Official reprint from UpToDate®
www.uptodate.com ©2017 UpToDate, Inc. and/or its affiliates. All Rights Reserved.

Pathology and molecular pathogenesis of gastric cancer

Pelayo Correa, MD
Section Editor
Richard M Goldberg, MD
Deputy Editor
Diane MF Savarese, MD


Gastric adenocarcinoma is one of the few malignant neoplasms for which infectious agents have been recognized as having an important etiologic role [1]:

In 1994, based mostly upon epidemiologic evidence, the International Agency for Research on Cancer (IARC), a part of the World Health Organization (WHO), recognized infection by Helicobacter pylori (H. pylori) as a primary cause of gastric adenocarcinoma [2]. Left untreated, H. pylori infection leads to life-long chronic active gastritis, which is a risk factor for both intestinal and diffuse gastric adenocarcinomas [3].

However, H. pylori-associated preneoplastic lesions are a feature of intestinal-type gastric cancer and not the diffuse-type. The diffuse type is more likely to have a primary genetic etiology, and the involvement of H. pylori is probably limited to a subset of sporadic cases [4].

Outcomes of H. pylori infection vary individually, and only a small minority of infected subjects develop gastric cancer (estimated at approximately three cases per year for every 10,000 infected persons). There are approximately 1,000,000 gastric cancer cases per year and 3.25 billion people infected with H. pylori worldwide. It is thought that modulation of the effects of H. pylori by genetic susceptibility, external (mostly environmental) forces, and possibly bacterial strain differences influence its evolution into a neoplastic or nonneoplastic process. (See "Association between Helicobacter pylori infection and gastrointestinal malignancy".)

Epstein–Barr virus (EBV) is detected in 2 to 16 percent of gastric adenocarcinomas worldwide; there is a higher frequency in tumors of the proximal and middle portion of the stomach [5-8]. Several EBV-related genes (including EBER-1, EBER2, EBNA1, LMP2A, BARF0, and BARF1) are expressed in gastric cancers. However, in contrast to H. pylori, their role in gastric carcinogenesis is not yet established.

To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:

Subscribers log in here

Literature review current through: Sep 2017. | This topic last updated: Nov 03, 2014.
The content on the UpToDate website is not intended nor recommended as a substitute for medical advice, diagnosis, or treatment. Always seek the advice of your own physician or other qualified health care professional regarding any medical questions or conditions. The use of this website is governed by the UpToDate Terms of Use ©2017 UpToDate, Inc.
  1. Parkin DM. The global health burden of infection-associated cancers in the year 2002. Int J Cancer 2006; 118:3030.
  2. Asim A, Chaturvedi R, Piazuelo MB, et al. Helicobacter pylori strains from regions at high gastric cancer risk exhibit increased ability to activate iNOS and SMO. Gastroenterology 2008; 134(suppl 1):A78.
  3. Solcia E, Fiocca R, Luinetti O, et al. Intestinal and diffuse gastric cancers arise in a different background of Helicobacter pylori gastritis through different gene involvement. Am J Surg Pathol 1996; 20 Suppl 1:S8.
  4. Carneiro F, Huntsman DG, Smyrk TC, et al. Model of the early development of diffuse gastric cancer in E-cadherin mutation carriers and its implications for patient screening. J Pathol 2004; 203:681.
  5. Takada K. Epstein-Barr virus and gastric carcinoma. Mol Pathol 2000; 53:255.
  6. Koriyama C, Akiba S, Corvalan A, et al. Histology-specific gender, age and tumor-location distributions of Epstein-Barr virus-associated gastric carcinoma in Japan. Oncol Rep 2004; 12:543.
  7. Carrascal E, Koriyama C, Akiba S, et al. Epstein-Barr virus-associated gastric carcinoma in Cali, Colombia. Oncol Rep 2003; 10:1059.
  8. Corvalan A, Koriyama C, Akiba S, et al. Epstein-Barr virus in gastric carcinoma is associated with location in the cardia and with a diffuse histology: a study in one area of Chile. Int J Cancer 2001; 94:527.
  9. Correa P. Gastric cancer: two epidemics? Dig Dis Sci 2011; 56:1585.
  11. Shah MA, Khanin R, Tang L, et al. Molecular classification of gastric cancer: a new paradigm. Clin Cancer Res 2011; 17:2693.
