nakamura K, Yamanaka T, Uchiyama A, Tanaka M. Nuclear factor-kappaB p65 (RelA) transcription factor is constitutively activated in human gastric carcinoma tissue. Clin Cancer Res. 2001;7:4136-4142.  [PubMed]  [DOI]
116.  Yamanaka N, Sasaki N, Tasaki A, Nakashima H, Kubo M, Morisaki T, Noshiro H, Yao T, Tsuneyoshi M, Tanaka M. Nuclear factor-kappaB p65 is a prognostic indicator in gastric carcinoma. Anticancer Res. 2004;24:1071-1075.  [PubMed]  [DOI]
117.  Roberts AB. The ever-increasing complexity of TGF-beta signaling. Cytokine Growth Factor Rev. 2002;13:3-5.  [PubMed]  [DOI]
118.  Shi Y, Massagué J. Mechanisms of TGF-beta signaling from cell membrane to the nucleus. Cell. 2003;113:685-700.  [PubMed]  [DOI]
119.  Wu WK, Cho CH, Lee CW, Fan D, Wu K, Yu J, Sung JJ. Dysregulation of cellular signaling in gastric cancer. Cancer Lett. 2010;295:144-153.  [PubMed]  [DOI]
120.  Guo W, Dong Z, Guo Y, Kuang G, Yang Z, Shan B. Concordant repression and aberrant methylation of transforming growth factor-beta signaling pathway genes occurs early in gastric cardia adenocarcinoma. Mol Biol Rep. 2012;39:9453-9462.  [PubMed]  [DOI]
121.  Lai KW, Koh KX, Loh M, Tada K, Subramaniam MM, Lim XY, Vaithilingam A, Salto-Tellez M, Iacopetta B, Ito Y. MicroRNA-130b regulates the tumour suppressor RUNX3 in gastric cancer. Eur J Cancer. 2010;46:1456-1463.  [PubMed]  [DOI]
122.  Lu XX, Yu JL, Ying LS, Han J, Wang S, Yu QM, Wang XB, Fang XH, Ling ZQ. Stepwise cumulation of RUNX3 methylation mediated by Helicobacter pylori infection contributes to gastric carcinoma progression. Cancer. 2012;118:5507-5517.  [PubMed]  [DOI]
123.  Lee SH, Kim J, Kim WH, Lee YM. Hypoxic silencing of tumor suppressor RUNX3 by histone modification in gastric cancer cells. Oncogene. 2009;28:184-194.  [PubMed]  [DOI]
124.  Tan SH, Ida H, Lau QC, Goh BC, Chieng WS, Loh M, Ito Y. Detection of promoter hypermethylation in serum samples of cancer patients by methylation-specific polymerase chain reaction for tumour suppressor genes including RUNX3. Oncol Rep. 2007;18:1225-1230.  [PubMed]  [DOI]
125.  Williams CS, Mann M, DuBois RN. The role of cyclooxygenases in inflammation, cancer, and development. Oncogene. 1999;18:7908-7916.  [PubMed]  [DOI]
126.  Xue YW, Zhang QF, Zhu ZB, Wang Q, Fu SB. Expression of cyclooxygenase-2 and clinicopathologic features in human gastric adenocarcinoma. World J Gastroenterol. 2003;9:250-253.  [PubMed]  [DOI]
127.  Shi H, Xu JM, Hu NZ, Xie HJ. Prognostic significance of expression of cyclooxygenase-2 and vascular endothelial growth factor in human gastric carcinoma. World J Gastroenterol. 2003;9:1421-1426.  [PubMed]  [DOI]
128.  Oshima H, Oguma K, Du YC, Oshima M. Prostaglandin E2, Wnt, and BMP in gastric tumor mouse models. Cancer Sci. 2009;100:1779-1785.  [PubMed]  [DOI]
129.  Murakami M, Naraba H, Tanioka T, Semmyo N, Nakatani Y, Kojima F, Ikeda T, Fueki M, Ueno A, Oh S. Regulation of prostaglandin E2 biosynthesis by inducible membrane-associated prostaglandin E2 synthase that acts in concert with cyclooxygenase-2. J Biol Chem. 2000;275:32783-32792.  [PubMed]  [DOI]
130.  Gross ND, Boyle JO, Morrow JD, Williams MK, Moskowitz CS, Subbaramaiah K, Dannenberg AJ, Duffield-Lillico AJ. Levels of prostaglandin E metabolite, the major urinary metabolite of prostaglandin E2, are increased in smokers. Clin Cancer Res. 2005;11:6087-6093.  [PubMed]  [DOI]
