Skip to main content
SpringerLink
Log in

Genetic variation in the promoter of DNMT3B is associated with the risk of colorectal cancer

  • Original Article
  • Published:
International Journal of Colorectal Disease Aims and scope Submit manuscript

Abstract

Purpose

DNA methyltransferase-3B (DNMT3B) plays an important role in the generation of aberrant methylation in carcinogenesis. Polymorphisms of the DNMT3B gene may influence DNMT3B enzyme activity on DNA methylation, thereby modulating the susceptibility to colorectal cancer (CRC).

Methods

The polymorphisms in the promoter region of the DNMT3B gene [−149C>T (rs2424913) and −579G>T (rs1569686)] were detected by polymerase chain reaction–restriction fragment length polymorphism (PCR-RFLP), and a total of 544 CRC patients and 533 age- and sex-matched healthy controls were enrolled in the case–control study.

Results

The results showed that the −579G allele was associated with a significantly decreased risk of CRC (adjusted OR, 0.50; 95%CI, 0.35–0.72; P = 0.0002) when compared with the −579TT genotype. However, the DNMT3B-149CT genotype was not associated with the risk of CRC (adjusted OR, 0.48; 95%CI, 0.18–1.30; P = 0.151). In addition, stratification analysis revealed that the increased risk was predominant in both colon cancer and rectal cancer showing no effect of primary occurrence site.

Conclusion

Our research demonstrated the −579G allele was a potential protective factor for the occurrence of CRC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Similar content being viewed by others

References

  1. Makinen MJ (2007) Colorectal serrated adenocarcinoma. Histopathology 50:131–150

    Article  PubMed  CAS  Google Scholar 

  2. Peto J (2001) Cancer epidemiology in the last century and the next decade. Nature 411:390–395

    Article  PubMed  CAS  Google Scholar 

  3. Weber BL, Nathanson KL (2000) Low penetrance genes associated with increased risk for breast cancer. Eur J Cancer 36:1193–1199

    Article  PubMed  CAS  Google Scholar 

  4. Ponder BA (2001) Cancer genetics. Nature 411:336–341

    Article  PubMed  CAS  Google Scholar 

  5. Linhart HG, Lin H, Yamada Y, Moran E, Steine EJ, Gokhale S, Lo G, Cantu E, Ehrich M, He T, Meissner A, Jaenisch R (2007) Dnmt3b promotes tumorigenesis in vivo by gene-specific de novo methylation and transcriptional silencing. Genes Dev 21:3110–3122

    Article  PubMed  CAS  Google Scholar 

  6. Bheemanaik S, Reddy YV, Rao DN (2006) Structure, function and mechanism of exocyclic DNA methyltransferases. Biochem J 399:177–190

    Article  PubMed  CAS  Google Scholar 

  7. Baylin SB, Herman JG (2000) DNA hypermethylation in tumorigenesis: epigenetics joins genetics. Trends Genet 16:168–174

    Article  PubMed  CAS  Google Scholar 

  8. Momparler RL, Bovenzi V (2000) DNA methylation and cancer. J Cell Physiol 183:145–154

    Article  PubMed  CAS  Google Scholar 

  9. Esteller M, Fraga MF, Guo M, Garcia-Foncillas J, Hedenfalk I (2001) DNA methylation patterns in hereditary human cancers mimic sporadic tumorigenesis. Hum Mol Genet 10:3001–3007

    Article  PubMed  CAS  Google Scholar 

  10. Issa JP (2000) The epigenetics of colorectal cancer. Ann NY Acad Sci 910:140–155

    Article  PubMed  CAS  Google Scholar 

  11. Robertson KD (2005) DNA methylation and human disease. Nat Rev Genet 6:597–610

    Article  PubMed  CAS  Google Scholar 

  12. Simao TA, Simoes GL, Ribeiro FS, Cidade DA, Andreollo NA, Lopes LR, Macedo JM, Acatauassu R, Teixeira AM, Felzenszwalb I, Pinto LF, Albano RM (2006) Lower expression of p14ARF and p16INK4a correlates with higher DNMT3B expression in human oesophageal squamous cell carcinomas. Hum Exp Toxicol 25:515–522