  12. Tan IB, Ivanova T, Lim KH, et al. Intrinsic subtypes of gastric cancer, based on gene expression pattern, predict survival and respond differently to chemotherapy. Gastroenterology 2011; 141:476.
  13. Machado JC, Soares P, Carneiro F, et al. E-cadherin gene mutations provide a genetic basis for the phenotypic divergence of mixed gastric carcinomas. Lab Invest 1999; 79:459.
  14. Henson DE, Dittus C, Younes M, 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. Arch Pathol Lab Med 2004; 128:765.
  15. Locke GR 3rd, Talley NJ, Carpenter HA, et al. Changes in the site- and histology-specific incidence of gastric cancer during a 50-year period. Gastroenterology 1995; 109:1750.
  16. Correa P, Haenszel W, Cuello C, et al. A model for gastric cancer epidemiology. Lancet 1975; 2:58.
  17. Correa P. Human gastric carcinogenesis: a multistep and multifactorial process--First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res 1992; 52:6735.
  18. Sipponen P, Graham DY. Importance of atrophic gastritis in diagnostics and prevention of gastric cancer: application of plasma biomarkers. Scand J Gastroenterol 2007; 42:2.
  19. Filipe MI, Potet F, Bogomoletz WV, et al. Incomplete sulphomucin-secreting intestinal metaplasia for gastric cancer. Preliminary data from a prospective study from three centres. Gut 1985; 26:1319.
  20. Tumours of the Digestive System. In: World Health Organization Classification of Tumours: Pathology and Genetics, Hamilton SR, Aaltonen LA (Eds), IARC Press, Lyon, France 2000.
  21. Rugge M, Correa P, Dixon MF, et al. Gastric dysplasia: the Padova international classification. Am J Surg Pathol 2000; 24:167.
  22. de Vries AC, Haringsma J, Kuipers EJ. The detection, surveillance and treatment of premalignant gastric lesions related to Helicobacter pylori infection. Helicobacter 2007; 12:1.
  23. El-Rifai W, Frierson HF Jr, Moskaluk CA, et al. Genetic differences between adenocarcinomas arising in Barrett's esophagus and gastric mucosa. Gastroenterology 2001; 121:592.
  24. Stocks SC, Pratt N, Sales M, et al. Chromosomal imbalances in gastric and esophageal adenocarcinoma: specific comparative genomic hybridization-detected abnormalities segregate with junctional adenocarcinomas. Genes Chromosomes Cancer 2001; 32:50.
  25. Yanagi M, Keller G, Mueller J, et al. Comparison of loss of heterozygosity and microsatellite instability in adenocarcinomas of the distal esophagus and proximal stomach. Virchows Arch 2000; 437:605.
  26. Tajima Y, Nakanishi Y, Yoshino T, et al. Clinicopathological study of early adenocarcinoma of the gastric cardia: comparison with early adenocarcinoma of the distal stomach and esophagus. Oncology 2001; 61:1.
  27. Simán JH, Engstrand L, Berglund G, et al. Helicobacter pylori and CagA seropositivity and its association with gastric and oesophageal carcinoma. Scand J Gastroenterol 2007; 42:933.
  28. Hansen S, Vollset SE, Derakhshan MH, et al. Two distinct aetiologies of cardia cancer; evidence from premorbid serological markers of gastric atrophy and Helicobacter pylori status. Gut 2007; 56:918.
  29. Tajima Y, Yamazaki K, Makino R, et al. Differences in the histological findings, phenotypic marker expressions and genetic alterations between adenocarcinoma of the gastric cardia and distal stomach. Br J Cancer 2007; 96:631.
  30. Piazuelo MB, Haque S, Delgado A, et al. Phenotypic differences between esophageal and gastric intestinal metaplasia. Mod Pathol 2004; 17:62.
  31. American Joint Committee on Cancer Staging Manual, 7th, Edge SB, Byrd DR, Compton CC, et al (Eds), Springer, New York 2010. p.117.
  32. Japanese Classification of Gastric Carcinoma. In: Gastric Cancer, 2nd, Japanese Gastric Cancer Association, 1998. p.10.
  33. Sayegh ME, Sano T, Dexter S, et al. TNM and Japanese staging systems for gastric cancer: how do they coexist? Gastric Cancer 2004; 7:140.
  34. Kunisaki C, Shimada H, Nomura M, et al. Comparative evaluation of gastric carcinoma staging: Japanese classification versus new american joint committee on cancer/international union against cancer classification. Ann Surg Oncol 2004; 11:203.
