Genomic and epigenetic profiles of gastric cancer: Potential diagnostic and therapeutic applications

Knowledge about the molecular profile of tumor tissues is crucial to effectively target cancer cells, because cancer is a genetic disease that involves multiple genetic and epigenetic alterations. Prominent aberrations include gene mutation, amplification, loss or deletion, as well as epigenetic alterations of the promoter DNA CpG islands. All of these aberrations can lead to dynamic changes in cancer cells, as demonstrated using resected tumor samples. There are two distinct pathological types of gastric cancer: the diffuse type and the intestinal type of gastric cancer. Diffuse type gastric cancer harbors aberrations in the FGFR2/ErbB3/PI3 kinase pathway, while intestinal type gastric cancer has an activated ErbB2 oncogenic pathway. On the other hand, the prometastatic oncogene PRL-3 is commonly activated in both types of advanced gastric cancer, and might represent a relevant therapeutic target for gastric cancer with lymph node metastasis or peritoneal dissemination. Numerous tumor suppressor genes can inhibit such oncogenic pathways, and DNA methylation in CpG islands of gene promoters is frequently found to suppress the expression of such genes in gastric cancer. Helicobacter pylori infection in normal gastric mucosa may cause p53 mutations through activation of activation-induced cytidine deaminase (AID) and/or promoter DNA methylation of E-cadherin, an initiator of gastric cancer, and such abnormalities are found even in the precancerous stage of gastric carcinogenesis. In addition, it has been demonstrated that there are highly relevant methylation genes involved in cancer (HRMGs) that exhibit very frequent cancer-specific methylation in gastric cancer. Such genes are potential targets for cancer treatment, and might also serve as biomarkers of gastric cancer for either the diagnosis or for determining the prognosis or the response to treatment.

[1]  L. Cantley,et al.  Oncogenes and signal transduction , 1991, Cell.

[2]  Kwang-Huei Lin,et al.  Glutamate receptor, ionotropic, kainate 2 silencing by DNA hypermethylation possesses tumor suppressor function in gastric cancer , 2010, International journal of cancer.

[3]  Carlos Barrientos,et al.  Reprimo as a Potential Biomarker for Early Detection in Gastric Cancer , 2008, Clinical Cancer Research.

[4]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[5]  M. Rugge,et al.  p53 alteration in gastric precancerous lesions. , 1994, The American journal of pathology.

[6]  K. Yanagihara,et al.  High PRL-3 expression in human gastric cancer is a marker of metastasis and grades of malignancies: an in situ hybridization study , 2007, Virchows Archiv.

[7]  L. Cantley,et al.  The erbB3 gene product is a receptor for heregulin. , 1994, The Journal of biological chemistry.

[8]  Jun Yu,et al.  Promoter hypermethylation of tumor‐related genes in gastric intestinal metaplasia of patients with and without gastric cancer , 2002, International journal of cancer.

[9]  J. Yokota,et al.  Isolation of an Amplified DNA Sequence in Stomach Cancer , 1990, Japanese journal of cancer research : Gann.

[10]  Jian-ming Li,et al.  PRL-3 promotes epithelial mesenchymal transition by regulating cadherin directly , 2009, Cancer biology & therapy.

[11]  A. Nashimoto,et al.  D2 lymphadenectomy alone or with para-aortic nodal dissection for gastric cancer. , 2008, The New England journal of medicine.

[12]  Suna Wang,et al.  Hypermethylation of HPP1 is associated with hMLH1 hypermethylation in gastric adenocarcinomas. , 2002, Cancer research.

[13]  David Sidransky,et al.  DNA methylation markers in colorectal cancer , 2010, Cancer and Metastasis Reviews.

[14]  C. Moon,et al.  The N-methyl-D-aspartate receptor type 2A is frequently methylated in human colorectal carcinoma and suppresses cell growth , 2008, Oncogene.

[15]  Jung Weon Lee,et al.  Aberrant methylation of integrin alpha4 gene in human gastric cancer cells. , 2004, Oncogene.

[16]  H. Grabsch,et al.  MAL promoter hypermethylation as a novel prognostic marker in gastric cancer , 2008, British Journal of Cancer.

[17]  C. Shou,et al.  Identification of integrin alpha1 as an interacting protein of protein tyrosine phosphatase PRL-3. , 2006, Biochemical and biophysical research communications.

[18]  K. Miyazaki,et al.  Helicobacter pylori infection is an independent risk factor for Runx3 methylation in gastric cancer. , 2008, Oncology reports.