131.  Huang RY, Chen GG. Cigarette smoking, cyclooxygenase-2 pathway and cancer. Biochim Biophys Acta. 2011;1815:158-169.  [PubMed]  [DOI]
132.  Cito L, Pentimalli F, Forte I, Mattioli E, Giordano A. Rb family proteins in gastric cancer (review). Oncol Rep. 2010;24:1411-1418.  [PubMed]  [DOI]
133.  Tian Y, Wan H, Tan G. Cell cycle-related kinase in carcinogenesis. Oncol Lett. 2012;4:601-606.  [PubMed]  [DOI]
134.  Lukas J, Parry D, Aagaard L, Mann DJ, Bartkova J, Strauss M, Peters G, Bartek J. Retinoblastoma-protein-dependent cell-cycle inhibition by the tumour suppressor p16. Nature. 1995;375:503-506.  [PubMed]  [DOI]
135.  Weinberg RA. The retinoblastoma protein and cell cycle control. Cell. 1995;81:323-330.  [PubMed]  [DOI]
136.  He XS, Su Q, Chen ZC, He XT, Long ZF, Ling H, Zhang LR. Expression, deletion [was deleton] and mutation of p16 gene in human gastric cancer. World J Gastroenterol. 2001;7:515-521.  [PubMed]  [DOI]
137.  Mitsuno M, Kitajima Y, Ide T, Ohtaka K, Tanaka M, Satoh S, Miyazaki K. Aberrant methylation of p16 predicts candidates for 5-fluorouracil-based adjuvant therapy in gastric cancer patients. J Gastroenterol. 2007;42:866-873.  [PubMed]  [DOI]
138.  Ikoma H, Ichikawa D, Koike H, Ikoma D, Tani N, Okamoto K, Ochiai T, Ueda Y, Otsuji E, Yamagishi H. Correlation between serum DNA methylation and prognosis in gastric cancer patients. Anticancer Res. 2006;26:2313-2316.  [PubMed]  [DOI]
139.  Lee TL, Leung WK, Chan MW, Ng EK, Tong JH, Lo KW, Chung SC, Sung JJ, To KF. Detection of gene promoter hypermethylation in the tumor and serum of patients with gastric carcinoma. Clin Cancer Res. 2002;8:1761-1766.  [PubMed]  [DOI]
140.  Hudler P. Genetic aspects of gastric cancer instability. ScientificWorldJournal. 2012;2012:761909.  [PubMed]  [DOI]
141.  Buffart TE, Louw M, van Grieken NC, Tijssen M, Carvalho B, Ylstra B, Grabsch H, Mulder CJ, van de Velde CJ, van der Merwe SW. Gastric cancers of Western European and African patients show different patterns of genomic instability. BMC Med Genomics. 2011;4:7.  [PubMed]  [DOI]
142.  Tao J, Deng NT, Ramnarayanan K, Huang B, Oh HK, Leong SH, Lim SS, Tan IB, Ooi CH, Wu J. CD44-SLC1A2 gene fusions in gastric cancer. Sci Transl Med. 2011;3:77ra30.  [PubMed]  [DOI]
143.  Jones PA, Baylin SB. The epigenomics of cancer. Cell. 2007;128:683-692.  [PubMed]  [DOI]
144.  Ellis L, Atadja PW, Johnstone RW. Epigenetics in cancer: targeting chromatin modifications. Mol Cancer Ther. 2009;8:1409-1420.  [PubMed]  [DOI]
145.  Esteller M. DNA methylation and cancer therapy: new developments and expectations. Curr Opin Oncol. 2005;17:55-60.  [PubMed]  [DOI]
146.  Lu J, Getz G, Miska EA, Alvarez-Saavedra E, Lamb J, Peck D, Sweet-Cordero A, Ebert BL, Mak RH, Ferrando AA. MicroRNA expression profiles classify human cancers. Nature. 2005;435:834-838.  [PubMed]  [DOI]
147.  Luo H, Zhang H, Zhang Z, Zhang X, Ning B, Guo J, Nie N, Liu B, Wu X. Down-regulated miR-9 and miR-433 in human gastric carcinoma. J Exp Clin Cancer Res. 2009;28:82.  [PubMed]  [DOI]
148.  Kanwal R, Gupta S. Epigenetic modifications in cancer. Clin Genet. 2012;81:303-311.  [PubMed]  [DOI]
149.  Sharma S, Kelly TK, Jones PA. Epigenetics in cancer. Carcinogenesis. 2010;31:27-36.  [PubMed]  [DOI]