  35. An international association between Helicobacter pylori infection and gastric cancer. The EUROGAST Study Group. Lancet 1993; 341:1359.
  36. Eslick GD, Lim LL, Byles JE, et al. Association of Helicobacter pylori infection with gastric carcinoma: a meta-analysis. Am J Gastroenterol 1999; 94:2373.
  37. Parsonnet J, Vandersteen D, Goates J, et al. Helicobacter pylori infection in intestinal- and diffuse-type gastric adenocarcinomas. J Natl Cancer Inst 1991; 83:640.
  38. Guarner J, Mohar A, Parsonnet J, Halperin D. The association of Helicobacter pylori with gastric cancer and preneoplastic gastric lesions in Chiapas, Mexico. Cancer 1993; 71:297.
  39. Ohkusa T, Fujiki K, Takashimizu I, et al. Improvement in atrophic gastritis and intestinal metaplasia in patients in whom Helicobacter pylori was eradicated. Ann Intern Med 2001; 134:380.
  40. Mera R, Fontham ET, Bravo LE, et al. Long term follow up of patients treated for Helicobacter pylori infection. Gut 2005; 54:1536.
  41. Wong BC, Lam SK, Wong WM, et al. Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA 2004; 291:187.
  42. Mannick EE, Bravo LE, Zarama G, et al. Inducible nitric oxide synthase, nitrotyrosine, and apoptosis in Helicobacter pylori gastritis: effect of antibiotics and antioxidants. Cancer Res 1996; 56:3238.
  43. Pignatelli B, Bancel B, Estève J, et al. Inducible nitric oxide synthase, anti-oxidant enzymes and Helicobacter pylori infection in gastritis and gastric precancerous lesions in humans. Eur J Cancer Prev 1998; 7:439.
  44. Asim A, Chaturvedi R, Piazuelo MB, et al. Helicobacter pylori strains from regions at high gastric cancer risk exhibit increased ability to activate iNOS and SMO. Gastroenterology 2008; 134(suppl 1):A78.
  45. Achtman M, Azuma T, Berg DE, et al. Recombination and clonal groupings within Helicobacter pylori from different geographical regions. Mol Microbiol 1999; 32:459.
  46. Falush D, Wirth T, Linz B, et al. Traces of human migrations in Helicobacter pylori populations. Science 2003; 299:1582.
  47. de Sablet T, Piazuelo MB, Shaffer CL, et al. Phylogeographic origin of Helicobacter pylori is a determinant of gastric cancer risk. Gut 2011; 60:1189.
  48. Holcombe C. Helicobacter pylori: the African enigma. Gut 1992; 33:429.
  49. Loh JT, Shaffer CL, Piazuelo MB, et al. Analysis of cagA in Helicobacter pylori strains from Colombian populations with contrasting gastric cancer risk reveals a biomarker for disease severity. Cancer Epidemiol Biomarkers Prev 2011; 20:2237.
  50. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990; 61:759.
  51. Yasui W, Sentani K, Motoshita J, Nakayama H. Molecular pathobiology of gastric cancer. Scand J Surg 2006; 95:225.
  52. Yasui W, Oue N, Kuniyasu H, et al. Molecular diagnosis of gastric cancer: present and future. Gastric Cancer 2001; 4:113.
  53. Smith MG, Hold GL, Tahara E, El-Omar EM. Cellular and molecular aspects of gastric cancer. World J Gastroenterol 2006; 12:2979.
  54. Churin Y, Al-Ghoul L, Kepp O, et al. Helicobacter pylori CagA protein targets the c-Met receptor and enhances the motogenic response. J Cell Biol 2003; 161:249.
  55. Morgan C, Jenkins GJ, Ashton T, et al. Detection of p53 mutations in precancerous gastric tissue. Br J Cancer 2003; 89:1314.
  56. Shiao YH, Rugge M, Correa P, et al. p53 alteration in gastric precancerous lesions. Am J Pathol 1994; 144:511.
  57. Yokozaki H, Shitara Y, Fujimoto J, et al. Alterations of p73 preferentially occur in gastric adenocarcinomas with foveolar epithelial phenotype. Int J Cancer 1999; 83:192.
  58. Tomkova K, Belkhiri A, El-Rifai W, Zaika AI. p73 isoforms can induce T-cell factor-dependent transcription in gastrointestinal cells. Cancer Res 2004; 64:6390.