[19]  A. Loriot,et al.  DNA hypomethylation in cancer: Epigenetic scars of a neoplastic journey , 2010, Epigenetics.

[20]  J. Isola,et al.  Amplification of HER-2 in gastric carcinoma: association with Topoisomerase IIalpha gene amplification, intestinal type, poor prognosis and sensitivity to trastuzumab. , 2005, Annals of oncology : official journal of the European Society for Medical Oncology.

[21]  Jia-Yun Chen,et al.  TGF-beta induces apoptosis through Smad-mediated expression of DAP-kinase. , 2002, Nature cell biology.

[22]  M. Yashiro,et al.  Synergistic antitumor effects of FGFR2 inhibitor with 5‐fluorouracil on scirrhous gastric carcinoma , 2009, International journal of cancer.

[23]  Yasuo Ohashi,et al.  Adjuvant chemotherapy for gastric cancer with S-1, an oral fluoropyrimidine. , 2007, The New England journal of medicine.

[24]  S. Cai,et al.  Association of Tyrosine PRL-3 Phosphatase Protein Expression with Peritoneal Metastasis of Gastric Carcinoma and Prognosis , 2007, Surgery Today.

[25]  J. Ferlay,et al.  Global Cancer Statistics, 2002 , 2005, CA: a cancer journal for clinicians.

[26]  S. Chi,et al.  Frequent epigenetic inactivation of RASSF1A by aberrant promoter hypermethylation in human gastric adenocarcinoma. , 2001, Cancer research.

[27]  M. Pacyna‐Gengelbach,et al.  Homeobox gene HOP has a potential tumor suppressive activity in human lung cancer , 2007, International journal of cancer.

[28]  F. Sato,et al.  Pharmacologic unmasking of epigenetically silenced tumor suppressor genes in esophageal squamous cell carcinoma. , 2002, Cancer cell.

[29]  Gerhard Christofori,et al.  A causal role for E-cadherin in the transition from adenoma to carcinoma , 1998, Nature.

[30]  D. Ichikawa,et al.  Clinical application of methylation specific-polymerase chain reaction in serum of patients with gastric cancer. , 2007, Hepato-Gastroenterology.

[31]  Juna Lee,et al.  Neurofilament Heavy Polypeptide Regulates the Akt-β-Catenin Pathway in Human Esophageal Squamous Cell Carcinoma , 2010, PloS one.

[32]  Mirang Kim,et al.  Epigenetic Down-Regulation and Suppressive Role of DCBLD2 in Gastric Cancer Cell Proliferation and Invasion , 2008, Molecular Cancer Research.

[33]  J. Kountouras,et al.  New aspects of Helicobacter pylori infection involvement in gastric oncogenesis. , 2008, The Journal of surgical research.

[34]  C. Fenoglio-Preiser,et al.  TP53 and gastric carcinoma: A review , 2003, Human mutation.

[35]  M. Carrington,et al.  Interleukin-1 polymorphisms associated with increased risk of gastric cancer , 2000, Nature.

[36]  Kyucheol Cho,et al.  Frequent monoallelic deletion of PTEN and its reciprocal associatioin with PIK3CA amplification in gastric carcinoma , 2003, International journal of cancer.

[37]  S. Cai,et al.  Expression and prognostic impact of PRL‐3 in lymph node metastasis of gastric cancer: Its molecular mechanism was investigated using artificial microRNA interference , 2008, International journal of cancer.

[38]  S. Nomoto,et al.  Biallelic inactivation of the RIZ1 gene in human gastric cancer , 2003, Oncogene.

[39]  Nobuyuki Tani,et al.  Correlation between serum DNA methylation and prognosis in gastric cancer patients. , 2006, Anticancer research.

[40]  S. Kitano,et al.  Suppression of tumor growth in human gastric cancer with HER2 overexpression by an anti-HER2 antibody in a murine model. , 2005, International journal of oncology.

[41]  S. Nishizuka,et al.  Promoter methylation status of DAP‐kinase and RUNX3 genes in neoplastic and non‐neoplastic gastric epithelia , 2003, Cancer science.

[42]  Jun Yu,et al.  Concurrent hypermethylation of multiple tumor‐related genes in gastric carcinoma and adjacent normal tissues , 2001, Cancer.

[43]  A. Jimeno,et al.  HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. , 2008, Annals of oncology : official journal of the European Society for Medical Oncology.

[44]  S. Nishizuka,et al.  E-Cadherin gene promoter hypermethylation in primary human gastric carcinomas. , 2000, Journal of the National Cancer Institute.