150.  Park YS, Jin MY, Kim YJ, Yook JH, Kim BS, Jang SJ. The global histone modification pattern correlates with cancer recurrence and overall survival in gastric adenocarcinoma. Ann Surg Oncol. 2008;15:1968-1976.  [PubMed]  [DOI]
151.  Bang YJ, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, Lordick F, Ohtsu A, Omuro Y, Satoh T. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376:687-697.  [PubMed]  [DOI]
152.  Park SC, Chun HJ. Chemotherapy for advanced gastric cancer: review and update of current practices. Gut Liver. 2013;7:385-393.  [PubMed]  [DOI]
153.  Maehara Y, Kabashima A, Koga T, Tokunaga E, Takeuchi H, Kakeji Y, Sugimachi K. Vascular invasion and potential for tumor angiogenesis and metastasis in gastric carcinoma. Surgery. 2000;128:408-416.  [PubMed]  [DOI]
154.  Yoshikawa T, Tsuburaya A, Kobayashi O, Sairenji M, Motohashi H, Yanoma S, Noguchi Y. Plasma concentrations of VEGF and bFGF in patients with gastric carcinoma. Cancer Lett. 2000;153:7-12.  [PubMed]  [DOI]
155.  Ohtsu A, Shah MA, Van Cutsem E, Rha SY, Sawaki A, Park SR, Lim HY, Yamada Y, Wu J, Langer B. Bevacizumab in combination with chemotherapy as first-line therapy in advanced gastric cancer: a randomized, double-blind, placebo-controlled phase III study. J Clin Oncol. 2011;29:3968-3976.  [PubMed]  [DOI]
156.  Li J, Qin S, Xu J, Guo W, Xiong J, Bai Y, Sun G, Yang Y, Wang L, Xu N. Apatinib for chemotherapy-refractory advanced metastatic gastric cancer: results from a randomized, placebo-controlled, parallel-arm, phase II trial. J Clin Oncol. 2013;31:3219-3225.  [PubMed]  [DOI]
157.  Liu L, Wu N, Li J. Novel targeted agents for gastric cancer. J Hematol Oncol. 2012;5:31.  [PubMed]  [DOI]
158.  Lordick F, Kang YK, Chung HC, Salman P, Oh SC, Bodoky G, Kurteva G, Volovat C, Moiseyenko VM, Gorbunova V. Capecitabine and cisplatin with or without cetuximab for patients with previously untreated advanced gastric cancer (EXPAND): a randomised, open-label phase 3 trial. Lancet Oncol. 2013;14:490-499.  [PubMed]  [DOI]
159.  Gadgeel SM, Lew DL, Synold TW, LoRusso P, Chung V, Christensen SD, Smith DC, Kingsbury L, Hoering A, Kurzrock R. Phase I study evaluating the combination of lapatinib (a Her2/Neu and EGFR inhibitor) and everolimus (an mTOR inhibitor) in patients with advanced cancers: South West Oncology Group (SWOG) Study S0528. Cancer Chemother Pharmacol. 2013;72:1089-1096.  [PubMed]  [DOI]
160.  Iqbal S, Goldman B, Fenoglio-Preiser CM, Lenz HJ, Zhang W, Danenberg KD, Shibata SI, Blanke CD. Southwest Oncology Group study S0413: a phase II trial of lapatinib (GW572016) as first-line therapy in patients with advanced or metastatic gastric cancer. Ann Oncol. 2011;22:2610-2615.  [PubMed]  [DOI]
161.  Wong H, Yau T. Targeted therapy in the management of advanced gastric cancer: are we making progress in the era of personalized medicine? Oncologist. 2012;17:346-358.  [PubMed]  [DOI]
162.  Ohtsu A, Ajani JA, Bai YX, Bang YJ, Chung HC, Pan HM, Sahmoud T, Shen L, Yeh KH, Chin K. Everolimus for previously treated advanced gastric cancer: results of the randomized, double-blind, phase III GRANITE-1 study. J Clin Oncol. 2013;31:3935-3943.  [PubMed]  [DOI]
163.  Lim T, Lee J, Lee DJ, Lee HY, Han B, Baek KK, Ahn HK, Lee SJ, Park SH, Park JO. Phase I trial of capecitabine plus everolimus (RAD001) in patients with previously treated metastatic gastric cancer. Cancer Chemother Pharmacol. 2011;68:255-262.  [PubMed]  [DOI]
