|Year : 2013 | Volume
| Issue : 2 | Page : 205-209
Analysis of risk factors associated with precancerous lesion of gastric cancer in patients from eastern China: A comparative study
Yanmin Wu1, Yaofu Fan2, Yangyang Jiang3, Yao Wang4, Hao Liu2, Muxin Wei2
1 Department of Traditional Chinese Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing; Department of Gastroenterology, The Third People's Hospital of Wuxi, Wuxi, China
2 Department of Traditional Chinese Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
3 Department of General Surgery, Wuxi Higher Health Vocational Technology School, Wuxi, China
4 Department of Emergency, The First Affiliated Hospital of Nanjing Medical University, Nanjing, China
|Date of Web Publication||13-Jun-2013|
Department of Traditional Chinese Medicine, 300 Guangzhou Road, First Affiliated Hospital of Nanjing Medical University, Nanjing - 210 029
Source of Support: This project was supported by grants from the
Special Fund of Six Talented Peak of Jiangsu Province No.07-B-15
(IB07), and Science and Technology Basic Research Program Jiangsu
Province (Natural Science Foundation) No. BK2009086., Conflict of Interest: None
Purpose: To investigate the association between various risk factors and precancerous lesion of gastric cancer (PLGC) in patients from eastern China.
Materials and Methods: 501 cases of PLGC and 523 cases of superficial gastritis were included. A comparative study of the relation between different risk factors and PGLC was performed.
Results: Statistical differences were noted in a series of indexes including Helicobacter pylori (HP) infection, family history of esophageal cancer (EC), gastric cancer (GC) and chronic atrophic gastritis (CAG), a history of CAG, gastric polyps (GP) and gastric ulcer (GU), usage of non-steroids (e.g., aspirin), gastroesophageal reflux disease (GERD), consuming alcohol, eating food rich in nitroso compounds, irregular eating habits with no breakfast, ingestion of smoked meat, fried food and spicy food, anxiety and depression. The risk factors associated with PLGC ranked in an order of a history of CAG, GP, family history of GC, usage of non-steroids (e.g., aspirin), ingestion of spicy food frequently, HP infection, family history of EC, consuming alcohol, anxiety, a history of GU, GERD and family history of CAG.
Conclusions: A history of CAG was most associated with PLGC in patients from eastern China, followed by a history of GP and family history of GC.
Keywords: Comparative study, precancerous lesion of gastric cancer, risk factors
|How to cite this article:|
Wu Y, Fan Y, Jiang Y, Wang Y, Liu H, Wei M. Analysis of risk factors associated with precancerous lesion of gastric cancer in patients from eastern China: A comparative study. J Can Res Ther 2013;9:205-9
|How to cite this URL:|
Wu Y, Fan Y, Jiang Y, Wang Y, Liu H, Wei M. Analysis of risk factors associated with precancerous lesion of gastric cancer in patients from eastern China: A comparative study. J Can Res Ther [serial online] 2013 [cited 2015 May 22];9:205-9. Available from: http://www.cancerjournal.net/text.asp?2013/9/2/205/113351
| > Introduction|| |
Gastric cancer (GC) is the fourth most common cancer in the world, and >1 million patients were diagnosed with GC annually.  As the most malignant tumor in China, GC caused great threats to the Chinese citizens.  The pathogenesis of GC is a gradual, multi-step process involving various genes and alternations of molecular pathways. ,,
Currently, several factors were reported to be associated with GC including gastritis, Helicobacter pylori (HP), intestinal metaplasia, etc. Growing evidences demonstrated a close relationship between HP and GC, e.g., HP infection could induce chronic inflammation and finally progress to gastric atrophy, intestinal metaplasia and gastric adenocarcinoma.  Intestinal metaplasia (IM) featured by loss of mucus-secreting goblet cells was also considered a risk factor in the development of GC.  However, it is still unknown whether IM was a premalignant condition for GC or a marker for increased cancer risk. Even though these factors were premalignant lesions for most of the patients with GC progression, few feasible suggestions and treatment plans were available as the insufficient understanding for their mechanisms. Thus, it is necessary to avoid the occurrence of GC by investigating the risk factors associated with precancerous lesions.