[45]  Tae-You Kim,et al.  Gene silencing of TSPYL5 mediated by aberrant promoter methylation in gastric cancers , 2008, Laboratory Investigation.

[46]  S. Nomoto,et al.  Inverse Correlation between Cyclin A1 Hypermethylation and p53 Mutation in Head and Neck Cancer Identified by Reversal of Epigenetic Silencing , 2004, Cancer Research.

[47]  S. Tsujitani,et al.  Recent results of therapy for scirrhous gastric cancer , 2009, Surgery Today.

[48]  鈴木 拓.  Distinct methylation pattern and microsatellite instability in sporadic gastric cancer , 2000 .

[49]  J. Herman,et al.  Hypermethylation of the hMLH1 gene promoter in human gastric cancers with microsatellite instability. , 1999, Cancer research.

[50]  P. Guilford,et al.  Hereditary diffuse gastric cancer: A manifestation of lost cell polarity , 2009, Cancer science.

[51]  R. Schwartz,et al.  Hop Is an Unusual Homeobox Gene that Modulates Cardiac Development , 2002, Cell.

[52]  Qiang Xu,et al.  Phosphatase of regenerating liver-3 promotes motility and metastasis of mouse melanoma cells. , 2004, The American journal of pathology.

[53]  Kazuhiro Yoshida,et al.  Frequent Loss of RUNX3 Expression by Promoter Hypermethylation in Gastric Carcinoma , 2004, Pathobiology.

[54]  S. Hirohashi,et al.  DNA methyltransferase expression and DNA methylation of CPG islands and peri‐centromeric satellite regions in human colorectal and stomach cancers , 2001, International journal of cancer.

[55]  佐藤 亜由美.  Epigenetic inactivation of CHFR and sensitivity to microtubule inhibitors in gastric cancer , 2004 .

[56]  I. Wistuba,et al.  Aberrant methylation of Reprimo in human malignancies , 2005, International journal of cancer.

[57]  D. Ichikawa,et al.  Comparison of methylation‐specific polymerase chain reaction (MSP) with reverse transcriptase‐polymerase chain reaction (RT‐PCR) in peripheral blood of gastric cancer patients , 2004, Journal of surgical oncology.

[58]  K. Yanagihara,et al.  Dedifferentiation of adenocarcinomas by activation of phosphatidylinositol 3-kinase. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[59]  J. Herman,et al.  Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands. , 1996, Proceedings of the National Academy of Sciences of the United States of America.

[60]  S. Hamilton,et al.  Sporadic fundic gland polyps: common gastric polyps arising through activating mutations in the beta-catenin gene. , 2001, The American journal of pathology.

[61]  K. Yamashita,et al.  Phosphatase of regenerating liver-3 as a prognostic biomarker in histologically node-negative gastric cancer. , 2009, Oncology reports.

[62]  T. Park,et al.  Methylation of O6‐methylguanine‐DNA methyltransferase gene is associated significantly with K‐ras mutation, lymph node invasion, tumor staging, and disease free survival in patients with gastric carcinoma , 2001, Cancer.

[63]  S. Leung,et al.  hMLH1 promoter methylation and lack of hMLH1 expression in sporadic gastric carcinomas with high-frequency microsatellite instability. , 1999, Cancer research.

[64]  Hui Zeng,et al.  Correlation between the single-site CpG methylation and expression silencing of the XAF1 gene in human gastric and colon cancers. , 2006, Gastroenterology.

[65]  M. Taniwaki,et al.  Epigenetic silencing of RELN in gastric cancer. , 2009, International journal of oncology.

[66]  D. Ichikawa,et al.  Detection of aberrant methylation as a tumor marker in serum of patients with gastric cancer. , 2004, Anticancer research.

[67]  Thomas M. Harris,et al.  Modulation of Cardiac Growth and Development by HOP, an Unusual Homeodomain Protein , 2002, Cell.

[68]  S. Nishizuka,et al.  Distinct methylation patterns of two APC gene promoters in normal and cancerous gastric epithelia , 2000, Oncogene.

[69]  S. Shirasawa,et al.  Altered growth of human colon cancer cell lines disrupted at activated Ki-ras. , 1993, Science.

[70]  W. Farrell,et al.  Preferential loss of Death Associated Protein kinase expression in invasive pituitary tumours is associated with either CpG island methylation or homozygous deletion , 2002, Oncogene.