    Article  CAS  Google Scholar 

  13. Wang L, Wang J, Sun S, Rodriguez M, Yue P, Jang SJ, Mao L (2006) A novel DNMT3B subfamily, DeltaDNMT3B, is the predominant form of DNMT3B in non-small cell lung cancer. Int J Oncol 29:201–207

    PubMed  CAS  Google Scholar 

  14. Robertson KD, Keyomarsi K, Gonzales FA, Velicescu M, Jones PA (2000) Differential mRNA expression of the human DNA methyltransferases (DNMTs) 1, 3a and 3b during the G(0)/G(1) to S phase transition in normal and tumor cells. Nucleic Acids Res 28:2108–2113

    Article  PubMed  CAS  Google Scholar 

  15. Nagai M, Nakamura A, Makino R, Mitamura K (2003) Expression of DNA (5-cytosin)-methyltransferases (DNMTs) in hepatocellular carcinomas. Hepatol Res 26:186–191

    Article  PubMed  CAS  Google Scholar 

  16. Yakushiji T, Uzawa K, Shibahara T, Noma H, Tanzawa H (2003) Over-expression of DNA methyltransferases and CDKN2A gene methylation status in squamous cell carcinoma of the oral cavity. Int J Oncol 22:1201–1207

    PubMed  CAS  Google Scholar 

  17. Shen H, Wang L, Spitz MR, Hong WK, Mao L, Wei Q (2002) A novel polymorphism in human cytosine DNA-methyltransferase-3B promoter is associated with an increased risk of lung cancer. Cancer Res 62:4992–4995

    PubMed  CAS  Google Scholar 

  18. Lee SJ, Jeon HS, Jang JS, Park SH, Lee GY, Lee BH, Kim CH, Kang YM, Lee WK, Kam S, Park RW, Kim IS, Cho YL, Jung TH, Park JY (2005) DNMT3B polymorphisms and risk of primary lung cancer. Carcinogenesis 26:403–409

    Article  PubMed  CAS  Google Scholar 

  19. Li Y, Dai Y, Wu SL, Pei P, Cao XH, Pu DF (2005) The C46359T polymorphism of DNMT3B promoter gene and pathogenesis of acute leukemia. Zhonghua Nei Ke Za Zhi 44:588–591

    PubMed  CAS  Google Scholar 

  20. Singal R, Das PM, Manoharan M, Reis IM, Schlesselman JJ (2005) Polymorphisms in the DNA methyltransferase 3b gene and prostate cancer risk. Oncol Rep 14:569–573

    PubMed  CAS  Google Scholar 

  21. Montgomery KG, Liu MC, Eccles DM, Campbell IG (2004) The DNMT3B C→T promoter polymorphism and risk of breast cancer in a British population: a case-control study. Breast Cancer Res 6:R390–R394

    Article  PubMed  CAS  Google Scholar 

  22. Jones JS, Amos CI, Pande M, Gu X, Chen J, Campos IM, Wei Q, Rodriguez-Bigas M, Lynch PM, Frazier ML (2006) DNMT3b polymorphism and hereditary nonpolyposis colorectal cancer age of onset. Cancer Epidemiol Biomark Prev 15:886–891

    Article  CAS  Google Scholar 

  23. Chang KP, Hao SP, Liu CT, Cheng MH, Chang YL, Lee YS, Wang TH, Tsai CN (2007) Promoter polymorphisms of DNMT3B and the risk of head and neck squamous cell carcinoma in Taiwan: a case-control study. Oral Oncol 43:345–351

    Article  PubMed  CAS  Google Scholar 

  24. Wu Y, Lin JS (2007) 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 13:6082–6086

    Article  PubMed  CAS  Google Scholar 

  25. Aung PP, Matsumura S, Kuraoka K, Kunimitsu K, Yoshida K, Matsusaki K, Nakayama H, Yasui W (2005) No evidence of correlation between the single nucleotide polymorphism of DNMT3B promoter and gastric cancer risk in a Japanese population. Oncol Rep 14:1151–1154

    PubMed  CAS  Google Scholar 

  26. Hong YS, Lee HJ, You CH, Roh MS, Kwak JY, Lee MJ, Kim JY (2007) DNMT3b 39179GT polymorphism and the risk of adenocarcinoma of the colon in Koreans. Biochem Genet 45:155–163