In this study, a comparative study was performed to investigate the various risk factors in patients from eastern China with precancerous lesion of gastric cancer (PLGC). Secondly, we aim to find the associated factors with PLGC, which can provide some guidance on its prevention. The results indicated that a history of chronic atrophic gastritis (CAG) was closely related with PLGC, followed by gastric polyps (GP) and family history of GC.
| > Materials and Methods|| |
In this study, 1024 subjects were enrolled. In the superficial gastritis group (control group), there were 231 male and 292 female patients aged between 29 and 73, with an average of 50.05 years. In the PLGC group, there were 241 male and 260 female patients aged between 29 and 75, with an average of 51.01 years. No statistical difference was observed in gender and age in both the groups. Gastroscopy and gastric mucosal histopathological examination was done on all subjects at Jiangsu Provincial Hospital from November 2009 to May 2011. The subjects were not related to each others, and no anti-HP therapy was given before gastroscopy. They then underwent gastroscopy, with biopsies taken from suspected lesions, lesser and greater curvatures of the antrum, angulus and lesser curvature of stomach. Patients with peptic ulcer, gastrointestinal polyposis, gastrointestinal tumor and multi-system organ failure were excluded.
This study was approved by the Ethics Committee of Nanjing Medical University. After signing informed consents, all subjects underwent a structured interview by a trained investigator. The structured questionnaire included family history of esophageal cancer (EC), family history of gastric disease, a history, eating habits and psychological factors.
The risk factors included in this study consisted of family history of esophageal carcinoma; relations infected with HP; family history of gastric disease including GC, CAG, gastric ulcer (GU) and gastroptosis; HP infection; a history of CAG, GU, GP and gastroptosis, usage of nonsteroidal anti-inflammatory drugs (e.g., aspirin) for three consecutive months, gastroesophageal reflux disease (GERD), and malignant anaemia; smoking (5 cigarettes per day, for >1 year); alcohol consumption (twice per week, equal to 500 ml beer, 250 ml yellow rice wine or 50 ml wine); ingestion of nitroso compounds (at least once per week); high salt diet; irregular eating habits with no breakfast; hard diet; eating very hot food; eating too fast; frequent ingestion of smoked meat (at least twice per week); frequent ingestion of fried food (at least twice per week); frequent ingestion of spicy food (at least twice per week); daily ingestion of fruit and vitamin; anxiety (self-rating anxiety scale ≥50 points); depression (self-rating depression scale ≥50 points); and insomnia (last for at least 1 month).
A database was established with EpiData Software by two investigators. Statistical analysis was performed with Statistics Analysis System (SAS) Software. All the data were presented as means ± standard deviation. A Student's t-test was applied to compare the differences between groups. The significance of proportions was tested using χ2 test. Odds ratios (OR) of gastric cancer and their respective 95% confidence intervals (95%) were calculated using conditional logistic regression analysis based on the incidence of superficial gastritis.
| > Results|| |
In [Table 1], a series of risk factors including family history of EC, personal and family history of gastric disease, life habits as well as mental health were analyzed. Significant difference was noted in the positive rates of patients with family histories of EC, GC and CAG in PLGC group compared with control group (P < 0.01). No statistical difference was noted at the terms of relations with HP infection, family history of GU and gastroptosis (P > 0.05).
|Table 1: Comparison of risk factors associated with precancerous lesion of gastric cancer|
Click here to view
With regards to the history, remarkable difference was observed in patients with a history of HP infection, CAG, GU, GP, GERD as well as usage of non-steroids (e.g., aspirin) in PLGC group compared with control group (P < 0.01). No statistical difference was noted in patients with a history of gastroptosis and malignant anaemia (P > 0.05).
