The relationship between gene polymorphism and gastric cancer development - How is salt sensitivity associated with gastric cancer development? -

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Tomoyuki Shibata


Since the discovery of Helicobacter pylori (H. pylori) approximately 30 years ago, the relationships between H. pylori and several diseases have been identified. In this review, we summarize studies that proved that H. pylori is a risk factor for gastric cancer as well as studies that investigated how salt intake, another proposed risk factor for gastric cancer, contributes to gastric cancer, with the focus on host factors in the form of genetic polymorphisms.

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SHIBATA, Tomoyuki. The relationship between gene polymorphism and gastric cancer development - How is salt sensitivity associated with gastric cancer development? -. Medical Research Archives, [S.l.], v. 4, n. 8, dec. 2016. ISSN 2375-1924. Available at: <>. Date accessed: 30 jan. 2023.
Helicobacter pylori, gastric cancer, salt sensitivity, polymorphism
Review Articles


1 Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of patients with gastritis and peptic ulceration. Lancet (London, England). 1984; 1: 1311-5.
2 Forman D, Newell DG, Fullerton F, Yarnell JW, Stacey AR, Wald N, et al. Association between infection with Helicobacter pylori and risk of gastric cancer: evidence from a prospective investigation. Bmj. 1991; 302: 1302-5.
3 Nomura A, Stemmermann GN, Chyou PH, Kato I, Perez-Perez GI, Blaser MJ. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N Engl J Med. 1991; 325: 1132-6.
4 Parsonnet J, Friedman GD, Vandersteen DP, Chang Y, Vogelman JH, Orentreich N, et al. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med. 1991; 325: 1127-31.
5 Schistosomes, liver flukes and Helicobacter pylori. IARC Working Group on the Evaluation of Carcinogenic Risks to Humans. Lyon, 7-14 June 1994. IARC Monogr Eval Carcinog Risks Hum. 1994; 61: 1-241.
6 Uemura N, Okamoto S, Yamamoto S, Matsumura N, Yamaguchi S, Yamakido M, et al. Helicobacter pylori infection and the development of gastric cancer. N Engl J Med. 2001; 345: 784-9.
7 Uemura N, Mukai T, Okamoto S, Yamaguchi S, Mashiba H, Taniyama K, et al. Effect of Helicobacter pylori eradication on subsequent development of cancer after endoscopic resection of early gastric cancer. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology. 1997; 6: 639-42.
8 Fukase K, Kato M, Kikuchi S, Inoue K, Uemura N, Okamoto S, et al. Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial. Lancet (London, England). 2008; 372: 392-7.
9 Ford AC, Forman D, Hunt RH, Yuan Y, Moayyedi P. Helicobacter pylori eradication therapy to prevent gastric cancer in healthy asymptomatic infected individuals: systematic review and meta-analysis of randomised controlled trials. Bmj. 2014; 348: g3174.
10 Mobley HL, Cortesia MJ, Rosenthal LE, Jones BD. Characterization of urease from Campylobacter pylori. Journal of clinical microbiology. 1988; 26: 831-6.
11 Suzuki M, Miura S, Suematsu M, Fukumura D, Kurose I, Suzuki H, et al. Helicobacter pylori-associated ammonia production enhances neutrophil-dependent gastric mucosal cell injury. The American journal of physiology. 1992; 263: G719-25.
12 Blaser MJ, Perez-Perez GI, Kleanthous H, Cover TL, Peek RM, Chyou PH, 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: 2111-5.
13 Crabtree JE, Farmery SM. Helicobacter pylori and gastric mucosal cytokines: evidence that CagA-positive strains are more virulent. Laboratory investigation; a journal of technical methods and pathology. 1995; 73: 742-5.
14 Tsutsumi R, Takahashi A, Azuma T, Higashi H, Hatakeyama M. Focal adhesion kinase is a substrate and downstream effector of SHP-2 complexed with Helicobacter pylori CagA. Molecular and cellular biology. 2006; 26: 261-76.
15 Leunk RD, Johnson PT, David BC, Kraft WG, Morgan DR. Cytotoxic activity in broth-culture filtrates of Campylobacter pylori. Journal of medical microbiology. 1988; 26: 93-9.
16 de Bernard M, Arico B, Papini E, Rizzuto R, Grandi G, Rappuoli R, et al. Helicobacter pylori toxin VacA induces vacuole formation by acting in the cell cytosol. Molecular microbiology. 1997; 26: 665-74.
17 Higashi H, Tsutsumi R, Fujita A, Yamazaki S, Asaka M, Azuma T, et al. Biological activity of the Helicobacter pylori virulence factor CagA is determined by variation in the tyrosine phosphorylation sites. Proceedings of the National Academy of Sciences of the United States of America. 2002; 99: 14428-33.
18 Atherton JC, Cao P, Peek RM, Jr., Tummuru MK, Blaser MJ, Cover TL. Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori. Association of specific vacA types with cytotoxin production and peptic ulceration. The Journal of biological chemistry. 1995; 270: 17771-7.