164.  Bramhall SR, Hallissey MT, Whiting J, Scholefield J, Tierney G, Stuart RC, Hawkins RE, McCulloch P, Maughan T, Brown PD. Marimastat as maintenance therapy for patients with advanced gastric cancer: a randomised trial. Br J Cancer. 2002;86:1864-1870.  [PubMed]  [DOI]
165.  Ku GY, Ilson DH, Schwartz LH, Capanu M, O’Reilly E, Shah MA, Kelsen DP, Schwartz GK. Phase II trial of sequential paclitaxel and 1 h infusion of bryostatin-1 in patients with advanced esophageal cancer. Cancer Chemother Pharmacol. 2008;62:875-880.  [PubMed]  [DOI]
166.  Jones PA, Taylor SM. Cellular differentiation, cytidine analogs and DNA methylation. Cell. 1980;20:85-93.  [PubMed]  [DOI]
167.  Kuendgen A, Lübbert M. Current status of epigenetic treatment in myelodysplastic syndromes. Ann Hematol. 2008;87:601-611.  [PubMed]  [DOI]
168.  Piekarz RL, Bates SE. Epigenetic modifiers: basic understanding and clinical development. Clin Cancer Res. 2009;15:3918-3926.  [PubMed]  [DOI]
169.  Weiss AJ, Metter GE, Nealon TF, Keanan JP, Ramirez G, Swaiminathan A, Fletcher WS, Moss SE, Manthei RW. Phase II study of 5-azacytidine in solid tumors. Cancer Treat Rep. 1977;61:55-58.  [PubMed]  [DOI]
170.  Yoo CB, Jeong S, Egger G, Liang G, Phiasivongsa P, Tang C, Redkar S, Jones PA. Delivery of 5-aza-2’-deoxycytidine to cells using oligodeoxynucleotides. Cancer Res. 2007;67:6400-6408.  [PubMed]  [DOI]
171.  Chuang JC, Warner SL, Vollmer D, Vankayalapati H, Redkar S, Bearss DJ, Qiu X, Yoo CB, Jones PA. S110, a 5-Aza-2’-deoxycytidine-containing dinucleotide, is an effective DNA methylation inhibitor in vivo and can reduce tumor growth. Mol Cancer Ther. 2010;9:1443-1450.  [PubMed]  [DOI]
172.  Yang CS, Wang X, Lu G, Picinich SC. Cancer prevention by tea: animal studies, molecular mechanisms and human relevance. Nat Rev Cancer. 2009;9:429-439.  [PubMed]  [DOI]
173.  Lee WJ, Shim JY, Zhu BT. Mechanisms for the inhibition of DNA methyltransferases by tea catechins and bioflavonoids. Mol Pharmacol. 2005;68:1018-1030.  [PubMed]  [DOI]
174.  Cornacchia E, Golbus J, Maybaum J, Strahler J, Hanash S, Richardson B. Hydralazine and procainamide inhibit T cell DNA methylation and induce autoreactivity. J Immunol. 1988;140:2197-2200.  [PubMed]  [DOI]
175.  Park JH, Jung Y, Kim TY, Kim SG, Jong HS, Lee JW, Kim DK, Lee JS, Kim NK, Kim TY. Class I histone deacetylase-selective novel synthetic inhibitors potently inhibit human tumor proliferation. Clin Cancer Res. 2004;10:5271-5281.  [PubMed]  [DOI]
176.  Duvic M, Vu J. Vorinostat in cutaneous T-cell lymphoma. Drugs Today (Barc). 2007;43:585-599.  [PubMed]  [DOI]
177.  Claerhout S, Lim JY, Choi W, Park YY, Kim K, Kim SB, Lee JS, Mills GB, Cho JY. Gene expression signature analysis identifies vorinostat as a candidate therapy for gastric cancer. PLoS One. 2011;6:e24662.  [PubMed]  [DOI]
178.  Yoo C, Ryu MH, Na YS, Ryoo BY, Lee CW, Maeng J, Kim SY, Koo DH, Park I, Kang YK. Phase I and pharmacodynamic study of vorinostat combined with capecitabine and cisplatin as first-line chemotherapy in advanced gastric cancer. Invest New Drugs. 2014;32:271-278.  [PubMed]  [DOI]
179.  Kingsmore SF, Saunders CJ. Deep sequencing of patient genomes for disease diagnosis: when will it become routine? Sci Transl Med. 2011;3:87ps23.  [PubMed]  [DOI]