For the eating habits, statistical difference was noted in alcohol consumption, ingestion of food rich in nitroso compounds, irregular eating habits with no breakfast, frequent ingestion of smoked meat, fried food and spicy food in both groups (P < 0.01). No significant difference was observed in smoking cigarettes, high salt diet, hard diet, eating very hot food, eating too fast as well as ingestion of fruit and vitamin daily (P > 0.05).
In this study, the association between psychological factors (i.e., depression, anxiety and insomnia) and PLGC was also investigated [Table 1]. Statistical differences were noted in the positive rates of depression and anxiety in PLGC group compared with those of control group (48.70% vs. 35.18%, P < 0.01; 42.51% vs. 35.18%, P < 0.05). For the positive rate of insomnia, no statistical difference was noted (13.97% vs. 13.96%, P > 0.05).
Multiple logistic regression analysis was performed to investigate the potential association of the risk factors and PLGC. And the results indicated PLGC was related with the following risk factors: HP infection, family history of EC, GC, CAG; familial adenomatous polyposis; a history of CAG, GU; usage of non-sterioids (e.g., aspirin); GERD; alcohol; frequent consumption of spicy food; and anxiety [Table 2]. Among these risk factors, a history of CAG was most closely related with PLGC.
|Table 2: Effects of different variations on precancerous lesion of gastric cancer|
Click here to view
| > Discussion|| |
According to our study, EC, GC and CAG observed in first degree relatives were closely related with PLGC with ORs of 4.55, 7.25 and 1.69, respectively. No direct association was noted between HP infection of relatives, GU, family history of gastroptosis and PLGC.
Patients with family history of carcinoma were reported to have high incidence of GC. , The relation between GC and genetics has been demonstrated by the non-random involvement of certain chromosomes and related oncogenes especially Ras and p53. , Another research showed GC was associated with IM among 52% of the patients included.  Currently, IM of the esophago-cardia junction was reported to be related with precancerous lesion of the adenocarcinoma of esophagus.  In this study, patients with family history of carcinoma were more apt to induce PLGC, which was consistent with the results mentioned above. However, we cannot identify whether this is due to environmental or genetic factors.
A history of portal hypertensive gastropathy, including HP infection, CAG, GU, GP, gastroptosis, GERD, use of non-steroids as well as malignant anemia, could enhance the incidence of PLGC. In this study, we found several factors, e.g., HP infection, CAG, GU, GP, GERD and the use of non-steroid were closely associated with PLGC with ORs of 5.09, 23.55, 2.72, 7.51, 6.14 and 2.49, respectively.
As the major cause for inducing PLGC, HP infection was closely related with GC and PLGC.  In this study, the OR for patients with HP infection was 5.09-fold compared with that of patients in control group, which was consistent with the previous report of Fontham et al.  with regards to the mechanism of HP-induced PLGC, no clear conclusions have been drawn. Previous report indicated HP infection could lead to cell proliferation and mutation of crucial oncogenes.  Moreover, HP infection had been reported to induce chronic gastritis and atrophic gastritis, thus leading to changes of the metabolism of gastric mucosa cells, and induced gastric premalignant lesions (e.g., intestinal metaplasia and gastric intraepithelial neoplasia). 
A series of precancerous lesions were reported to be related with CAG, and progressed to IM, dysplasia, and finally lead to gastric cancer. CAG is considered a process of chronic inflammation of the stomach mucosa, leading to loss of gastric glandular cells. Then the secretion of hydrochloric acid pepsin and intrinsic factors is impaired. Even though only a small subset of hosts infected by HP progressed to CAG, a condition featured by loss of acid-producing parietal cells, CAG is considered an antecedent to gastric adenocarcinoma. 
Previous report indicated about 88.6% of the patients with CAG always concurred with IM. Thus, CAG was supposed a risk factor for PLGC.  Our results demonstrated patients with CAG were more likely to develop PLGC, and was consistent with the foregoing results. Thus, it is necessary to keep close attention to the CAG as it is crucial for the prevention of PLGC.