    Article  PubMed  CAS  Google Scholar 

  27. Fan H, Liu DS, Zhang SH, Hu JB, Zhang F, Zhao ZJ (2008) DNMT3B 579G>T promoter polymorphism and risk of esophagus carcinoma in Chinese. World J Gastroenterol 14:2230–2234

    Article  PubMed  CAS  Google Scholar 

  28. Saito Y, Kanai Y, Nakagawa T, Sakamoto M, Saito H, Ishii H, Hirohashi S (2003) Increased protein expression of DNA methyltransferase (DNMT) 1 is significantly correlated with the malignant potential and poor prognosis of human hepatocellular carcinomas. Int J Cancer 105:527–532

    Article  PubMed  CAS  Google Scholar 

  29. Chen CL, Yan X, Gao YN, Liao QP (2005) Expression of DNA methyltransferase 1, 3A and 3B mRNA in the epithelial ovarian carcinoma. Zhonghua Fu Chan Ke Za Zhi 40:770–774

    PubMed  Google Scholar 

  30. Kim H, Kwon YM, Kim JS, Han J, Shim YM, Park J, Kim DH (2006) Elevated mRNA levels of DNA methyltransferase-1 as an independent prognostic factor in primary nonsmall cell lung cancer. Cancer 107:1042–1049

    Article  PubMed  CAS  Google Scholar 

  31. Schmidt WM, Sedivy R, Forstner B, Steger GG, Zochbauer-Muller S, Mader RM (2007) Progressive up-regulation of genes encoding DNA methyltransferases in the colorectal adenoma-carcinoma sequence. Mol Carcinog 46:766–772

    Article  PubMed  CAS  Google Scholar 

  32. Fan H, Zhang F, Hu J, Liu D, Zhao Z (2008) Promoter polymorphisms of DNMT3B and the risk of colorectal cancer in Chinese: a case–control study. J Exp Clin Cancer Res 27:24

    Article  PubMed  Google Scholar 

  33. Teodoridis JM, Hall J, Marsh S, Kannall HD, Smyth C, Curto J, Siddiqui N, Gabra H, McLeod HL, Strathdee G, Brown R (2005) CpG island methylation of DNA damage response genes in advanced ovarian cancer. Cancer Res 65:8961–8967

    Article  PubMed  CAS  Google Scholar 

  34. Wang YM, Wang R, Wen DG, Li Y, Guo W, Wang N, Wei LZ, He YT, Chen ZF, Zhang XF, Zhang JH (2005) Single nucleotide polymorphism in DNA methyltransferase 3B promoter and its association with gastric cardiac adenocarcinoma in North China. World J Gastroenterol 11:3623–3627

    PubMed  CAS  Google Scholar 

Download references

Acknowledgement

This project was supported by a grant from The Personnel Ministry of China (2008-86), the Nature Science Foundation of Jiangsu Provience, China (BK2009045), and Social Development Technology Projects of Kunshan City, China (KS1013)

Conflicts of interest

The authors declare that they have no conflict of interest.

Author information

Authors and Affiliations

  1. Department of Life Sciences, Nanjing Normal University, Nanjing, 210046, Jiangsu Province, China

    Qian Bao, Yongfei Xu, Chan Zhu & Fuliang Tian

  2. The Central Laboratory of Nanjing First Hospital Affiliated to Nanjing Medical University, Nanjing, 210006, Jiangsu Province, China

    Qian Bao, Bangshun He, Yuqin Pan, Zhipeng Tang, Ying Zhang, Lili Qu, Yongfei Xu, Chan Zhu, Fuliang Tian & Shukui Wang

  3. Inspection Division Triditional Chinese Medicine Hospital of Kunshan, Kunshan, 215300, Jiangsu Province, China

    Ying Zhang

Authors
  1. Qian Bao
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bangshun He
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yuqin Pan
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Zhipeng Tang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Ying Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lili Qu
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Yongfei Xu
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Chan Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Fuliang Tian
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Shukui Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Shukui Wang.

Additional information

Q. Bao and B. He contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Bao, Q., He, B., Pan, Y. et al. Genetic variation in the promoter of DNMT3B is associated with the risk of colorectal cancer. Int J Colorectal Dis 26, 1107–1112 (2011). https://doi.org/10.1007/s00384-011-1199-3

Download citation

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00384-011-1199-3

Keywords

Search

Navigation