[71]  T. Tahara,et al.  Effect of promoter methylation of multidrug resistance 1 (MDR1) gene in gastric carcinogenesis. , 2009, Anticancer research.

[72]  Y. Yuasa,et al.  Alterations and hypermethylation of the p14ARF gene in gastric cancer , 2000, International journal of cancer.

[73]  Sang Gyun Kim,et al.  Transcriptional inactivation of the tissue inhibitor of metalloproteinase‐3 gene by dna hypermethylation of the 5'‐CpG island in human gastric cancer cell lines , 2000, International journal of cancer.

[74]  J. G. Park,et al.  Mutations in fibroblast growth factor receptor 2 and fibroblast growth factor receptor 3 genes associated with human gastric and colorectal cancers. , 2001, Cancer research.

[75]  J. Rubin,et al.  Expression cDNA cloning of the KGF receptor by creation of a transforming autocrine loop. , 1991, Science.

[76]  Jung Weon Lee,et al.  Aberrant methylation of integrin α4 gene in human gastric cancer cells , 2004, Oncogene.

[77]  J. Ptak,et al.  High Frequency of Mutations of the PIK3CA Gene in Human Cancers , 2004, Science.

[78]  S. Nishizuka,et al.  Promoter methylation status of E-cadherin, hMLH1, and p16 genes in nonneoplastic gastric epithelia. , 2002, The American journal of pathology.

[79]  D. Sidransky,et al.  HOP/OB1/NECC1 Promoter DNA Is Frequently Hypermethylated and Involved in Tumorigenic Ability in Esophageal Squamous Cell Carcinoma , 2008, Molecular Cancer Research.

[80]  S. Cai,et al.  High Expression of PRL-3 can Promote Growth of Gastric Cancer and Exhibits a Poor Prognostic Impact on Patients , 2008, Annals of Surgical Oncology.

[81]  K. Kinzler,et al.  PRL-3 expression in metastatic cancers. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[82]  S. Itohara,et al.  Causal Relationship between the Loss of RUNX3 Expression and Gastric Cancer , 2002, Cell.

[83]  S. Groshen,et al.  Hypermethylated APC DNA in plasma and prognosis of patients with esophageal adenocarcinoma. , 2000, Journal of the National Cancer Institute.

[84]  J. Herman,et al.  CpG island methylator phenotype in colorectal cancer. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[85]  A. Corvalán,et al.  DNA methylation profile in diffuse type gastric cancer: evidence for hypermethylation of the BRCA1 promoter region in early-onset gastric carcinogenesis. , 2008, Biological research.

[86]  Jun Yu,et al.  Frequent epigenetic inactivation of secreted frizzled-related protein 2 (SFRP2) by promoter methylation in human gastric cancer , 2007, British Journal of Cancer.

[87]  N. Niikawa,et al.  NECC1, a candidate choriocarcinoma suppressor gene that encodes a homeodomain consensus motif. , 2003, Genomics.

[88]  H. Watanabe,et al.  Frequent hypermethylation of the hMLH1 gene promoter in differentiated-type tumors of the stomach with the gastric foveolar phenotype. , 2000, The American journal of pathology.

[89]  J. Califano,et al.  DCC promoter hypermethylation in esophageal squamous cell carcinoma , 2006, International journal of cancer.

[90]  C. Caldas,et al.  E-cadherin gene (CDH1) promoter methylation as the second hit in sporadic diffuse gastric carcinoma , 2001, Oncogene.

[91]  Kun Yang,et al.  D2 plus para-aortic lymphadenectomy versus standardized D2 lymphadenectomy in gastric cancer surgery , 2009, Surgery Today.

[92]  S. Semba,et al.  Expression of PRL-3 Phosphatase in Human Gastric Carcinomas: Close Correlation with Invasion and Metastasis , 2004, Pathobiology.

[93]  Derek Y. Chiang,et al.  Characterizing the cancer genome in lung adenocarcinoma , 2007, Nature.

[94]  Hong Nguyen,et al.  Differential trends in the intestinal and diffuse types of gastric carcinoma in the United States, 1973-2000: increase in the signet ring cell type. , 2004, Archives of pathology & laboratory medicine.

[95]  J. Błasiak,et al.  Promoter methylation of cancer-related genes in gastric carcinoma. , 2008, Experimental oncology.

[96]  Y. Kodera,et al.  Gastric cancer treated in 1991 in Japan: data analysis of nationwide registry , 2006, Gastric Cancer.