  59. Ushiku T, Chong JM, Uozaki H, et al. p73 gene promoter methylation in Epstein-Barr virus-associated gastric carcinoma. Int J Cancer 2007; 120:60.
  60. Li JH, Shi XZ, Lv S, et al. Effect of Helicobacter pylori infection on p53 expression of gastric mucosa and adenocarcinoma with microsatellite instability. World J Gastroenterol 2005; 11:4363.
  61. Kodama M, Fujioka T, Murakami K, et al. Eradication of Helicobacter pylori reduced the immunohistochemical detection of p53 and MDM2 in gastric mucosa. J Gastroenterol Hepatol 2005; 20:941.
  62. Ashktorab H, Ahmed A, Littleton G, et al. p53 and p14 increase sensitivity of gastric cells to H. pylori-induced apoptosis. Dig Dis Sci 2003; 48:1284.
  63. Mingchao, Devereux TR, Stockton P, et al. Loss of E-cadherin expression in gastric intestinal metaplasia and later stage p53 altered expression in gastric carcinogenesis. Exp Toxicol Pathol 2001; 53:237.
  64. Sato K, Tamura G, Tsuchiya T, et al. Frequent loss of expression without sequence mutations of the DCC gene in primary gastric cancer. Br J Cancer 2001; 85:199.
  65. 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.
  66. Noguchi T, Müller W, Wirtz HC, et al. FHIT gene in gastric cancer: association with tumour progression and prognosis. J Pathol 1999; 188:378.
  67. Baffa R, Veronese ML, Santoro R, et al. Loss of FHIT expression in gastric carcinoma. Cancer Res 1998; 58:4708.
  68. Lee SH, Kim WH, Kim HK, et al. Altered expression of the fragile histidine triad gene in primary gastric adenocarcinomas. Biochem Biophys Res Commun 2001; 284:850.
  69. Kodama M, Murakami K, Okimoto T, et al. Expression of mutant type-p53 products in H pylori-associated chronic gastritis. World J Gastroenterol 2007; 13:1541.
  70. Staib F, Robles AI, Varticovski L, et al. The p53 tumor suppressor network is a key responder to microenvironmental components of chronic inflammatory stress. Cancer Res 2005; 65:10255.
  71. Fang DC, Luo YH, Yang SM, et al. Mutation analysis of APC gene in gastric cancer with microsatellite instability. World J Gastroenterol 2002; 8:787.
  72. Nakatsuru S, Yanagisawa A, Furukawa Y, et al. Somatic mutations of the APC gene in precancerous lesion of the stomach. Hum Mol Genet 1993; 2:1463.
  73. Lefebvre O, Chenard MP, Masson R, et al. Gastric mucosa abnormalities and tumorigenesis in mice lacking the pS2 trefoil protein. Science 1996; 274:259.
  74. Wu MS, Shun CT, Wang HP, et al. Loss of pS2 protein expression is an early event of intestinal-type gastric cancer. Jpn J Cancer Res 1998; 89:278.
  75. Leung WK, Yu J, Chan FK, et al. Expression of trefoil peptides (TFF1, TFF2, and TFF3) in gastric carcinomas, intestinal metaplasia, and non-neoplastic gastric tissues. J Pathol 2002; 197:582.
  76. Akama Y, Yasui W, Yokozaki H, et al. Frequent amplification of the cyclin E gene in human gastric carcinomas. Jpn J Cancer Res 1995; 86:617.
  77. Bani-Hani KE, Almasri NM, Khader YS, et al. Combined evaluation of expressions of cyclin E and p53 proteins as prognostic factors for patients with gastric cancer. Clin Cancer Res 2005; 11:1447.
  78. Sun Y, Li JY, He JS, et al. Tissue microarray analysis of multiple gene expression in intestinal metaplasia, dysplasia and carcinoma of the stomach. Histopathology 2005; 46:505.
  79. Takano Y, Kato Y, van Diest PJ, et al. Cyclin D2 overexpression and lack of p27 correlate positively and cyclin E inversely with a poor prognosis in gastric cancer cases. Am J Pathol 2000; 156:585.
  80. So JB, Samarasinge K, Raju GC, et al. Expression of cell-cycle regulators p27 and cyclin E correlates with survival in gastric carcinoma patients. J Surg Res 2000; 94:56.