180.  Cooke S, Campbell P. Circulating DNA and next-generation sequencing. Recent Results Cancer Res. 2012;195:143-149.  [PubMed]  [DOI]
181.  Shi Y, Zhou Y. The role of surgery in the treatment of gastric cancer. J Surg Oncol. 2010;101:687-692.  [PubMed]  [DOI]
182.  Lee HK, Lee HS, Yang HK, Kim WH, Lee KU, Choe KJ, Kim JP. Prognostic significance of Bcl-2 and p53 expression in gastric cancer. Int J Colorectal Dis. 2003;18:518-525.  [PubMed]  [DOI]
183.  Guilford P, Hopkins J, Harraway J, McLeod M, McLeod N, Harawira P, Taite H, Scoular R, Miller A, Reeve AE. E-cadherin germline mutations in familial gastric cancer. Nature. 1998;392:402-405.  [PubMed]  [DOI]
184.  Corso G, Carvalho J, Marrelli D, Vindigni C, Carvalho B, Seruca R, Roviello F, Oliveira C. Somatic mutations and deletions of the E-cadherin gene predict poor survival of patients with gastric cancer. J Clin Oncol. 2013;31:868-875.  [PubMed]  [DOI]
185.  Li JH, Shi XZ, Lü S, Liu M, Cui WM, Liu LN, Jiang J, Xu GW. HMLH1 gene mutation in gastric cancer patients and their kindred. World J Gastroenterol. 2005;11:3144-3146.  [PubMed]  [DOI]
186.  Günther T, Schneider-Stock R, Pross M, Manger T, Malfertheiner P, Lippert H, Roessner A. Alterations of the p16/MTS1-tumor suppressor gene in gastric cancer. Pathol Res Pract. 1998;194:809-813.  [PubMed]  [DOI]
187.  Wu MS, Shun CT, Sheu JC, Wang HP, Wang JT, Lee WJ, Chen CJ, Wang TH, Lin JT. Overexpression of mutant p53 and c-erbB-2 proteins and mutations of the p15 and p16 genes in human gastric carcinoma: with respect to histological subtypes and stages. J Gastroenterol Hepatol. 1998;13:305-310.  [PubMed]  [DOI]
188.  Tokumaru Y, Nomoto S, Jerónimo C, Henrique R, Harden S, Trink B, Sidransky D. Biallelic inactivation of the RIZ1 gene in human gastric cancer. Oncogene. 2003;22:6954-6958.  [PubMed]  [DOI]
189.  Piao Z, Fang W, Malkhosyan S, Kim H, Horii A, Perucho M, Huang S. Frequent frameshift mutations of RIZ in sporadic gastrointestinal and endometrial carcinomas with microsatellite instability. Cancer Res. 2000;60:4701-4704.  [PubMed]  [DOI]
190.  Pan KF, Lu YY, Liu WG, Zhang L, You WC. Detection of frameshift mutations of RIZ in gastric cancers with microsatellite instability. World J Gastroenterol. 2004;10:2719-2722.  [PubMed]  [DOI]
191.  Menoyo A, Alazzouzi H, Espín E, Armengol M, Yamamoto H, Schwartz S. Somatic mutations in the DNA damage-response genes ATR and CHK1 in sporadic stomach tumors with microsatellite instability. Cancer Res. 2001;61:7727-7730.  [PubMed]  [DOI]
192.  Ohmiya N, Matsumoto S, Yamamoto H, Baranovskaya S, Malkhosyan SR, Perucho M. Germline and somatic mutations in hMSH6 and hMSH3 in gastrointestinal cancers of the microsatellite mutator phenotype. Gene. 2001;272:301-313.  [PubMed]  [DOI]
193.  Tate G, Suzuki T, Nemoto H, Kishimoto K, Hibi K, Mitsuya T. Allelic loss of the PTEN gene and mutation of the TP53 gene in choriocarcinoma arising from gastric adenocarcinoma: analysis of loss of heterozygosity in two male patients with extragonadal choriocarcinoma. Cancer Genet Cytogenet. 2009;193:104-108.  [PubMed]  [DOI]
194.  Oki E, Kakeji Y, Baba H, Tokunaga E, Nakamura T, Ueda N, Futatsugi M, Yamamoto M, Ikebe M, Maehara Y. Impact of loss of heterozygosity of encoding phosphate and tensin homolog on the prognosis of gastric cancer. J Gastroenterol Hepatol. 2006;21:814-818.  [PubMed]  [DOI]