Gastro-duodenal content reflux from GERD could induce the inflammation-metaplasia- dysplasia-adenocar-cinoma sequence. Proton pump inhibitors (PPIs) are potent blockers of gastric acid secretion, which are widely used for treating GERD and peptic ulcer-associated acid-secreting diseases. PPIs are both effective and remarkably safe. However, long-term PPI administration may be associated with several adverse effects. We find that both GERD and non-steroid drugs could induce GU, which triggered the occurrence of PLGC. For its mechanism, two speculations were concluded: Firstly, chronic inflammation caused by the mucous membrane in the ulcer region during the adaptation to the microenvironments, promoted the progress of mucosal erosion, thus triggering the decrease of gastric immunity, atrophy of gastric mucosa, reduction of blood supply and clearance of HP. All these could induce IM. Secondly, GU was always concurrent with HP infection which could induce PLGC.  PPI therapy in HP-positive patients changes the gastritis pattern from antral-predominant to corpus-predominant pangastritis, and in antral-predominant gastritis, inflammation of the antral mucosa stimulates gastrin secretion, which maintains acid production at a normal to high level and thus keeps the acid production pattern intact, in contrast with corpus-predominant gastritis, in which inflammation of the gastric corpus mucosa further impairs acid secretion, despite the increase in gastrin. , Some studies concluded that, in patients with HP infection, long-term PPI use is associated with an increased incidence of atrophic gastritis, which is a precursor of gastric cancer. ,,
As is known to all, gastric polypus is acknowledged to be related with gastric cancer. Studies indicated it was associated with mutation of oncogene and tumor suppressor gene, and promoted the progress of carcinoma.  In addition, patients with adenomatous polyps showed higher incidence of carcinoma, while the incidence of hyperplastic polyp patients ranged from 0.3% to 0.6%.  Furthermore, patients with inflammatory polyp had less chance of carcinoma, but this did have the opportunity to develop carcinoma. ,
To date, few reports about the association between gastric polypus and PLGC were published as most of the studies concentrated on the effects of gastric polypus on gastric cancer. According to our knowledge, GP were sessile or pedunculated lesions that stemmed from gastric epithelium or submucosa. Adenomas and hyperplastic polyps were apt to induce malignant carcinoma and were considered precursors of early gastric cancer. Our results indicated the risk of patients with gastric cancer was 7.5-fold compared with those of control group, demonstrating it was an important risk factor for PLGC.
According to previous reports, many factors including smoking, consuming alcohol, ingestion of nitroso compounds, high salt diet, irregular eating habits, eating too fast, eating fried food and spicy food frequently could induce PLGC.  Based on our study, consuming alcohol and frequent ingestion of spicy food were associated with PLGC. Although statistical difference was noted at the terms of taking nitroso compounds, irregular eating habits (no breakfast), frequent ingestion of smoked meat and fried food, these factors were not associated with PLGC after multiple logistic regression analysis.
The effect of alcohol on PLGC has been conflicting. Studies have indicated a negative association between consuming alcohol and PLGC while other studies proposed a synergy of consuming alcohol and smoking enhance PLGC. ,, Both alcohol and spicy food could cause some damage to gastric mucosa and induce chronic gastritis. In addition, alcohol could promote the absorption of carcinogen and decrease the detoxication activity of liver.
Adverse mental health was reported to be related with PLGC. In this study, the OR for patients with anxiety was 2.88-fold compared with patients without anxiety during the study. Although statistical difference was noted in depression conditions of PLGC group and control group, it was not included in the risk factor after multiple logistic regression analysis. Patients with anxiety were apt to induce PLGC as it could inhibit the parasympathetic nerve, prohibit the expression of acetyl choline and decrease the immunity of individuals. Moreover, anxiety could activate sympathetic nerve and promote the release of adrenal medulla. All these could promote the progress of PLGC.