[97]  Masahiro Takeuchi,et al.  S-1 plus cisplatin versus S-1 alone for first-line treatment of advanced gastric cancer (SPIRITS trial): a phase III trial. , 2008, The Lancet. Oncology.

[98]  M. Toyota,et al.  DNA methylation and histone deacetylation associated with silencing DAP kinase gene expression in colorectal and gastric cancers , 2002, British Journal of Cancer.

[99]  Yoichi Tanaka,et al.  PGP9.5 promoter methylation is an independent prognostic factor for esophageal squamous cell carcinoma. , 2005, Cancer research.

[100]  B. Leggett,et al.  HPP1: a transmembrane protein-encoding gene commonly methylated in colorectal polyps and cancers. , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[101]  富井 邦年.  Aberrant promoter methylation of insulin-like growth factor binding protein-3 gene in human cancers , 2006 .

[102]  K. Kinzler,et al.  Cancer genes and the pathways they control , 2004, Nature Medicine.

[103]  E. Schuuring,et al.  Genome-wide promoter analysis uncovers portions of the cancer methylome. , 2008, Cancer research.

[104]  H. Yokozaki,et al.  Promoter hypermethylation of MGMT is associated with protein loss in gastric carcinoma , 2001, International journal of cancer.

[105]  C. Shou,et al.  PRL-3 promotes the motility, invasion, and metastasis of LoVo colon cancer cells through PRL-3-integrin β1-ERK1/2 and-MMP2 signaling , 2009, Molecular Cancer.

[106]  Y. Kakeji,et al.  Phase II study of weekly paclitaxel by one-hour infusion for advanced gastric cancer , 2008, Surgery Today.

[107]  W. H. Kim,et al.  CpG island methylation in premalignant stages of gastric carcinoma. , 2001, Cancer research.

[108]  C. Moon,et al.  Quantitative hypermethylation of NMDAR2B in human gastric cancer , 2007, International journal of cancer.

[109]  M. Taniwaki,et al.  Tissue factor pathway inhibitor 2 (TFPI2) is frequently silenced by aberrant promoter hypermethylation in gastric cancer. , 2010, Cancer genetics and cytogenetics.

[110]  W. Kim,et al.  Identification of genes epigenetically silenced by CpG methylation in human gastric carcinoma. , 2009, European journal of cancer.

[111]  Keishi Yamashita,et al.  A Promoter Methylation Pattern in the N-Methyl-d-Aspartate Receptor 2B Gene Predicts Poor Prognosis in Esophageal Squamous Cell Carcinoma , 2007, Clinical Cancer Research.

[112]  Kentaro Yamashita,et al.  Global DNA demethylation in gastrointestinal cancer is age dependent and precedes genomic damage. , 2006, Cancer cell.

[113]  Y. Bang,et al.  Transcriptional silencing of Cyclooxygenase-2 by hyper-methylation of the 5' CpG island in human gastric carcinoma cells. , 2001, Cancer research.

[114]  B. Xia,et al.  Association of diminished expression of RASSF1A with promoter methylation in primary gastric cancer from patients of central China , 2007, BMC Cancer.

[115]  Teruhiko Yoshida,et al.  K-sam, an amplified gene in stomach cancer, is a member of the heparin-binding growth factor receptor genes. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[116]  S. Nishizuka,et al.  Promoter hypermethylation of the Chfr gene in neoplastic and non-neoplastic gastric epithelia , 2004, British Journal of Cancer.

[117]  K. Yamashita,et al.  Liver metastasis of colorectal cancer by protein-tyrosine phosphatase type 4A, 3 (PRL-3) is mediated through lymph node metastasis and elevated serum tumor markers such as CEA and CA19-9. , 2008, Oncology reports.

[118]  Y. Lam,et al.  CHD5 is down-regulated through promoter hypermethylation in gastric cancer , 2009, Journal of Biomedical Science.

[119]  D. Sidransky,et al.  PGP9.5 methylation in diffuse-type gastric cancer. , 2006, Cancer research.

[120]  J. Willis,et al.  Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer , 2000, Nature Genetics.

[121]  Anthony E. Reeve,et al.  E-cadherin germline mutations in familial gastric cancer , 1998, Nature.

[122]  Jun Yu,et al.  Fibulin 1 is downregulated through promoter hypermethylation in gastric cancer , 2008, British Journal of Cancer.

[123]  H. Yokozaki,et al.  Distinct promoter hypermethylation of p16INK4a, CDH1, and RAR‐beta in intestinal, diffuse–adherent, and diffuse–scattered type gastric carcinomas , 2002, The Journal of pathology.