195.  Ayhan A, Yasui W, Yokozaki H, Seto M, Ueda R, Tahara E. Loss of heterozygosity at the bcl-2 gene locus and expression of bcl-2 in human gastric and colorectal carcinomas. Jpn J Cancer Res. 1994;85:584-591.  [PubMed]  [DOI]
196.  Candusso ME, Luinetti O, Villani L, Alberizzi P, Klersy C, Fiocca R, Ranzani GN, Solcia E. Loss of heterozygosity at 18q21 region in gastric cancer involves a number of cancer-related genes and correlates with stage and histology, but lacks independent prognostic value. J Pathol. 2002;197:44-50.  [PubMed]  [DOI]
197.  Lee KE, Lee HJ, Kim YH, Yu HJ, Yang HK, Kim WH, Lee KU, Choe KJ, Kim JP. Prognostic significance of p53, nm23, PCNA and c-erbB-2 in gastric cancer. Jpn J Clin Oncol. 2003;33:173-179.  [PubMed]  [DOI]
198.  Ouatas T, Salerno M, Palmieri D, Steeg PS. Basic and translational advances in cancer metastasis: Nm23. J Bioenerg Biomembr. 2003;35:73-79.  [PubMed]  [DOI]
199.  Mönig SP, Nolden B, Lübke T, Pohl A, Grass G, Schneider PM, Dienes HP, Hölscher AH, Baldus SE. Clinical significance of nm23 gene expression in gastric cancer. Anticancer Res. 2007;27:3029-3033.  [PubMed]  [DOI]
200.  Xiao YP, Wu DY, Xu L, Xin Y. Loss of heterozygosity and microsatellite instabilities of fragile histidine triad gene in gastric carcinoma. World J Gastroenterol. 2006;12:3766-3769.  [PubMed]  [DOI]
201.  Zhang ZZ, Liu YJ, Yin XL, Zhan P, Gu Y, Ni XZ. Loss of BRCA1 expression leads to worse survival in patients with gastric carcinoma. World J Gastroenterol. 2013;19:1968-1974.  [PubMed]  [DOI]
202.  Chen W, Wang J, Li X, Li J, Zhou L, Qiu T, Zhang M, Liu P. Prognostic significance of BRCA1 expression in gastric cancer. Med Oncol. 2013;30:423.  [PubMed]  [DOI]
203.  Kim IJ, Park JH, Kang HC, Shin Y, Park HW, Park HR, Ku JL, Lim SB, Park JG. Mutational analysis of BRAF and K-ras in gastric cancers: absence of BRAF mutations in gastric cancers. Hum Genet. 2003;114:118-120.  [PubMed]  [DOI]
204.  Warneke VS, Behrens HM, Haag J, Balschun K, Böger C, Becker T, Ebert MP, Lordick F, Röcken C. Prognostic and putative predictive biomarkers of gastric cancer for personalized medicine. Diagn Mol Pathol. 2013;22:127-137.  [PubMed]  [DOI]
205.  Oh HS, Eom DW, Kang GH, Ahn YC, Lee SJ, Kim JH, Jang HJ, Kim EJ, Oh KH, Ahn HJ. Prognostic implications of EGFR and HER-2 alteration assessed by immunohistochemistry and silver in situ hybridization in gastric cancer patients following curative resection. Gastric Cancer. 2014;17:402-411.  [PubMed]  [DOI]
206.  Huang TJ, Wang JY, Lin SR, Lian ST, Hsieh JS. Overexpression of the c-met protooncogene in human gastric carcinoma--correlation to clinical features. Acta Oncol. 2001;40:638-643.  [PubMed]  [DOI]
207.  Toyokawa T, Yashiro M, Hirakawa K. Co-expression of keratinocyte growth factor and K-sam is an independent prognostic factor in gastric carcinoma. Oncol Rep. 2009;21:875-880.  [PubMed]  [DOI]
208.  Yasui W, Oue N, Aung PP, Matsumura S, Shutoh M, Nakayama H. Molecular-pathological prognostic factors of gastric cancer: a review. Gastric Cancer. 2005;8:86-94.  [PubMed]  [DOI]
209.  Yamaguchi A, Goi T, Yu J, Hirono Y, Ishida M, Iida A, Kimura T, Takeuchi K, Katayama K, Hirose K. Expression of CD44v6 in advanced gastric cancer and its relationship to hematogenous metastasis and long-term prognosis. J Surg Oncol. 2002;79:230-235.  [PubMed]  [DOI]