In conclusion, a history of CAG was most associated with PLGC in patients from eastern China, followed by a history of GP and family history of gastric cancer. Early diagnosis and treatment together with establishing a healthy diet and mental health was recommended to the citizens living in eastern China to prevent the occurrence of PLGC.
| > Acknowledgments|| |
This project was supported by grants from the Ministry of Education, Culture, Science, and Technology, Japan Society for the Promotion of Science, Special Fund of Six Talented Peak of Jiangsu Province No.07-B-15 (IB07), and Science and Technology Basic Research Program Jiangsu Province (Natural Science Foundation) No. BK2009086.
| > References|| |
|1.||Busuttil RA, Boussioutas A. Intestinal metaplasia: A premalignant lesion involved in gastric carcinogenesis. J Gastroenterol Hepatol 2009;24:193-201. |
|2.||You WC, Zhang L, Gail MH, Li JY, Chang YS, Blot WJ, et al. Precancerous lesions in two counties of China with contrasting gastric cancer risk. Int J Epidemiol 1998;27:945-8. |
|3.||Correa P, Haenszel W, Cuello C, Tannenbaum S, Archer M. A model for gastric cancer epidemiology. Lancet 1975;2:58-60. |
|4.||Yasui W, Yokozaki H, Fujimoto J, Naka K, Kuniyasu H, Tahara E. Genetic and epigenetic alterations in multistep carcinogenesis of the stomach. J Gastroenterol 2000;35:111-5. |
|5.||Yu J, Miehlke S, Ebert MP, Hoffmann J, Breidert M, Alpen B, et al. Frequency of TPR-MET rearrangement in patients with gastric carcinoma and in first-degree relatives. Cancer 2000;88:1801-6. |
|6.||Ladeira MS, Rodrigues MA, Salvadori DM, Queiroz DM, Freire-Maia DV. DNA damage in patients infected by Helicobacter pylori. Cancer Epidemiol Biomarkers Prev 2004;13:631-7. |
|7.||Gutierrez-Gonzalez L, Graham TA, Rodriguez-Justo M, Leedham SJ, Novelli MR, Gay LJ, et al. The clonal origins of dysplasia from intestinal metaplasia in the human stomach. Gastroenterology 2011;140:1251-60. |
|8.||Chen JD, Kearns S, Porter T, Richards FM, Maher ER, Teh BT. MET mutation and familial gastric cancer. J Med Genet 2001;38:E26. |
|9.||Kato I, Tominaga S, Matsumoto K. A prospective study of stomach cancer among a rural Japanese population: A 6-year survey. Jpn J Cancer Res 1992;83:568-75. |
|10.||Hsieh LL, Hsieh JT, Wang LY, Fang CY, Chang SH, Chen TC. p53 mutations in gastric cancers from Taiwan. Cancer Lett 1996;100:107-13. |
|11.||Peddanna N, Holt S, Verma RS. Genetics of gastric cancer. Anticancer Res 1995;15:2055-64. |
|12.||Ruol A, Parenti A, Zaninotto G, Merigliano S, Costantini M, Cagol M, et al. Intestinal metaplasia is the probable common precursor of adenocarcinoma in barrett esophagus and adenocarcinoma of the gastric cardia. Cancer 2000;88:2520-8. |
|13.||Rios-Castellanos E, Sitas F, Shepherd NA, Jewell DP. Changing pattern of gastric cancer in Oxfordshire. Gut 1992;33:1312-7. |
|14.||Marusawa H. Mechanisms of H. pylori infection-induced gastric carcinogenesis. Gan To Kagaku Ryoho 2010;37:23-7. |
|15.||Fontham ET, Ruiz B, Perez A, Hunter F, Correa P. Determinants of Helicobacter pylori infection and chronic gastritis. Am J Gastroenterol 1995;90:1094-101. |
|16.||Ohata H, Kitauchi S, Yoshimura N, Mugitani K, Iwane M, Nakamura H, et al. Progression of chronic atrophic gastritis associated with Helicobacter pylori infection increases risk of gastric cancer. Int J Cancer 2004;109:138-43. |
