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. 1996 Sep;39(3):434–438. doi: 10.1136/gut.39.3.434

Global DNA hypomethylation occurs in the early stages of intestinal type gastric carcinoma.

M Cravo 1, R Pinto 1, P Fidalgo 1, P Chaves 1, L Glória 1, C Nobre-Leitão 1, F Costa Mira 1
PMCID: PMC1383352  PMID: 8949650

Abstract

BACKGROUND: Global DNA hypomethylation has been found in the premalignant stages of some neoplasms and has been implicated as an important factor for tumour progression. AIMS: The aim of this study was to evaluate whether DNA hypomethylation occurs during the process of gastric carcinogenesis. METHODS: Gastric specimens were obtained from 49 patients and histologically classified as: normal 10, superficial gastritis 14, chronic atrophic gastritis with intestinal metaplasia 15, and intestinal type of gastric carcinoma 10. Global DNA methylation was assessed by incubating DNA with (3H)-S-adenosylmethionine and Sss1 methylase. A higher incorporation of (3H) methyl groups reflects a lower degree of intrinsic methylation. RESULTS: A graduated increase in (3H) methyl group incorporation into DNA was found over the range extending from normal gastric mucosa, to superficial gastritis and to chronic atrophic gastritis (136,556 (24,085) v 235,725 (38,636) v 400,998 (26,747 dpm/micrograms/DNA respectively; p = 0.0002). No further increase was found in specimens from patients with carcinoma. No differences were found between extent of DNA methylation in neoplastic or non-neoplastic mucosa from patients with gastric carcinoma. Hypomethylation of DNA increased substantially with severe atrophy (p = 0.01) or with type III intestinal metaplasia (p = 0.15). CONCLUSIONS: Global DNA hypomethylation occurs in the early stages of gastric carcinogenesis, and it may be a novel biomarker of gastric neoplasia, useful in monitoring the response to chemopreventive agents.