210.  Bessette DC, Qiu D, Pallen CJ. PRL PTPs: mediators and markers of cancer progression. Cancer Metastasis Rev. 2008;27:231-252.  [PubMed]  [DOI]
211.  Dai N, Lu AP, Shou CC, Li JY. Expression of phosphatase regenerating liver 3 is an independent prognostic indicator for gastric cancer. World J Gastroenterol. 2009;15:1499-1505.  [PubMed]  [DOI]
212.  Sanz-Ortega J, Steinberg SM, Moro E, Saez M, Lopez JA, Sierra E, Sanz-Esponera J, Merino MJ. Comparative study of tumor angiogenesis and immunohistochemistry for p53, c-ErbB2, c-myc and EGFr as prognostic factors in gastric cancer. Histol Histopathol. 2000;15:455-462.  [PubMed]  [DOI]
213.  Han S, Kim HY, Park K, Cho HJ, Lee MS, Kim HJ, Kim YD. c-Myc expression is related with cell proliferation and associated with poor clinical outcome in human gastric cancer. J Korean Med Sci. 1999;14:526-530.  [PubMed]  [DOI]
214.  Liu SZ, Zhang F, Chang YX, Ma J, Li X, Li XH, Fan JH, Duan GC, Sun XB. Prognostic impact of cyclin D1, cyclin E and P53 on gastroenteropancreatic neuroendocrine tumours. Asian Pac J Cancer Prev. 2013;14:419-422.  [PubMed]  [DOI]
215.  Bernal C, Vargas M, Ossandón F, Santibáñez E, Urrutia J, Luengo V, Zavala LF, Backhouse C, Palma M, Argandoña J. DNA methylation profile in diffuse type gastric cancer: evidence for hypermethylation of the BRCA1 promoter region in early-onset gastric carcinogenesis. Biol Res. 2008;41:303-315.  [PubMed]  [DOI]
216.  Leung WK, To KF, Chu ES, Chan MW, Bai AH, Ng EK, Chan FK, Sung JJ. Potential diagnostic and prognostic values of detecting promoter hypermethylation in the serum of patients with gastric cancer. Br J Cancer. 2005;92:2190-2194.  [PubMed]  [DOI]
217.  Graziano F, Arduini F, Ruzzo A, Bearzi I, Humar B, More H, Silva R, Muretto P, Guilford P, Testa E. Prognostic analysis of E-cadherin gene promoter hypermethylation in patients with surgically resected, node-positive, diffuse gastric cancer. Clin Cancer Res. 2004;10:2784-2789.  [PubMed]  [DOI]
218.  Hu SL, Kong XY, Cheng ZD, Sun YB, Shen G, Xu WP, Wu L, Xu XC, Jiang XD, Huang DB. Promoter methylation of p16, Runx3, DAPK and CHFR genes is frequent in gastric carcinoma. Tumori. 2010;96:726-733.  [PubMed]  [DOI]
219.  Chen HY, Zhu BH, Zhang CH, Yang DJ, Peng JJ, Chen JH, Liu FK, He YL. High CpG island methylator phenotype is associated with lymph node metastasis and prognosis in gastric cancer. Cancer Sci. 2012;103:73-79.  [PubMed]  [DOI]
220.  Hu SL, Huang DB, Sun YB, Wu L, Xu WP, Yin S, Chen J, Jiang XD, Shen G. Pathobiologic implications of methylation and expression status of Runx3 and CHFR genes in gastric cancer. Med Oncol. 2011;28:447-454.  [PubMed]  [DOI]
221.  Leung WK, Yu J, Ng EK, To KF, Ma PK, Lee TL, Go MY, Chung SC, Sung JJ. Concurrent hypermethylation of multiple tumor-related genes in gastric carcinoma and adjacent normal tissues. Cancer. 2001;91:2294-2301.  [PubMed]  [DOI]
222.  Takada H, Imoto I, Tsuda H, Nakanishi Y, Ichikura T, Mochizuki H, Mitsufuji S, Hosoda F, Hirohashi S, Ohki M. ADAM23, a possible tumor suppressor gene, is frequently silenced in gastric cancers by homozygous deletion or aberrant promoter hypermethylation. Oncogene. 2005;24:8051-8060.  [PubMed]  [DOI]
