Digestive Diseases and Sciences

, Volume 55, Issue 4, pp 1011–1016 | Cite as

DNMT3B Promoter Polymorphism and Risk of Gastric Cancer

  • Jiabo Hu
  • Hong Fan
  • Dongsheng Liu
  • Shuhong Zhang
  • Feng Zhang
  • Huaxi Xu
Original Article


To investigate the association of single-nucleotide polymorphism (SNP) in DNA methyltransferase 3B (DNMT3B) gene and the risk of gastric cancer (GC), we detected -149C>T and -579G>T in the promoter region of the DNMT3B gene by polymerase chain reaction restriction fragment length polymorphism (PCR–RFLP) and DNA sequencing analysis. The DNMT3B genotype was determined in 259 gastric cancer patients and 262 healthy controls that were frequency matched for age and gender. Results showed that individuals with at least one -579G allele were also at significantly decreased risk of gastric cancer [odds ratio (OR), 0.43; 95% confidence interval (CI) 0.26–0.72] compared with those having a -579TT genotype. The -149C>T genotype distribution was irrelevant to the risk of gastric cancer (OR, 1.49; 95% CI, 0.17–17.94) in the studied Chinese population. In addition, data suggested that DNMT3B genetic polymorphism varied among different races, ethnic groups, and geographic areas.


Gastric cancer DNA methylation DNMT3B SNP Cancer risk 



This work was supported by The National Natural Science Foundation of China, No. 30470950 and The Natural Science Foundation of Zhenjiang, No. SH2007073.