  81. Kuzushita N, Rogers AB, Monti NA, et al. p27kip1 deficiency confers susceptibility to gastric carcinogenesis in Helicobacter pylori-infected mice. Gastroenterology 2005; 129:1544.
  82. Leal M, Lima E, Silva P, et al. Promoter hypermethylation of CDH1, FHIT, MTAP and PLAGL1 in gastric adenocarcinoma in individuals from Northern Brazil. World J Gastroenterol 2007; 13:2568.
  83. Corso G, Carvalho J, Marrelli D, et al. Somatic mutations and deletions of the E-cadherin gene predict poor survival of patients with gastric cancer. J Clin Oncol 2013; 31:868.
  84. Tahara T, Arisawa T, Shibata T, et al. Risk prediction of gastric cancer by analysis of aberrant DNA methylation in non-neoplastic gastric epithelium. Digestion 2007; 75:54.
  85. Perri F, Cotugno R, Piepoli A, et al. Aberrant DNA methylation in non-neoplastic gastric mucosa of H. Pylori infected patients and effect of eradication. Am J Gastroenterol 2007; 102:1361.
  86. Nakajima T, Maekita T, Oda I, et al. Higher methylation levels in gastric mucosae significantly correlate with higher risk of gastric cancers. Cancer Epidemiol Biomarkers Prev 2006; 15:2317.
  87. Leung WK, Man EP, Yu J, et al. Effects of Helicobacter pylori eradication on methylation status of E-cadherin gene in noncancerous stomach. Clin Cancer Res 2006; 12:3216.
  88. Peek RM Jr, Schneider BG, Correa P. Coming unglued. Clin Cancer Res 2006; 12:2951.
  89. Ushijima T, Nakajima T, Maekita T. DNA methylation as a marker for the past and future. J Gastroenterol 2006; 41:401.
  90. Bernal C, Aguayo F, Villarroel C, et al. Reprimo as a potential biomarker for early detection in gastric cancer. Clin Cancer Res 2008; 14:6264.
  91. Alpízar-Alpízar W, Nielsen BS, Sierra R, et al. Urokinase plasminogen activator receptor is expressed in invasive cells in gastric carcinomas from high- and low-risk countries. Int J Cancer 2010; 126:405.
  92. Brabletz T, Jung A, Spaderna S, et al. Opinion: migrating cancer stem cells - an integrated concept of malignant tumour progression. Nat Rev Cancer 2005; 5:744.
  93. Hlubek F, Spaderna S, Schmalhofer O, et al. Wnt/FZD signaling and colorectal cancer morphogenesis. Front Biosci 2007; 12:458.
  94. Brabletz T, Jung A, Kirchner T. Beta-catenin and the morphogenesis of colorectal cancer. Virchows Arch 2002; 441:1.
  95. Murata-Kamiya N, Kurashima Y, Teishikata Y, et al. Helicobacter pylori CagA interacts with E-cadherin and deregulates the beta-catenin signal that promotes intestinal transdifferentiation in gastric epithelial cells. Oncogene 2007; 26:4617.
  96. Clements WM, Wang J, Sarnaik A, et al. beta-Catenin mutation is a frequent cause of Wnt pathway activation in gastric cancer. Cancer Res 2002; 62:3503.
  97. Lowy AM, Clements WM, Bishop J, et al. beta-Catenin/Wnt signaling regulates expression of the membrane type 3 matrix metalloproteinase in gastric cancer. Cancer Res 2006; 66:4734.
  98. Faller G, Kirchner T. Immunological and morphogenic basis of gastric mucosa atrophy and metaplasia. Virchows Arch 2005; 446:1.
  99. Miehlke S, Kirsch C, Agha-Amiri K, et al. The Helicobacter pylori vacA s1, m1 genotype and cagA is associated with gastric carcinoma in Germany. Int J Cancer 2000; 87:322.
  100. Blaser MJ, Perez-Perez GI, Kleanthous H, et al. Infection with Helicobacter pylori strains possessing cagA is associated with an increased risk of developing adenocarcinoma of the stomach. Cancer Res 1995; 55:2111.
  101. Plummer M, van Doorn LJ, Franceschi S, et al. Helicobacter pylori cytotoxin-associated genotype and gastric precancerous lesions. J Natl Cancer Inst 2007; 99:1328.