223.  Watanabe Y, Kim HS, Castoro RJ, Chung W, Estecio MR, Kondo K, Guo Y, Ahmed SS, Toyota M, Itoh F. Sensitive and specific detection of early gastric cancer with DNA methylation analysis of gastric washes. Gastroenterology. 2009;136:2149-2158.  [PubMed]  [DOI]
224.  Shu XS, Geng H, Li L, Ying J, Ma C, Wang Y, Poon FF, Wang X, Ying Y, Yeo W. The epigenetic modifier PRDM5 functions as a tumor suppressor through modulating WNT/β-catenin signaling and is frequently silenced in multiple tumors. PLoS One. 2011;6:e27346.  [PubMed]  [DOI]
225.  Chang X, Li Z, Ma J, Deng P, Zhang S, Zhi Y, Chen J, Dai D. DNA methylation of NDRG2 in gastric cancer and its clinical significance. Dig Dis Sci. 2013;58:715-723.  [PubMed]  [DOI]
226.  Murai M, Toyota M, Suzuki H, Satoh A, Sasaki Y, Akino K, Ueno M, Takahashi F, Kusano M, Mita H. Aberrant methylation and silencing of the BNIP3 gene in colorectal and gastric cancer. Clin Cancer Res. 2005;11:1021-1027.  [PubMed]  [DOI]
227.  Sugita H, Iida S, Inokuchi M, Kato K, Ishiguro M, Ishikawa T, Takagi Y, Enjoji M, Yamada H, Uetake H. Methylation of BNIP3 and DAPK indicates lower response to chemotherapy and poor prognosis in gastric cancer. Oncol Rep. 2011;25:513-518.  [PubMed]  [DOI]
228.  Kato K, Iida S, Uetake H, Takagi Y, Yamashita T, Inokuchi M, Yamada H, Kojima K, Sugihara K. Methylated TMS1 and DAPK genes predict prognosis and response to chemotherapy in gastric cancer. Int J Cancer. 2008;122:603-608.  [PubMed]  [DOI]
229.  Kang GH, Lee S, Kim WH, Lee HW, Kim JC, Rhyu MG, Ro JY. Epstein-barr virus-positive gastric carcinoma demonstrates frequent aberrant methylation of multiple genes and constitutes CpG island methylator phenotype-positive gastric carcinoma. Am J Pathol. 2002;160:787-794.  [PubMed]  [DOI]
230.  Wang S, Cheng Y, Du W, Lu L, Zhou L, Wang H, Kang W, Li X, Tao Q, Sung JJ. Zinc-finger protein 545 is a novel tumour suppressor that acts by inhibiting ribosomal RNA transcription in gastric cancer. Gut. 2013;62:833-841.  [PubMed]  [DOI]
231.  Kinoshita T, Nomoto S, Kodera Y, Koike M, Fujiwara M, Nakao A. Decreased expression and aberrant hypermethylation of the SFRP genes in human gastric cancer. Hepatogastroenterology. 2011;58:1051-1056.  [PubMed]  [DOI]
232.  Ueda T, Volinia S, Okumura H, Shimizu M, Taccioli C, Rossi S, Alder H, Liu CG, Oue N, Yasui W. Relation between microRNA expression and progression and prognosis of gastric cancer: a microRNA expression analysis. Lancet Oncol. 2010;11:136-146.  [PubMed]  [DOI]
233.  Liu R, Zhang C, Hu Z, Li G, Wang C, Yang C, Huang D, Chen X, Zhang H, Zhuang R. A five-microRNA signature identified from genome-wide serum microRNA expression profiling serves as a fingerprint for gastric cancer diagnosis. Eur J Cancer. 2011;47:784-791.  [PubMed]  [DOI]
234.  Ji Q, Hao X, Meng Y, Zhang M, Desano J, Fan D, Xu L. Restoration of tumor suppressor miR-34 inhibits human p53-mutant gastric cancer tumorspheres. BMC Cancer. 2008;8:266.  [PubMed]  [DOI]
235.  Wan HY, Guo LM, Liu T, Liu M, Li X, Tang H. Regulation of the transcription factor NF-kappaB1 by microRNA-9 in human gastric adenocarcinoma. Mol Cancer. 2010;9:16.  [PubMed]  [DOI]
236.  Tsukamoto Y, Nakada C, Noguchi T, Tanigawa M, Nguyen LT, Uchida T, Hijiya N, Matsuura K, Fujioka T, Seto M. MicroRNA-375 is downregulated in gastric carcinomas and regulates cell survival by targeting PDK1 and 14-3-3zeta. Cancer Res. 2010;70:2339-2349.  [PubMed]  [DOI]