[124]  Michael A. Choti,et al.  A Phosphatase Associated with Metastasis of Colorectal Cancer , 2001, Science.

[125]  T. Park,et al.  Methylation of O(6)-methylguanine-DNA methyltransferase gene is associated significantly with K-ras mutation, lymph node invasion, tumor staging, and disease free survival in patients with gastric carcinoma. , 2001, Cancer.

[126]  P. Guilford,et al.  E-cadherin deficiency initiates gastric signet-ring cell carcinoma in mice and man. , 2009, Cancer research.

[127]  D. Sidransky,et al.  The role of PGP9.5 as a tumor suppressor gene in human cancer , 2008, International journal of cancer.

[128]  George A. Calin,et al.  Frequent Aberrant Methylation of the CDH4 Gene Promoter in Human Colorectal and Gastric Cancer , 2004, Cancer Research.

[129]  Jun Yu,et al.  Increased beta-catenin mRNA levels and mutational alterations of the APC and beta-catenin gene are present in intestinal-type gastric cancer. , 2002, Carcinogenesis.

[130]  I Petersen,et al.  Genomic profiling identifies TITF1 as a lineage-specific oncogene amplified in lung cancer , 2008, Oncogene.

[131]  Gerhard Christofori,et al.  Cell adhesion and signalling by cadherins and Ig-CAMs in cancer , 2004, Nature Reviews Cancer.

[132]  D. Sidransky,et al.  Potential utility of HOP homeobox gene promoter methylation as a marker of tumor aggressiveness in gastric cancer , 2010, Oncogene.

[133]  Cem Elbi,et al.  FGFR2-amplified gastric cancer cell lines require FGFR2 and Erbb3 signaling for growth and survival. , 2008, Cancer research.

[134]  Jude Kendall,et al.  Oncogenic cooperation and coamplification of developmental transcription factor genes in lung cancer , 2007, Proceedings of the National Academy of Sciences.

[135]  P. Galle,et al.  Treatment of nonalcoholic fatty liver disease. , 2006, World journal of gastroenterology.

[136]  J. Califano,et al.  Methylation of the DFNA5 increases risk of lymph node metastasis in human breast cancer. , 2008, Biochemical and biophysical research communications.

[137]  S. Goodman,et al.  Sensitive digital quantification of DNA methylation in clinical samples , 2009, Nature Biotechnology.

[138]  M. M. Soundarapandian,et al.  DAPK1 Interaction with NMDA Receptor NR2B Subunits Mediates Brain Damage in Stroke , 2010, Cell.

[139]  Jen-Hao Chen,et al.  Nodal dissection for patients with gastric cancer: a randomised controlled trial. , 2006, The Lancet. Oncology.

[140]  S. Corsale,et al.  Aberrant methylation within RUNX3 CpG island associated with the nuclear and mitochondrial microsatellite instability in sporadic gastric cancers. Results of a GOIM (Gruppo Oncologico dell'Italia Meridionale) prospective study. , 2007, Annals of oncology : official journal of the European Society for Medical Oncology.

[141]  B. Goh,et al.  Detection of promoter hypermethylation in serum samples of cancer patients by methylation-specific polymerase chain reaction for tumour suppressor genes including RUNX3. , 2007, Oncology reports.

[142]  M. Kuwano,et al.  The association of death-associated protein kinase hypermethylation with early recurrence in superficial bladder cancers. , 2002, Cancer research.

[143]  Mihaela Campan,et al.  DNA methylation profiles of gastric carcinoma characterized by quantitative DNA methylation analysis , 2008, Laboratory Investigation.

[144]  D. Graham,et al.  Possible role of Helicobacter pylori infection in early gastric cancer development , 1994, Cancer.

[145]  Tsung-Teh Wu,et al.  Drastic down-regulation of Krüppel-like factor 4 expression is critical in human gastric cancer development and progression. , 2005, Cancer research.

[146]  D. Ichikawa,et al.  Comparison of serum aberrant methylation and conventional tumor markers in gastric cancer patients. , 2005, Hepato-Gastroenterology.

[147]  G. Meijer,et al.  Promoter DNA Methylation of Oncostatin M receptor-β as a Novel Diagnostic and Therapeutic Marker in Colon Cancer , 2009, PloS one.

[148]  Jia-Yun Chen,et al.  TGF-β induces apoptosis through Smad-mediated expression of DAP-kinase , 2002, Nature Cell Biology.