  102. Bagnoli F, Buti L, Tompkins L, et al. Helicobacter pylori CagA induces a transition from polarized to invasive phenotypes in MDCK cells. Proc Natl Acad Sci U S A 2005; 102:16339.
  103. Weydig C, Starzinski-Powitz A, Carra G, et al. CagA-independent disruption of adherence junction complexes involves E-cadherin shedding and implies multiple steps in Helicobacter pylori pathogenicity. Exp Cell Res 2007; 313:3459.
  104. Franco AT, Israel DA, Washington MK, et al. Activation of beta-catenin by carcinogenic Helicobacter pylori. Proc Natl Acad Sci U S A 2005; 102:10646.
  105. Suzuki M, Mimuro H, Suzuki T, et al. Interaction of CagA with Crk plays an important role in Helicobacter pylori-induced loss of gastric epithelial cell adhesion. J Exp Med 2005; 202:1235.
  106. Houghton J, Stoicov C, Nomura S, et al. Gastric cancer originating from bone marrow-derived cells. Science 2004; 306:1568.
  107. Okumura T, Wang SS, Takaishi S, et al. Identification of a bone marrow-derived mesenchymal progenitor cell subset that can contribute to the gastric epithelium. Lab Invest 2009; 89:1410.
  108. Takaishi S, Okumura T, Wang TC. Gastric cancer stem cells. J Clin Oncol 2008; 26:2876.
  109. Li HC, Stoicov C, Rogers AB, Houghton J. Stem cells and cancer: evidence for bone marrow stem cells in epithelial cancers. World J Gastroenterol 2006; 12:363.
  110. Yashiro M, Chung YS, Nishimura S, et al. Establishment of two new scirrhous gastric cancer cell lines: analysis of factors associated with disseminated metastasis. Br J Cancer 1995; 72:1200.
  111. Kunz PL, Gubens M, Fisher GA, et al. Long-term survivors of gastric cancer: a California population-based study. J Clin Oncol 2012; 30:3507.
  112. Piessen G, Messager M, Leteurtre E, et al. Signet ring cell histology is an independent predictor of poor prognosis in gastric adenocarcinoma regardless of tumoral clinical presentation. Ann Surg 2009; 250:878.
  113. Ribeiro MM, Sarmento JA, Sobrinho Simões MA, Bastos J. Prognostic significance of Lauren and Ming classifications and other pathologic parameters in gastric carcinoma. Cancer 1981; 47:780.
  114. Zhang M, Zhu G, Zhang H, et al. Clinicopathologic features of gastric carcinoma with signet ring cell histology. J Gastrointest Surg 2010; 14:601.
  115. Kunisaki C, Shimada H, Nomura M, et al. Therapeutic strategy for signet ring cell carcinoma of the stomach. Br J Surg 2004; 91:1319.
  116. Kim DY, Park YK, Joo JK, et al. Clinicopathological characteristics of signet ring cell carcinoma of the stomach. ANZ J Surg 2004; 74:1060.
  117. Hyung WJ, Noh SH, Lee JH, et al. Early gastric carcinoma with signet ring cell histology. Cancer 2002; 94:78.
  118. Taghavi S, Jayarajan SN, Davey A, Willis AI. Prognostic significance of signet ring gastric cancer. J Clin Oncol 2012; 30:3493.
  119. Bamboat ZM, Tang LH, Vinuela E, et al. Stage-stratified prognosis of signet ring cell histology in patients undergoing curative resection for gastric adenocarcinoma. Ann Surg Oncol 2014; 21:1678.
  120. Graziano F, Humar B, Guilford P. The role of the E-cadherin gene (CDH1) in diffuse gastric cancer susceptibility: from the laboratory to clinical practice. Ann Oncol 2003; 14:1705.
  121. Guilford P, Hopkins J, Harraway J, et al. E-cadherin germline mutations in familial gastric cancer. Nature 1998; 392:402.
  122. Gayther SA, Gorringe KL, Ramus SJ, et al. Identification of germ-line E-cadherin mutations in gastric cancer families of European origin. Cancer Res 1998; 58:4086.
  123. Barber M, Murrell A, Ito Y, et al. Mechanisms and sequelae of E-cadherin silencing in hereditary diffuse gastric cancer. J Pathol 2008; 216:295.
  124. Oliveira C, Sousa S, Pinheiro H, et al. Quantification of epigenetic and genetic 2nd hits in CDH1 during hereditary diffuse gastric cancer syndrome progression. Gastroenterology 2009; 136:2137.