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Selected References

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

  1. Balaghi M., Horne D. W., Wagner C. Hepatic one-carbon metabolism in early folate deficiency in rats. Biochem J. 1993 Apr 1;291(Pt 1):145–149. doi: 10.1042/bj2910145. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Balaghi M., Wagner C. DNA methylation in folate deficiency: use of CpG methylase. Biochem Biophys Res Commun. 1993 Jun 30;193(3):1184–1190. doi: 10.1006/bbrc.1993.1750. [DOI] [PubMed] [Google Scholar]
  3. Barr L. H., Menard J. W. Marjolin's ulcer. The LSU experience. Cancer. 1983 Jul 1;52(1):173–175. doi: 10.1002/1097-0142(19830701)52:1<173::aid-cncr2820520131>3.0.co;2-6. [DOI] [PubMed] [Google Scholar]
  4. Baylin S. B., Makos M., Wu J. J., Yen R. W., de Bustros A., Vertino P., Nelkin B. D. Abnormal patterns of DNA methylation in human neoplasia: potential consequences for tumor progression. Cancer Cells. 1991 Oct;3(10):383–390. [PubMed] [Google Scholar]
  5. Bird A. The essentials of DNA methylation. Cell. 1992 Jul 10;70(1):5–8. doi: 10.1016/0092-8674(92)90526-i. [DOI] [PubMed] [Google Scholar]
  6. Butterworth C. E., Jr, Hatch K. D., Macaluso M., Cole P., Sauberlich H. E., Soong S. J., Borst M., Baker V. V. Folate deficiency and cervical dysplasia. JAMA. 1992 Jan 22;267(4):528–533. [PubMed] [Google Scholar]
  7. Cedar H. DNA methylation and gene activity. Cell. 1988 Apr 8;53(1):3–4. doi: 10.1016/0092-8674(88)90479-5. [DOI] [PubMed] [Google Scholar]
  8. Chyou P. H., Nomura A. M., Hankin J. H., Stemmermann G. N. A case-cohort study of diet and stomach cancer. Cancer Res. 1990 Dec 1;50(23):7501–7504. [PubMed] [Google Scholar]
  9. Correa P., Haenszel W., Cuello C., Tannenbaum S., Archer M. A model for gastric cancer epidemiology. Lancet. 1975 Jul 12;2(7924):58–60. doi: 10.1016/s0140-6736(75)90498-5. [DOI] [PubMed] [Google Scholar]
  10. Correa P., Haenszel W., Cuello C., Zavala D., Fontham E., Zarama G., Tannenbaum S., Collazos T., Ruiz B. Gastric precancerous process in a high risk population: cohort follow-up. Cancer Res. 1990 Aug 1;50(15):4737–4740. [PubMed] [Google Scholar]
  11. Correa P., Haenszel W., Cuello C., Zavala D., Fontham E., Zarama G., Tannenbaum S., Collazos T., Ruiz B. Gastric precancerous process in a high risk population: cross-sectional studies. Cancer Res. 1990 Aug 1;50(15):4731–4736. [PubMed] [Google Scholar]
  12. 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]
  13. Correa P. The epidemiology and pathogenesis of chronic gastritis: three etiologic entites. Front Gastrointest Res. 1980;6:98–108. doi: 10.1159/000403325. [DOI] [PubMed] [Google Scholar]
  14. Counts J. L., Goodman J. I. Alterations in DNA methylation may play a variety of roles in carcinogenesis. Cell. 1995 Oct 6;83(1):13–15. doi: 10.1016/0092-8674(95)90228-7. [DOI] [PubMed] [Google Scholar]
  15. Cravo M. L., Mason J. B., Dayal Y., Hutchinson M., Smith D., Selhub J., Rosenberg I. H. Folate deficiency enhances the development of colonic neoplasia in dimethylhydrazine-treated rats. Cancer Res. 1992 Sep 15;52(18):5002–5006. [PubMed] [Google Scholar]
  16. Cravo M., Fidalgo P., Pereira A. D., Gouveia-Oliveira A., Chaves P., Selhub J., Mason J. B., Mira F. C., Leitao C. N. DNA methylation as an intermediate biomarker in colorectal cancer: modulation by folic acid supplementation. Eur J Cancer Prev. 1994 Nov;3(6):473–479. doi: 10.1097/00008469-199411000-00004. [DOI] [PubMed] [Google Scholar]
  17. Demirer T., Icli F., Uzunalimoglu O., Kucuk O. Diet and stomach cancer incidence. A case-control study in Turkey. Cancer. 1990 May 15;65(10):2344–2348. doi: 10.1002/1097-0142(19900515)65:10<2344::aid-cncr2820651030>3.0.co;2-h. [DOI] [PubMed] [Google Scholar]