  1. 1.
    Yang L. Incidence and mortality of gastric cancer in China. World J Gastroenterol. 2006;12:17–20.PubMedGoogle Scholar
  2. 2.
    Leung WK, Wu MS, Kakugawa Y, et al. Asia pacific working group on gastric cancer: screening for gastric cancer in Asia: current evidence and practice. Lancet Oncol. 2008;9:279–287. doi: 10.1016/S1470-2045(08)70072-X.CrossRefPubMedGoogle Scholar
  3. 3.
    Bheemanaik S, Reddy YV, Rao DN. Structure, function and mechanism of exocyclic DNA methyltransferases. Biochem J. 2006;399:177–190. doi: 10.1042/BJ20060854.CrossRefPubMedGoogle Scholar
  4. 4.
    Suzuki M, Shigematsu H, Shames DS, et al. Methylation and gene silencing of the Ras-related GTPase gene in lung and breast cancers. Ann Surg Oncol. 2007;14:1397–1404. doi: 10.1245/s10434-006-9089-6.CrossRefPubMedGoogle Scholar
  5. 5.
    Fang JY, Lu R, Mikovits JA, Cheng ZH, Zhu HY, Chen YX. Regulation of hMSH2 and hMLH1 expression in the human colon cancer cell line SW1116 by DNA methyltransferase. Cancer Lett. 2006;233:124–130. doi: 10.1016/j.canlet.2005.03.005.CrossRefPubMedGoogle Scholar
  6. 6.
    Fang JY, Xiao SD. Alteration of DNA methylation in gastrointestinal carcinogenesis. J Gastroenterol Hepatol. 2001;16:960–968. doi: 10.1046/j.1440-1746.2001.02554.x.CrossRefPubMedGoogle Scholar
  7. 7.
    Jeltsch A. Molecular enzymology of mammalian DNA methyltransferases. Curr Top Microbiol Immunol. 2006;301:203–225. doi: 10.1007/3-540-31390-7_7.CrossRefPubMedGoogle Scholar
  8. 8.
    Bachman KE, Rountree MR, Baylin SB. Dnmt3a and Dnmt3b are transcriptional repressors that exhibit unique localization properties to heterochromatin. J Biol Chem. 2001;276:32282–32287. doi: 10.1074/jbc.M104661200.CrossRefPubMedGoogle Scholar
  9. 9.
    Okano M, Bell DW, Haber DA, Li E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell. 1999;99:247–257. doi: 10.1016/S0092-8674(00)81656-6.CrossRefPubMedGoogle Scholar
  10. 10.
    Robertson KD. DNA methylation, methyltransferases, and cancer. Oncogene. 2001;20:3139–3155. doi: 10.1038/sj.onc.1204341.CrossRefPubMedGoogle Scholar
  11. 11.
    Jones JS, Amos CI, Pande M, et al. DNMT3B polymorphism and hereditary nonpolyposis colorectal cancer age of onset. Cancer Epidemiol Biomarkers Prev. 2006;15:886–891. doi: 10.1158/1055-9965.EPI-05-0644.CrossRefPubMedGoogle Scholar
  12. 12.
    Montgomery KG, Liu MC, Eccles DM, Campbell IG. The DNMT3B C > T promoter polymorphism and risk of breast cancer in a British population: a case–control study. Breast Cancer Res. 2004;6:R390–R394. doi: 10.1186/bcr807.CrossRefPubMedGoogle Scholar
  13. 13.
    Shen H, Wang L, Spitz MR, Hong WK, Mao L, Wei Q. A novel polymorphism in human cytosine DNA-methyltransferase-3B promoter is associated with an increased risk of lung cancer. Cancer Res. 2002;62:4992–4995.PubMedGoogle Scholar
  14. 14.
    Singal R, Das PM, Manoharan M, Reis IM, Schlesselman JJ. Schlesselman, polymorphisms in the DNA methyltransferase 3B gene and prostate cancer risk. Oncol Rep. 2005;14:569–573.PubMedGoogle Scholar
  15. 15.
    Liu Z, Wang L, Wang LE, Sturgis EM, Wei Q. Polymorphisms of the DNMT3B gene and risk of squamous cell carcinoma of the head and neck: a case-control study. Cancer Lett. 2008;268:158–165. doi: 10.1016/j.canlet.2008.03.034.CrossRefPubMedGoogle Scholar
  16. 16.
    Shen H, Wang L, Spitz MR, Hong WK, Mao L, Wei Q. A novel polymorphism in human cytosine DNA-methyltransferase-3B promoter is associated with an increased risk of lung cancer. Cancer Res 2002;62:4992–4995.PubMedGoogle Scholar
  17. 17.
    Lee SJ, Jeon HS, Jang JS, et al. DNMT3B polymorphisms and risk of primary lung cancer. Carcinogenesis. 2005;26:403–409. doi: 10.1093/carcin/bgh307.CrossRefPubMedGoogle Scholar
  18. 18.
    Fan H, Liu DS, Zhang SH, Hu JB, Zhang F, Zhao ZJ. DNMT3B 579 G > T promoter polymorphism and risk of esophagus carcinoma in Chinese. World J Gastroenterol. 2008;14:2230–2234. doi: 10.3748/wjg.14.2230.CrossRefPubMedGoogle Scholar
  19. 19.
    Miller SA, Dykes DD, Polesky HF. A simple salting out procedure for extracting DNA from human nucleated cells. Nucleic Acids Res. 1988;16:1215. doi: 10.1093/nar/16.3.1215.CrossRefPubMedGoogle Scholar
  20. 20.
    Chang KP, Hao SP, Liu CT, et al. Promoter polymorphisms of DNMT3B and the risk of head and neck squamous cell carcinoma in Taiwan: a case–control study. Oral Oncol. 2007;43:345–351. doi: 10.1016/j.oraloncology.2006.04.006.CrossRefPubMedGoogle Scholar