  125. Fitzgerald RC, Hardwick R, Huntsman D, et al. Hereditary diffuse gastric cancer: updated consensus guidelines for clinical management and directions for future research. J Med Genet 2010; 47:436.
  126. Charlton A, Blair V, Shaw D, et al. Hereditary diffuse gastric cancer: predominance of multiple foci of signet ring cell carcinoma in distal stomach and transitional zone. Gut 2004; 53:814.
  127. Caldas C, Carneiro F, Lynch HT, et al. Familial gastric cancer: overview and guidelines for management. J Med Genet 1999; 36:873.
  128. Humar B, Graziano F, Cascinu S, et al. Association of CDH1 haplotypes with susceptibility to sporadic diffuse gastric cancer. Oncogene 2002; 21:8192.
  129. Ramos-de la Medina A, More H, Medina-Franco H, et al. Single nucleotide polymorphisms (SNPs) at CDH1 promoter region in familial gastric cancer. Rev Esp Enferm Dig 2006; 98:36.
  130. Grady WM, Willis J, Guilford PJ, et al. Methylation of the CDH1 promoter as the second genetic hit in hereditary diffuse gastric cancer. Nat Genet 2000; 26:16.
  131. Tamura G, Yin J, Wang S, et al. E-Cadherin gene promoter hypermethylation in primary human gastric carcinomas. J Natl Cancer Inst 2000; 92:569.
  132. Machado JC, Oliveira C, Carvalho R, et al. E-cadherin gene (CDH1) promoter methylation as the second hit in sporadic diffuse gastric carcinoma. Oncogene 2001; 20:1525.
  133. Study Group of Millennium Genome Project for Cancer, Sakamoto H, Yoshimura K, et al. Genetic variation in PSCA is associated with susceptibility to diffuse-type gastric cancer. Nat Genet 2008; 40:730.
  134. Oliveira C, Seruca R, Carneiro F. Genetics, pathology, and clinics of familial gastric cancer. Int J Surg Pathol 2006; 14:21.
  135. Naito M, Yamazaki T, Tsutsumi R, et al. Influence of EPIYA-repeat polymorphism on the phosphorylation-dependent biological activity of Helicobacter pylori CagA. Gastroenterology 2006; 130:1181.
  136. Cover TL, Glupczynski Y, Lage AP, et al. Serologic detection of infection with cagA+ Helicobacter pylori strains. J Clin Microbiol 1995; 33:1496.
  137. Ghose C, Perez-Perez GI, Torres VJ, et al. Serological assays for identification of human gastric colonization by Helicobacter pylori strains expressing VacA m1 or m2. Clin Vaccine Immunol 2007; 14:442.
  138. Zintzaras E. Association of methylenetetrahydrofolate reductase (MTHFR) polymorphisms with genetic susceptibility to gastric cancer: a meta-analysis. J Hum Genet 2006; 51:618.
  139. Lu W, Pan K, Zhang L, et al. Genetic polymorphisms of interleukin (IL)-1B, IL-1RN, IL-8, IL-10 and tumor necrosis factor {alpha} and risk of gastric cancer in a Chinese population. Carcinogenesis 2005; 26:631.
  140. Taguchi A, Ohmiya N, Shirai K, et al. Interleukin-8 promoter polymorphism increases the risk of atrophic gastritis and gastric cancer in Japan. Cancer Epidemiol Biomarkers Prev 2005; 14:2487.
  141. Fock KM, Talley N, Moayyedi P, et al. Asia-Pacific consensus guidelines on gastric cancer prevention. J Gastroenterol Hepatol 2008; 23:351.
  142. Talley NJ. Is it time to screen and treat H pylori to prevent gastric cancer? Lancet 2008; 372:350.
  143. Fuccio L, Zagari RM, Minardi ME, Bazzoli F. Systematic review: Helicobacter pylori eradication for the prevention of gastric cancer. Aliment Pharmacol Ther 2007; 25:133.
  144. Correa P, Piazuelo MB, Wilson KT. Pathology of gastric intestinal metaplasia: clinical implications. Am J Gastroenterol 2010; 105:493.
  145. Wu CY, Wu MS, Kuo KN, et al. Effective reduction of gastric cancer risk with regular use of nonsteroidal anti-inflammatory drugs in Helicobacter pylori-infected patients. J Clin Oncol 2010; 28:2952.