[149]  C. Sakakura,et al.  Quantitative analysis of tumor-derived methylated RUNX3 sequences in the serum of gastric cancer patients. , 2009, Anticancer research.

[150]  Hai-Meng Zhou,et al.  Promoter hypermethylation correlates with the Hsulf‐1 silencing in human breast and gastric cancer , 2009, International journal of cancer.

[151]  Carlos Manterola,et al.  Epidemiology of esophageal adenocarcinoma , 2005, Journal of surgical oncology.

[152]  M. Magnani,et al.  Prognostic Analysis of E-Cadherin Gene Promoter Hypermethylation in Patients with Surgically Resected, Node-Positive, Diffuse Gastric Cancer , 2004, Clinical Cancer Research.

[153]  G. Lauwers.  Defining the Pathologic Diagnosis of Metaplasia, Atrophy, Dysplasia, and Gastric Adenocarcinoma , 2003, Journal of clinical gastroenterology.

[154]  Ren-Min Zhu,et al.  Detection of RASSF1A promoter hypermethylation in serum from gastric and colorectal adenocarcinoma patients. , 2008, World journal of gastroenterology.

[155]  F. Chan,et al.  Potential diagnostic and prognostic values of detecting promoter hypermethylation in the serum of patients with gastric cancer , 2005, British Journal of Cancer.

[156]  Y. Shimono,et al.  Enhancer of Polycomb1, a Novel Homeodomain Only Protein-binding Partner, Induces Skeletal Muscle Differentiation* , 2007, Journal of Biological Chemistry.

[157]  K. Yamashita,et al.  Diffuse type advanced gastric cancer showing dismal prognosis is characterized by deeper invasion and emerging peritoneal cancer cell: the latest comparative study to intestinal advanced gastric cancer. , 2009, Hepato-gastroenterology.

[158]  W. Leung,et al.  Detection of gene promoter hypermethylation in the tumor and serum of patients with gastric carcinoma. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.

[159]  S Ichii,et al.  The APC gene, responsible for familial adenomatous polyposis, is mutated in human gastric cancer. , 1992, Cancer research.

[160]  R. De Francesco,et al.  Ezrin is a specific and direct target of protein tyrosine phosphatase PRL-3. , 2008, Biochimica et biophysica acta.

[161]  M. Rhyu,et al.  Epstein-barr virus-positive gastric carcinoma demonstrates frequent aberrant methylation of multiple genes and constitutes CpG island methylator phenotype-positive gastric carcinoma. , 2002, The American journal of pathology.

[162]  Takeshi Azuma,et al.  Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium , 2007, Nature Medicine.

[163]  M. Toyota,et al.  Genetic, epigenetic, and clinicopathologic features of gastric carcinomas with the CpG island methylator phenotype and an association with Epstein–Barr virus , 2006, Cancer.

[164]  Kazuhiro Yoshida,et al.  Frequent epigenetic inactivation of RIZ1 by promoter hypermethylation in human gastric carcinoma , 2004, International journal of cancer.

[165]  T. Yano,et al.  Comparison of HER2 gene amplification assessed by fluorescence in situ hybridization and HER2 protein expression assessed by immunohistochemistry in gastric cancer. , 2006, Oncology reports.

[166]  S. Polak‐Charcon,et al.  DAP kinase links the control of apoptosis to metastasis , 1997, Nature.

[167]  S. Nishizuka,et al.  Inactivation of the E‐Cadherin Gene in Primary Gastric Carcinomas and Gastric Carcinoma Cell Lines , 1996, Japanese journal of cancer research : Gann.

[168]  Y. Bang,et al.  Alterations of p16INK4A and p15INK4B genes in gastric carcinomas , 1997, Cancer.

[169]  M. Lemmon,et al.  ErbB2 resembles an autoinhibited invertebrate epidermal growth factor receptor , 2009, Nature.

[170]  A. Veronese,et al.  Multigene Methylation Analysis of Gastrointestinal Tumors , 2012, Molecular Diagnosis.

[171]  J. Li,et al.  PRL-3 and PRL-1 promote cell migration, invasion, and metastasis. , 2003, Cancer research.

[172]  K. Mori,et al.  Antitumor activity of trastuzumab in combination with chemotherapy in human gastric cancer xenograft models , 2007, Cancer Chemotherapy and Pharmacology.

[173]  S. Hirohashi,et al.  Immunohistochemical detection of K-sam protein in stomach cancer. , 1996, Clinical cancer research : an official journal of the American Association for Cancer Research.