  21. 21.
    Wang DG, Fan JB, Siao CJ, et al. Large-scale identification, mapping, and genotyping of single-nucleotide polymorphisms in the human genome. Science. 1988;280:1077–1082. doi: 10.1126/science.280.5366.1077.CrossRefGoogle Scholar
  22. 22.
    Skoog T, van’t Hooft FM, Kallin B, et al. A common functional polymorphism (C → A substitution at position -863) in the promoter region of the tumour necrosis factor alpha (TNF-alpha) gene associated with reduced circulating levels of TNF-alpha. Hum Mol Genet. 1999;8:1443–1449. doi: 10.1093/hmg/8.8.1443.CrossRefPubMedGoogle Scholar
  23. 23.
    Momparler RL, Bovenzi V. DNA methylation and cancer. J Cell Physiol. 2000;183:145–154. doi: 10.1002/(SICI)1097-4652(200005)183:2<145::AID-JCP1>3.0.CO;2-V.CrossRefPubMedGoogle Scholar
  24. 24.
    Aung PP, Matsumura S, Kuraoka K, et al. No evidence of correlation between the single nucleotide polymorphism of DNMT3B promoter and gastric cancer risk in a Japanese population. Oncol Rep. 2005;14:1151–1154.PubMedGoogle Scholar
  25. 25.
    Wang YM, Wang R, Wen DG, et al. Single nucleotide polymorphism in DNA methyltransferase 3B promoter and its association with gastric cardiac adenocarcinoma in North China. World J Gastroenterol. 2005;11:3623–3627.PubMedGoogle Scholar
  26. 26.
    Chen Z, Zhou Z, Chen X, et al. Single nucleotide polymorphism in DNMT3B promoter and the risk for idiopathic thrombocytopenic purpura in Chinese population. J Clin Immunol. 2008;28:399–404. doi: 10.1007/s10875-008-9198-z.CrossRefPubMedGoogle Scholar
  27. 27.
    Wu Y, Lin JS. DNA methyltransferase 3B promoter polymorphism and its susceptibility to primary hepatocellular carcinoma in the Chinese Han nationality population: a case-control study. World J Gastroenterol. 2007;13:6082–6086. doi: 10.3748/wjg.13.6082.CrossRefPubMedGoogle Scholar
  28. 28.
    Hong YS, Lee HJ, You CH, et al. DNMT3B 39179GT polymorphism and the risk of adenocarcinoma of the colon in Koreans. Biochem Genet. 2007;45:155–163. doi: 10.1007/s10528-006-9047-9.CrossRefPubMedGoogle Scholar
  29. 29.
    Wang J, Walsh G, Liu DD, Lee JJ, Mao L. Expression of Delta DNMT3B variants and its association with promoter methylation of p16 and RASSF1A in primary non-small cell lung cancer. Cancer Res. 2006;66:8361–8366. doi: 10.1158/0008-5472.CAN-06-2031.CrossRefPubMedGoogle Scholar
  30. 30.
    Saito Y, Kanai Y, Sakamoto M, Saito H, Ishii H, Hirohashi S. Overexpression of a splice variant of DNA methyltransferase 3b, DNMT3B4, associated with DNA hypomethylation on pericentromeric satellite regions during human hepatocarcinogenesis. Proc Natl Acad Sci USA. 2002;99:10060–10065. doi: 10.1073/pnas.152121799.CrossRefPubMedGoogle Scholar
  31. 31.
    Chen T, Ueda Y, Xie S, Li E. A novel Dnmt3a isoform produced from an alternative promoter localizes to euchromatin and its expression correlates with active de novo methylation. J Biol Chem. 2002;277:38746–38754. doi: 10.1074/jbc.M205312200.CrossRefPubMedGoogle Scholar
  32. 32.
    Soejima K, Fang W, Rollins BJ. DNA methyltransferase 3b contributes to oncogenic transformation induced by SV40 T antigen and activated Ras. Oncogene. 2003;22:4723–4733. doi: 10.1038/sj.onc.1206510.CrossRefPubMedGoogle Scholar
  33. 33.
    Weisenberger DJ, Velicescu M, Cheng JC, Gonzales FA, Liang G, Jones PA. Role of the DNA methyltransferase variant DNMT3B3 in DNA methylation. Mol Cancer Res. 2004;2:62–72.PubMedGoogle Scholar
  34. 34.
    Yu Z, Kone BC. Hypermethylation of the inducible nitricoxide synthase gene promoter inhibits its transcription. J Biol Chem. 2004;279:46954–46961. doi: 10.1074/jbc.M407192200.CrossRefPubMedGoogle Scholar
  35. 35.
    Kim SH, Park J, Choi MC, et al. Zinc-fingers and homeoboxes 1 (ZHX1) binds DNA methyltransferase (DNMT)3B to enhance DNMT3B-mediated transcriptional repression. Biochem Biophys Res Commun. 2007;355:318–323. doi: 10.1016/j.bbrc.2007.01.187.CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  • Jiabo Hu
    • 1
    • 2
  • Hong Fan
    • 1
  • Dongsheng Liu
    • 1
  • Shuhong Zhang
    • 3
  • Feng Zhang
    • 1
  • Huaxi Xu
    • 2
  1. 1.Key Laboratory of Developmental Genes and Human Diseases, Ministry of EducationSoutheast UniversityNanjingChina
  2. 2.School of Medical Science and Laboratory MedicineJiangsu UniversityZhenjiangChina
  3. 3.School of MedicineJiamusi UniversityJiamusiChina

Personalised recommendations