|17.||Giuliani A, Spada S, Corona M, Demoro M, Di Bari M, Ricciardulli T, et al. Cancer precursor lesions in intact stomach Helicobacter pylori gastritis and in resected stomach gastritis. J Exp Clin Cancer Res 2003;22:371-8. |
|18.||Syder AJ, Guruge JL, Li Q, Hu Y, Oleksiewicz CM, Lorenz RG, et al. Helicobacter pylori attaches to NeuAc alpha 2,3Gal beta 1,4 glycoconjugates produced in the stomach of transgenic mice lacking parietal cells. Mol Cell 1999;3:263-74. |
|19.||Wang J, Chi DS, Kalin GB, Sosinski C, Miller LE, Burja I, et al. Helicobacter pylori infection and oncogene expressions in gastric carcinoma and its precursor lesions. Dig Dis Sci 2002;47:107-13. |
|20.||Kuipers EJ. Proton pump inhibitors and gastric neoplasia. Gut 2006;55:1217-21. |
|21.||Kuipers EJ, Sipponen P. Helicobacter pylori eradication for the prevention of gastric cancer. Helicobacter 2006;11:52-7. |
|22.||Ubukata H, Nagata H, Tabuchi T, Konishi S, Kasuga T, Tabuchi T. Why is the coexistence of gastric cancer and duodenal ulcer rare? Examination of factors related to both gastric cancer and duodenal ulcer. Gastric Cancer 2011;14:4-12. |
|23.||Huiping C, Kristjansdottir S, Bergthorsson JT, Jonasson JG, Magnusson J, Egilsson V, et al. High frequency of LOH, MSI and abnormal expression of FHIT in gastric cancer. Eur J Cancer 2002;38:728-35. |
|24.||Abraham SC, Singh VK, Yardley JH, Wu TT. Hyperplastic polyps of the stomach: Associations with histologic patterns of gastritis and gastric atrophy. Am J Surg Pathol 2001;25:500-7. |
|25.||Murakami K, Mitomi H, Yamashita K, Tanabe S, Saigenji K, Okayasu I. p53, but not c-Ki-ras, mutation and down-regulation of p21WAF1/CIP1 and cyclin D1 are associated with malignant transformation in gastric hyperplastic polyps. Am J Clin Pathol 2001;115:224-34. |
|26.||Yao T, Kajiwara M, Kuroiwa S, Iwashita A, Oya M, Kabashima A, et al. Malignant transformation of gastric hyperplastic polyps: Alteration of phenotypes, proliferative activity, and p53 expression. Hum Pathol 2002;33:1016-22. |
|27.||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. Jpn J Clin Oncol 2006;36:800-7. |
|28.||Chow WH, Swanson CA, Lissowska J, Groves FD, Sobin LH, Nasierowska-Guttmejer A, et al. Risk of stomach cancer in relation to consumption of cigarettes, alcohol, tea and coffee in Warsaw, Poland. Int J Cancer 1999;81:871-6. |
|29.||Franceschi S, La Vecchia C. Alcohol and the risk of cancers of the stomach and colon-rectum. Dig Dis 1994;12:276-89. |
|30.||Kneller RW, You WC, Chang YS, Liu WD, Zhang L, Zhao L, et al. Cigarette smoking and other risk factors for progression of precancerous stomach lesions. J Natl Cancer Inst 1992;84:1261-6. |
[Table 1], [Table 2]
|This article has been cited by|
||Modeling of influential predictors of gastric cancer incidence rates in Golestan Province, North Iran
| ||Behnampour, N., Hajizadeh, E., Zayeri, F., Semnani, S. |
| ||Asian Pacific Journal of Cancer Prevention. 2014; 15(3): 1111-1117 |
||Clinical and Forensic Signs Related to Ethanol Abuse: A Mechanistic Approach
| ||Ricardo Jorge Dinis-Oliveira,Teresa Magalhães,Roxana Moreira,Jorge Brandão Proença,Helena Pontes,Agostinho Santos,José Alberto Duarte,Félix Carvalho |
| ||Toxicology Mechanisms and Methods. 2014; 24(2): 81-110 |
||Advances in development of animal models of chronic atrophic gastritis
| ||Leng, X.-M. and Wei, M.-X. |
| ||World Chinese Journal of Digestology. 2013; 21(20): 1901-1906 |