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. 1998 Mar;42(3):351–356. doi: 10.1136/gut.42.3.351

Oxidative DNA damage accumulation in gastric carcinogenesis

F Farinati 1, R Cardin 1, P Degan 1, M Rugge 1, M Di 1, P Bonvicini 1, R Naccarato 1
PMCID: PMC1727017  PMID: 9577340

Abstract

Background—Gastric carcinogenesis is a multifactorial, multistep process, in which chronic inflammation plays a major role. 
Aims—In order to ascertain whether free radical mediated oxidative DNA damage is involved in such a process, concentrations of 8-hydroxydeoxyguanosine (8OHdG), a mutagenic/carcinogenic adduct, and thiobarbituric acid reactive substances (TBARS), as an indirect measure of free radical mediated damage, were determined in biopsy specimens from patients undergoing endoscopy. 
Patients—Eighty eight patients were divided into histological subgroups as follows: 27 with chronic non-atrophic gastritis, 41 with atrophic gastritis, six with gastric cancer, and 14 unaffected controls. 
Methods—Intestinal metaplasia, Helicobacter pylori infection, and disease activity were semiquantitatively scored. 8OHdG concentrations were assessed by HPLC with electrochemical detection, and TBARS concentrations were fluorimetrically assayed. 
Results—8OHdG concentrations (mean number of adducts/105 dG residues) were significantly higher in chronic atrophic gastritis (p=0.0009). Significantly higher concentrations were also detected in the presence of severe disease activity (p=0.02), intestinal metaplasia (p=0.035), and H pylori infection (p=0.001). TBARS concentrations were also higher in atrophic gastritis, though not significantly so. In a multiple logistic regression analysis, 8OHdG concentrations correlated best with the presence and severity of H pylori infection (r=0.53, p=0.002). 
Conclusions—Chronic gastritis is characterised by the accumulation of oxidative DNA damage with mutagenic and carcinogenic potential. H pylori infection is the major determinant for DNA adduct formation. 



Keywords: free radicals; oxidative DNA damage; gastric carcinogenesis; precancerous changes; peroxidative damage

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Figure 1 .

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Mean (SEM) concentrations of 80HdG and TBARS in gastric mucosa. 


Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adelman R., Saul R. L., Ames B. N. Oxidative damage to DNA: relation to species metabolic rate and life span. Proc Natl Acad Sci U S A. 1988 Apr;85(8):2706–2708. doi: 10.1073/pnas.85.8.2706. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Ames B. N. Endogenous oxidative DNA damage, aging, and cancer. Free Radic Res Commun. 1989;7(3-6):121–128. doi: 10.3109/10715768909087933. [DOI] [PubMed] [Google Scholar]
  3. Ames B. N. Mutagenesis and carcinogenesis: endogenous and exogenous factors. Environ Mol Mutagen. 1989;14 (Suppl 16):66–77. doi: 10.1002/em.2850140614. [DOI] [PubMed] [Google Scholar]
  4. Aruoma O. I., Kaur H., Halliwell B. Oxygen free radicals and human diseases. J R Soc Health. 1991 Oct;111(5):172–177. doi: 10.1177/146642409111100506. [DOI] [PubMed] [Google Scholar]
  5. Baik S. C., Youn H. S., Chung M. H., Lee W. K., Cho M. J., Ko G. H., Park C. K., Kasai H., Rhee K. H. Increased oxidative DNA damage in Helicobacter pylori-infected human gastric mucosa. Cancer Res. 1996 Mar 15;56(6):1279–1282. [PubMed] [Google Scholar]
  6. Basaga H. S. Biochemical aspects of free radicals. Biochem Cell Biol. 1990 Jul-Aug;68(7-8):989–998. doi: 10.1139/o90-146. [DOI] [PubMed] [Google Scholar]
  7. Bingham S. A., Gill C., Welch A., Day K., Cassidy A., Khaw K. T., Sneyd M. J., Key T. J., Roe L., Day N. E. Comparison of dietary assessment methods in nutritional epidemiology: weighed records v. 24 h recalls, food-frequency questionnaires and estimated-diet records. Br J Nutr. 1994 Oct;72(4):619–643. doi: 10.1079/bjn19940064. [DOI] [PubMed] [Google Scholar]
  8. Cathcart R., Schwiers E., Saul R. L., Ames B. N. Thymine glycol and thymidine glycol in human and rat urine: a possible assay for oxidative DNA damage. Proc Natl Acad Sci U S A. 1984 Sep;81(18):5633–5637. doi: 10.1073/pnas.81.18.5633. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Correa P. Human gastric carcinogenesis: a multistep and multifactorial process--First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res. 1992 Dec 15;52(24):6735–6740. [PubMed] [Google Scholar]
  10. Davies G. R., Simmonds N. J., Stevens T. R., Sheaff M. T., Banatvala N., Laurenson I. F., Blake D. R., Rampton D. S. Helicobacter pylori stimulates antral mucosal reactive oxygen metabolite production in vivo. Gut. 1994 Feb;35(2):179–185. doi: 10.1136/gut.35.2.179. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Degan P., Bonassi S., De Caterina M., Korkina L. G., Pinto L., Scopacasa F., Zatterale A., Calzone R., Pagano G. In vivo accumulation of 8-hydroxy-2'-deoxyguanosine in DNA correlates with release of reactive oxygen species in Fanconi's anaemia families. Carcinogenesis. 1995 Apr;16(4):735–741. doi: 10.1093/carcin/16.4.735. [DOI] [PubMed] [Google Scholar]
  12. Degan P., Shigenaga M. K., Park E. M., Alperin P. E., Ames B. N. Immunoaffinity isolation of urinary 8-hydroxy-2'-deoxyguanosine and 8-hydroxyguanine and quantitation of 8-hydroxy-2'-deoxyguanosine in DNA by polyclonal antibodies. Carcinogenesis. 1991 May;12(5):865–871. doi: 10.1093/carcin/12.5.865. [DOI] [PubMed] [Google Scholar]
  13. Dyke G. W., Craven J. L., Hall R., Garner R. C. DNA damage as measured by 32P-postlabelling in normal and pre-malignant gastric mucosa. Cancer Lett. 1994 Feb 28;77(1):45–50. doi: 10.1016/0304-3835(94)90346-8. [DOI] [PubMed] [Google Scholar]
  14. Dyke G. W., Craven J. L., Hall R., Garner R. C. Effect of vitamin C supplementation on gastric mucosal DNA damage. Carcinogenesis. 1994 Feb;15(2):291–295. doi: 10.1093/carcin/15.2.291. [DOI] [PubMed] [Google Scholar]
  15. Farinati F., Cardin R., De Maria N., Della Libera G., Marafin C., Lecis E., Burra P., Floreani A., Cecchetto A., Naccarato R. Iron storage, lipid peroxidation and glutathione turnover in chronic anti-HCV positive hepatitis. J Hepatol. 1995 Apr;22(4):449–456. doi: 10.1016/0168-8278(95)80108-1. [DOI] [PubMed] [Google Scholar]
  16. Farinati F., Della Libera G., Cardin R., Molari A., Plebani M., Rugge M., Di Mario F., Naccarato R. Gastric antioxidant, nitrites, and mucosal lipoperoxidation in chronic gastritis and Helicobacter pylori infection. J Clin Gastroenterol. 1996 Jun;22(4):275–281. doi: 10.1097/00004836-199606000-00007. [DOI] [PubMed] [Google Scholar]
  17. Forman D., Newell D. G., Fullerton F., Yarnell J. W., Stacey A. R., Wald N., Sitas F. Association between infection with Helicobacter pylori and risk of gastric cancer: evidence from a prospective investigation. BMJ. 1991 Jun 1;302(6788):1302–1305. doi: 10.1136/bmj.302.6788.1302. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Fraga C. G., Shigenaga M. K., Park J. W., Degan P., Ames B. N. Oxidative damage to DNA during aging: 8-hydroxy-2'-deoxyguanosine in rat organ DNA and urine. Proc Natl Acad Sci U S A. 1990 Jun;87(12):4533–4537. doi: 10.1073/pnas.87.12.4533. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Hall C. N., Badawi A. F., O'Connor P. J., Saffhill R. The detection of alkylation damage in the DNA of human gastrointestinal tissues. Br J Cancer. 1991 Jul;64(1):59–63. doi: 10.1038/bjc.1991.239. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Halliwell B., Aruoma O. I. DNA damage by oxygen-derived species. Its mechanism and measurement in mammalian systems. FEBS Lett. 1991 Apr 9;281(1-2):9–19. doi: 10.1016/0014-5793(91)80347-6. [DOI] [PubMed] [Google Scholar]