19 El-Omar EM, Carrington M, Chow WH, McColl KE, Bream JH, Young HA, et al. Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature. 2000; 404: 398-402.
20 Sugimoto M, Furuta T, Shirai N, Nakamura A, Xiao F, Kajimura M, et al. Different effects of polymorphisms of tumor necrosis factor-alpha and interleukin-1 beta on development of peptic ulcer and gastric cancer. Journal of gastroenterology and hepatology. 2007; 22: 51-9.
21 Kakiuchi M, Nishizawa T, Ueda H, Gotoh K, Tanaka A, Hayashi A, et al. Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma. Nat Genet. 2014; 46: 583-7.
22 Gonzalez CA, Pera G, Agudo A, Palli D, Krogh V, Vineis P, et al. Smoking and the risk of gastric cancer in the European Prospective Investigation Into Cancer and Nutrition (EPIC). Int J Cancer. 2003; 107: 629-34.
23 Nishino Y, Inoue M, Tsuji I, Wakai K, Nagata C, Mizoue T, et al. Tobacco smoking and gastric cancer risk: an evaluation based on a systematic review of epidemiologic evidence among the Japanese population. Japanese journal of clinical oncology. 2006; 36: 800-7.
24 Sato T FT, Suzuki T, Takayanagi J, Murakami T, Shiotsuki N, Tanaka R, Tsuji R. The relation between gastric cancer mortality rate and salted food intake in several places in Japan. Bull Inst Public Health. 1959; 8: 187-98.
25 La Vecchia C, Negri E, D'Avanzo B, Franceschi S. Electric refrigerator use and gastric cancer risk. British journal of cancer. 1990; 62: 136-7.
26 Boeing H, Frentzel-Beyme R. Regional risk factors for stomach cancer in the FRG. Environmental health perspectives. 1991; 94: 83-9.
27 Tsugane S, Tei Y, Takahashi T, Watanabe S, Sugano K. Salty food intake and risk of Helicobacter pylori infection. Jpn J Cancer Res. 1994; 85: 474-8.
28 Charnley G, Tannenbaum SR. Flow cytometric analysis of the effect of sodium chloride on gastric cancer risk in the rat. Cancer Res. 1985; 45: 5608-16.
29 Furihata C, Ohta H, Katsuyama T. Cause and effect between concentration-dependent tissue damage and temporary cell proliferation in rat stomach mucosa by NaCl, a stomach tumor promoter. Carcinogenesis. 1996; 17: 401-6.
30 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: 101-6.
31 Nozaki K, Shimizu N, Inada K, Tsukamoto T, Inoue M, Kumagai T, et al. Synergistic promoting effects of Helicobacter pylori infection and high-salt diet on gastric carcinogenesis in Mongolian gerbils. Jpn J Cancer Res. 2002; 93: 1083-9.
32 Kato S, Tsukamoto T, Mizoshita T, Tanaka H, Kumagai T, Ota H, et al. High salt diets dose-dependently promote gastric chemical carcinogenesis in Helicobacter pylori-infected Mongolian gerbils associated with a shift in mucin production from glandular to surface mucous cells. Int J Cancer. 2006; 119: 1558-66.
33 Fox JG, Dangler CA, Taylor NS, King A, Koh TJ, Wang TC. High-salt diet induces gastric epithelial hyperplasia and parietal cell loss, and enhances Helicobacter pylori colonization in C57BL/6 mice. Cancer Res. 1999; 59: 4823-8.
34 Loh JT, Torres VJ, Cover TL. Regulation of Helicobacter pylori cagA expression in response to salt. Cancer Res. 2007; 67: 4709-15.
35 MacGregor GA, Markandu ND, Roulston JE, Jones JC, Morton JJ. Maintenance of blood pressure by the renin-angiotensin system in normal man. Nature. 1981; 291: 329-31.
36 Caulfield M, Lavender P, Farrall M, Munroe P, Lawson M, Turner P, et al. Linkage of the angiotensinogen gene to essential hypertension. N Engl J Med. 1994; 330: 1629-33.
37 Jeunemaitre X, Soubrier F, Kotelevtsev YV, Lifton RP, Williams CS, Charru A, et al. Molecular basis of human hypertension: role of angiotensinogen. Cell. 1992; 71: 169-80.
38 Corvol P, Jeunemaitre X, Charru A, Kotelevtsev Y, Soubrier F. Role of the renin-angiotensin system in blood pressure regulation and in human hypertension: new insights from molecular genetics. Recent progress in hormone research. 1995; 50: 287-308.
39 Staessen JA, Kuznetsova T, Wang JG, Emelianov D, Vlietinck R, Fagard R. M235T angiotensinogen gene polymorphism and cardiovascular renal risk. Journal of hypertension. 1999; 17: 9-17.
40 Shibata T, Tahara T, Arisawa T, Hirata I. Polymorphism of the salt sensitivity gene angiotensinogen and gastric cancer risk. Mol Med Rep. 2011; 4: 723-6.
41 Sugimoto M, Furuta T, Shirai N, Kodaira C, Nishino M, Ikuma M, et al. Role of angiotensinogen gene polymorphism on Helicobacter pylori infection-related gastric cancer risk in Japanese. Carcinogenesis. 2007; 28: 2036-40.
42 Shibata T, Tahara T, Yonemura J, Okubo M, Yoshioka D, Nakamura M, et al. The G-protein beta3 polymorphism is associated with diffuse type gastric cancer in Japanese. Asian Pacific journal of cancer prevention : APJCP. 2010; 11: 1195-9.