  18. Doerfler W., Toth M., Kochanek S., Achten S., Freisem-Rabien U., Behn-Krappa A., Orend G. Eukaryotic DNA methylation: facts and problems. FEBS Lett. 1990 Aug 1;268(2):329–333. doi: 10.1016/0014-5793(90)81280-2. [DOI] [PubMed] [Google Scholar]
  19. Feinberg A. P., Gehrke C. W., Kuo K. C., Ehrlich M. Reduced genomic 5-methylcytosine content in human colonic neoplasia. Cancer Res. 1988 Mar 1;48(5):1159–1161. [PubMed] [Google Scholar]
  20. Feinberg A. P., Vogelstein B. Hypomethylation of ras oncogenes in primary human cancers. Biochem Biophys Res Commun. 1983 Feb 28;111(1):47–54. doi: 10.1016/s0006-291x(83)80115-6. [DOI] [PubMed] [Google Scholar]
  21. Ferguson A. T., Lapidus R. G., Baylin S. B., Davidson N. E. Demethylation of the estrogen receptor gene in estrogen receptor-negative breast cancer cells can reactivate estrogen receptor gene expression. Cancer Res. 1995 Jun 1;55(11):2279–2283. [PubMed] [Google Scholar]
  22. Fuchs C. S., Mayer R. J. Gastric carcinoma. N Engl J Med. 1995 Jul 6;333(1):32–41. doi: 10.1056/NEJM199507063330107. [DOI] [PubMed] [Google Scholar]
  23. Gama-Sosa M. A., Slagel V. A., Trewyn R. W., Oxenhandler R., Kuo K. C., Gehrke C. W., Ehrlich M. The 5-methylcytosine content of DNA from human tumors. Nucleic Acids Res. 1983 Oct 11;11(19):6883–6894. doi: 10.1093/nar/11.19.6883. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Goelz S. E., Vogelstein B., Hamilton S. R., Feinberg A. P. Hypomethylation of DNA from benign and malignant human colon neoplasms. Science. 1985 Apr 12;228(4696):187–190. doi: 10.1126/science.2579435. [DOI] [PubMed] [Google Scholar]
  25. Heimburger D. C., Alexander C. B., Birch R., Butterworth C. E., Jr, Bailey W. C., Krumdieck C. L. Improvement in bronchial squamous metaplasia in smokers treated with folate and vitamin B12. Report of a preliminary randomized, double-blind intervention trial. JAMA. 1988 Mar 11;259(10):1525–1530. [PubMed] [Google Scholar]
  26. Hongyo T., Buzard G. S., Palli D., Weghorst C. M., Amorosi A., Galli M., Caporaso N. E., Fraumeni J. F., Jr, Rice J. M. Mutations of the K-ras and p53 genes in gastric adenocarcinomas from a high-incidence region around Florence, Italy. Cancer Res. 1995 Jun 15;55(12):2665–2672. [PubMed] [Google Scholar]
  27. Johns M. B., Jr, Paulus-Thomas J. E. Purification of human genomic DNA from whole blood using sodium perchlorate in place of phenol. Anal Biochem. 1989 Aug 1;180(2):276–278. doi: 10.1016/0003-2697(89)90430-2. [DOI] [PubMed] [Google Scholar]
  28. Kaibara N., Kawaguchi H., Nishidoi H., Kimura O., Okamoto T., Koga S., Fukumoto S. Significance of mass survey for gastric cancer from the standpoint of surgery. Am J Surg. 1981 Nov;142(5):543–545. doi: 10.1016/0002-9610(81)90421-9. [DOI] [PubMed] [Google Scholar]
  29. Kim Y. I., Giuliano A., Hatch K. D., Schneider A., Nour M. A., Dallal G. E., Selhub J., Mason J. B. Global DNA hypomethylation increases progressively in cervical dysplasia and carcinoma. Cancer. 1994 Aug 1;74(3):893–899. doi: 10.1002/1097-0142(19940801)74:3<893::aid-cncr2820740316>3.0.co;2-b. [DOI] [PubMed] [Google Scholar]
  30. LAUREN P. THE TWO HISTOLOGICAL MAIN TYPES OF GASTRIC CARCINOMA: DIFFUSE AND SO-CALLED INTESTINAL-TYPE CARCINOMA. AN ATTEMPT AT A HISTO-CLINICAL CLASSIFICATION. Acta Pathol Microbiol Scand. 1965;64:31–49. doi: 10.1111/apm.1965.64.1.31. [DOI] [PubMed] [Google Scholar]
  31. Laird P. W., Jackson-Grusby L., Fazeli A., Dickinson S. L., Jung W. E., Li E., Weinberg R. A., Jaenisch R. Suppression of intestinal neoplasia by DNA hypomethylation. Cell. 1995 Apr 21;81(2):197–205. doi: 10.1016/0092-8674(95)90329-1. [DOI] [PubMed] [Google Scholar]