  21. Hollstein M. C., Brooks P., Linn S., Ames B. N. Hydroxymethyluracil DNA glycosylase in mammalian cells. Proc Natl Acad Sci U S A. 1984 Jul;81(13):4003–4007. doi: 10.1073/pnas.81.13.4003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Kaneko T., Tahara S., Matsuo M. Non-linear accumulation of 8-hydroxy-2'-deoxyguanosine, a marker of oxidized DNA damage, during aging. Mutat Res. 1996 May;316(5-6):277–285. doi: 10.1016/s0921-8734(96)90010-7. [DOI] [PubMed] [Google Scholar]
  23. Kuchino Y., Mori F., Kasai H., Inoue H., Iwai S., Miura K., Ohtsuka E., Nishimura S. Misreading of DNA templates containing 8-hydroxydeoxyguanosine at the modified base and at adjacent residues. Nature. 1987 May 7;327(6117):77–79. doi: 10.1038/327077a0. [DOI] [PubMed] [Google Scholar]
  24. Langton S. R., Cesareo S. D. Helicobacter pylori associated phospholipase A2 activity: a factor in peptic ulcer production? J Clin Pathol. 1992 Mar;45(3):221–224. doi: 10.1136/jcp.45.3.221. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Ming S. C., Bajtai A., Correa P., Elster K., Jarvi O. H., Munoz N., Nagayo T., Stemmerman G. N. Gastric dysplasia. Significance and pathologic criteria. Cancer. 1984 Nov 1;54(9):1794–1801. doi: 10.1002/1097-0142(19841101)54:9<1794::aid-cncr2820540907>3.0.co;2-w. [DOI] [PubMed] [Google Scholar]
  26. Mooney C., Keenan J., Munster D., Wilson I., Allardyce R., Bagshaw P., Chapman B., Chadwick V. Neutrophil activation by Helicobacter pylori. Gut. 1991 Aug;32(8):853–857. doi: 10.1136/gut.32.8.853. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. Morson B. C., Sobin L. H., Grundmann E., Johansen A., Nagayo T., Serck-Hanssen A. Precancerous conditions and epithelial dysplasia in the stomach. J Clin Pathol. 1980 Aug;33(8):711–721. doi: 10.1136/jcp.33.8.711. [DOI] [PMC free article] [PubMed] [Google Scholar]
  28. Nomura A., Stemmermann G. N., Chyou P. H., Kato I., Perez-Perez G. I., Blaser M. J. Helicobacter pylori infection and gastric carcinoma among Japanese Americans in Hawaii. N Engl J Med. 1991 Oct 17;325(16):1132–1136. doi: 10.1056/NEJM199110173251604. [DOI] [PubMed] [Google Scholar]
  29. Parsonnet J., Friedman G. D., Vandersteen D. P., Chang Y., Vogelman J. H., Orentreich N., Sibley R. K. Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med. 1991 Oct 17;325(16):1127–1131. doi: 10.1056/NEJM199110173251603. [DOI] [PubMed] [Google Scholar]
  30. Price A. B. The Sydney System: histological division. J Gastroenterol Hepatol. 1991 May-Jun;6(3):209–222. doi: 10.1111/j.1440-1746.1991.tb01468.x. [DOI] [PubMed] [Google Scholar]
  31. Rautelin H., Blomberg B., Fredlund H., Järnerot G., Danielsson D. Incidence of Helicobacter pylori strains activating neutrophils in patients with peptic ulcer disease. Gut. 1993 May;34(5):599–603. doi: 10.1136/gut.34.5.599. [DOI] [PMC free article] [PubMed] [Google Scholar]
  32. Rugge M., Farinati F., Baffa R., Sonego F., Di Mario F., Leandro G., Valiante F. Gastric epithelial dysplasia in the natural history of gastric cancer: a multicenter prospective follow-up study. Interdisciplinary Group on Gastric Epithelial Dysplasia. Gastroenterology. 1994 Nov;107(5):1288–1296. doi: 10.1016/0016-5085(94)90529-0. [DOI] [PubMed] [Google Scholar]
  33. Shigenaga M. K., Gimeno C. J., Ames B. N. Urinary 8-hydroxy-2'-deoxyguanosine as a biological marker of in vivo oxidative DNA damage. Proc Natl Acad Sci U S A. 1989 Dec;86(24):9697–9701. doi: 10.1073/pnas.86.24.9697. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Sobala G. M., Pignatelli B., Schorah C. J., Bartsch H., Sanderson M., Dixon M. F., Shires S., King R. F., Axon A. T. Levels of nitrite, nitrate, N-nitroso compounds, ascorbic acid and total bile acids in gastric juice of patients with and without precancerous conditions of the stomach. Carcinogenesis. 1991 Feb;12(2):193–198. doi: 10.1093/carcin/12.2.193. [DOI] [PubMed] [Google Scholar]
  35. Sobala G. M., Schorah C. J., Sanderson M., Dixon M. F., Tompkins D. S., Godwin P., Axon A. T. Ascorbic acid in the human stomach. Gastroenterology. 1989 Aug;97(2):357–363. doi: 10.1016/0016-5085(89)90071-1. [DOI] [PubMed] [Google Scholar]
  36. Troll W., Wiesner R. The role of oxygen radicals as a possible mechanism of tumor promotion. Annu Rev Pharmacol Toxicol. 1985;25:509–528. doi: 10.1146/annurev.pa.25.040185.002453. [DOI] [PubMed] [Google Scholar]
  37. Weitzman S. A., Gordon L. I. Inflammation and cancer: role of phagocyte-generated oxidants in carcinogenesis. Blood. 1990 Aug 15;76(4):655–663. [PubMed] [Google Scholar]
  38. de Groot H. Reactive oxygen species in tissue injury. Hepatogastroenterology. 1994 Aug;41(4):328–332. [PubMed] [Google Scholar]

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