[174]  M. Suntharalingam,et al.  Promoter methylation and response to chemotherapy and radiation in esophageal cancer. , 2006, Clinical gastroenterology and hepatology : the official clinical practice journal of the American Gastroenterological Association.

[175]  Jun Yu,et al.  Increased β-catenin mRNA levels and mutational alterations of the APC and β-catenin gene are present in intestinal-type gastric cancer , 2002 .

[176]  R. Kerbel,et al.  Mutant ras oncogenes upregulate VEGF/VPF expression: implications for induction and inhibition of tumor angiogenesis. , 1995, Cancer research.

[177]  Dong Xu,et al.  Comparative Study on Overexpression of HER2/neu and HER3 in Gastric Cancer , 2009, World Journal of Surgery.

[178]  Kai-lai Sun,et al.  Analysis of metastasis suppressing function of E-cadherin in gastric cancer cells by RNAi. , 2005, World journal of gastroenterology.

[179]  A. Iwamatsu,et al.  Activation of ErbB3–PI3-kinase pathway is correlated with malignant phenotypes of adenocarcinomas , 2003, Oncogene.

[180]  Rudolf Jaenisch,et al.  DNA hypomethylation leads to elevated mutation rates , 1998, Nature.

[181]  Seung-Moo Noh,et al.  Epigenetic inactivation of protein kinase D1 in gastric cancer and its role in gastric cancer cell migration and invasion. , 2007, Carcinogenesis.

[182]  Mohammad Reza Abbaszadegan,et al.  p16 promoter hypermethylation: a useful serum marker for early detection of gastric cancer. , 2008, World journal of gastroenterology.

[183]  Yoon-Koo Kang,et al.  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 , 2010, The Lancet.

[184]  Q. Zeng,et al.  PRL-3 initiates tumor angiogenesis by recruiting endothelial cells in vitro and in vivo. , 2006, Cancer research.

[185]  R. Hunt,et al.  Meta-analysis of the relationship between cagA seropositivity and gastric cancer. , 2003, Gastroenterology.

[186]  Stefan David,et al.  Silencing of Claudin-11 Is Associated with Increased Invasiveness of Gastric Cancer Cells , 2009, PloS one.

[187]  H. Höfler,et al.  E-cadherin gene mutations provide clues to diffuse type gastric carcinomas. , 1994, Cancer research.

[188]  K. Kinzler,et al.  Lessons from Hereditary Colorectal Cancer , 1996, Cell.

[189]  R. Lotan,et al.  Inactivation of retinoic acid receptor beta by promoter CpG hypermethylation in gastric cancer. , 2001, Differentiation; research in biological diversity.

[190]  C. Shou,et al.  Expression of phosphatase regenerating liver 3 is an independent prognostic indicator for gastric cancer. , 2009, World journal of gastroenterology.

[191]  J. Epstein,et al.  Cardiac hypertrophy and histone deacetylase-dependent transcriptional repression mediated by the atypical homeodomain protein Hop. , 2003, The Journal of clinical investigation.

[192]  D. Chan,et al.  Mechanisms inactivating the gene for E-cadherin in sporadic gastric carcinomas. , 2006, World journal of gastroenterology.

[193]  B. Gumbiner,et al.  Adhesion-independent mechanism for suppression of tumor cell invasion by E-cadherin , 2003, The Journal of cell biology.

[194]  T. Taniguchi,et al.  Reprimo, a New Candidate Mediator of the p53-mediated Cell Cycle Arrest at the G2 Phase* , 2000, The Journal of Biological Chemistry.

[195]  A. Rashid,et al.  E-cadherin promoter hypermethylation induced by interleukin-1beta treatment or H. pylori infection in human gastric cancer cell lines. , 2008, Cancer letters.

[196]  Guojun Wu,et al.  Aberrant promoter methylation and tumor suppressive activity of the DFNA5 gene in colorectal carcinoma , 2008, Oncogene.

[197]  F. Chan,et al.  ZIC1 is downregulated through promoter hypermethylation in gastric cancer. , 2009, Biochemical and biophysical research communications.

[198]  A. Carvalho,et al.  N-methyl-D-aspartate receptor type 2B is epigenetically inactivated and exhibits tumor-suppressive activity in human esophageal cancer. , 2006, Cancer research.

[199]  S. Cai,et al.  Elevated PRL-3 expression was more frequently detected in the large primary gastric cancer and exhibits a poor prognostic impact on the patients , 2009, Journal of Cancer Research and Clinical Oncology.