  32. Miller J. W., Nadeau M. R., Smith J., Smith D., Selhub J. Folate-deficiency-induced homocysteinaemia in rats: disruption of S-adenosylmethionine's co-ordinate regulation of homocysteine metabolism. Biochem J. 1994 Mar 1;298(Pt 2):415–419. doi: 10.1042/bj2980415. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Oda N., Tsujino T., Tsuda T., Yoshida K., Nakayama H., Yasui W., Tahara E. DNA ploidy pattern and amplification of ERBB and ERBB2 genes in human gastric carcinomas. Virchows Arch B Cell Pathol Incl Mol Pathol. 1990;58(4):273–277. doi: 10.1007/BF02890081. [DOI] [PubMed] [Google Scholar]
  34. Ramón J. M., Serra L., Cerdó C., Oromí J. Dietary factors and gastric cancer risk. A case-control study in Spain. Cancer. 1993 Mar 1;71(5):1731–1735. doi: 10.1002/1097-0142(19930301)71:5<1731::aid-cncr2820710505>3.0.co;2-x. [DOI] [PubMed] [Google Scholar]
  35. Razin A., Cedar H. DNA methylation and gene expression. Microbiol Rev. 1991 Sep;55(3):451–458. doi: 10.1128/mr.55.3.451-458.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  36. Razin A., Szyf M. DNA methylation patterns. Formation and function. Biochim Biophys Acta. 1984 Sep 10;782(4):331–342. doi: 10.1016/0167-4781(84)90043-5. [DOI] [PubMed] [Google Scholar]
  37. Rhyu M. G., Park W. S., Jung Y. J., Choi S. W., Meltzer S. J. Allelic deletions of MCC/APC and p53 are frequent late events in human gastric carcinogenesis. Gastroenterology. 1994 Jun;106(6):1584–1588. doi: 10.1016/0016-5085(94)90414-6. [DOI] [PubMed] [Google Scholar]
  38. Rokkas T., Filipe M. I., Sladen G. E. Detection of an increased incidence of early gastric cancer in patients with intestinal metaplasia type III who are closely followed up. Gut. 1991 Oct;32(10):1110–1113. doi: 10.1136/gut.32.10.1110. [DOI] [PMC free article] [PubMed] [Google Scholar]
  39. Sharrard R. M., Royds J. A., Rogers S., Shorthouse A. J. Patterns of methylation of the c-myc gene in human colorectal cancer progression. Br J Cancer. 1992 May;65(5):667–672. doi: 10.1038/bjc.1992.142. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Silverman A. L., Park J. G., Hamilton S. R., Gazdar A. F., Luk G. D., Baylin S. B. Abnormal methylation of the calcitonin gene in human colonic neoplasms. Cancer Res. 1989 Jul 1;49(13):3468–3473. [PubMed] [Google Scholar]
  41. Sipponen P., Kekki M., Haapakoski J., Ihamäki T., Siurala M. Gastric cancer risk in chronic atrophic gastritis: statistical calculations of cross-sectional data. Int J Cancer. 1985 Feb 15;35(2):173–177. doi: 10.1002/ijc.2910350206. [DOI] [PubMed] [Google Scholar]
  42. Sipponen P., Kekki M., Siurala M. Atrophic chronic gastritis and intestinal metaplasia in gastric carcinoma. Comparison with a representative population sample. Cancer. 1983 Sep 15;52(6):1062–1068. doi: 10.1002/1097-0142(19830915)52:6<1062::aid-cncr2820520622>3.0.co;2-p. [DOI] [PubMed] [Google Scholar]
  43. Sipponen P., Seppälä K., Varis K., Hjelt L., Ihamäki T., Kekki M., Siurala M. Intestinal metaplasia with colonic-type sulphomucins in the gastric mucosa; its association with gastric carcinoma. Acta Pathol Microbiol Scand A. 1980 Jul;88(4):217–224. doi: 10.1111/j.1699-0463.1980.tb02489.x. [DOI] [PubMed] [Google Scholar]
  44. Stemmermann G. N., Hayashi T. Intestinal metaplasia of the gastric mucosa: a gross and microscopic study of its distribution in various disease states. J Natl Cancer Inst. 1968 Sep;41(3):627–634. [PubMed] [Google Scholar]
  45. Tahara E. Molecular mechanism of stomach carcinogenesis. J Cancer Res Clin Oncol. 1993;119(5):265–272. doi: 10.1007/BF01212724. [DOI] [PubMed] [Google Scholar]
  46. de Bustros A., Nelkin B. D., Silverman A., Ehrlich G., Poiesz B., Baylin S. B. The short arm of chromosome 11 is a "hot spot" for hypermethylation in human neoplasia. Proc Natl Acad Sci U S A. 1988 Aug;85(15):5693–5697. doi: 10.1073/pnas.85.15.5693. [DOI] [PMC free article] [PubMed] [Google Scholar]

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