The Role of O6-methylguanine-DNA Methyltransferase Polymorphisms in Prostate Cancer Susceptibility: a Meta-Analysis

Abstract

To assess the associations between O6-methylguanine-DNA methyltransferase(MGMT) polymorphisms and prostate cancer risk. We retrieved PubMed, Cochrane Library and Embase electronic database to search for all eligible studies published from Jan 1, 1970 to Sep 31, 2017 to conduct a Meta-analysis. we identified 11 independent studies in 5 eligible reports, including 5143 cases and 8118 controls. The data suggested that rs12917 was associated with higher PCa risk under the contrast of TT vs CC and recessive model in overall population (TT vs CC: OR = 1.599, 95%CI: 1.007–2.539, P = 0.047; TT vs CC + CT: OR = 1.627, 95%CI: 1.026–2.580, P = 0.038). In subgroup analyses stratified by ethnicity, the remarkable association with higher PCa risk was detected under allelic model, dominant model, the contrast of TC vs CC, and the contrast of TC vs CC + TT in Asian population. (T vs C: OR = 1.911, 95%CI: 1.182–3.090, P = 0.008; TC vs CC: OR = 1.948, 95%CI: 1.152–3.295, P = 0.013; TC + TT vs CC: OR = 1.994, 95%CI: 1.190–3.342, P = 0.009; TC vs CC + TT: OR = 1.926, 95%CI: 1.140–3.255, P = 0.014). However, the data suggest the rs2308327 and rs2308321 polymorphisms of the MGMT gene were nor associated with the susceptibility of prostate cancer. Based on the meta-analysis, MGMT rs12917 polymorphism increase the susceptibility to prostate cancer, which can be taken for a diagnosis and screening molecular biomarker for prostate cancer patients.

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

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

References

  1. 1.

    Hung RJ, Baragatti M, Thomas D, McKay J, Szeszenia-Dabrowska N, Zaridze D, Lissowska J, Rudnai P, Fabianova E, Mates D, Foretova L, Janout V, Bencko V, Chabrier A, Moullan N, Canzian F, Hall J, Boffetta P, Brennan P (2007) Inherited predisposition of lung cancer: a hierarchical modeling approach to DNA repair and cell cycle control pathways. Cancer Epidem Biomar 16(12):2736–2744

    CAS  Article  Google Scholar 

  2. 2.

    Chae MH, Jang JS, Kang HG, Park JH, Park JM, Lee WK, Kam S, Lee EB, Son JW, Park JY (2006)O6-alkylguanine-DNA alkyltransferase gene polymorphisms and the risk of primary lung cancer. Mol Carcinog 45(4):239–249

    CAS  Article  Google Scholar 

  3. 3.

    Daniels DS, Woo TT, Luu KX, Noll DM, Clarke ND, Pegg AE, Tainer JA (2004) DNA binding and nucleotide flipping by the human DNA repair protein AGT. Nat Struct Mol Biol 11(8):714–720

    CAS  Article  Google Scholar 

  4. 4.

    Calegari MA, Inno A, Monterisi S, Orlandi A, Santini D, Basso M, Cassano A, Martini M, Cenci T, de Pascalis I, Camarda F, Barbaro B, Larocca LM, Gori S, Tonini G, Barone C (2017) A phase 2 study of temozolomide in pretreated metastatic colorectal cancer with MGMT promoter methylation. Br J Cancer 116(10):1279–1286

    CAS  Article  Google Scholar 

  5. 5.

    Chen GD, Qian DY, Li ZG, Fan GY, You KL, Wu YL (2017)Down-regulation of p16 and MGMT promotes the anti-proliferative and pro-apoptotic effects of 5-Aza-dC and radiation on cervical cancer cells. Cell Biochem Funct 35(8):488–496

    CAS  Article  Google Scholar 

  6. 6.

    Tomaszowski KH, Hellmann N, Ponath V, Takatsu H, Shin HW, Kaina B (2017) Uptake of glucose-conjugated MGMT inhibitors in cancer cells: role of flippases and type IV P-type ATPases. Sci Rep 7(1):13925

    Article  Google Scholar 

  7. 7.

    Siegel RL, Miller KD, Jemal A (2016) Cancer statistics, 2016. CA Cancer J Clin 66(1):7–30

    Article  Google Scholar 

  8. 8.

    Siegel RL, Miller KD, Jemal A (2017) Cancer statistics, 2017. CA Cancer J Clin 67(1):7–30

    Article  Google Scholar 

  9. 9.

    Liu TZ, Guo ZQ, Wang T, Cao Y, Huang D, Wang XH (2017)Meta-analysis of the role of IL-6 rs1800795 polymorphism in the susceptibility to prostate cancer: evidence based on 17 studies. Medicine 96(11):e6126

    CAS  Article  Google Scholar 

  10. 10.

    Zhang L, Zhang Y, Zhang X, Hong B (2015)Prostaglandin-endoperoxide synthase 2 (PTGS2) rs20417 polymorphism and prostate cancer risk: a meta analysis. Int J Clin Exp Med 8(11):20454–20462

    CAS  PubMed  PubMed Central  Google Scholar 

  11. 11.

    Agalliu I, Kwon EM, Salinas CA, Koopmeiners JS, Ostrander EA, Stanford JL (2010) Genetic variation in DNA repair genes and prostate cancer risk: results from a population-based study. Cancer Causes & Control 21(2):289–300

    Article  Google Scholar 

  12. 12.

    Loh YH, Mitrou PN, Bowman R, Wood A, Jeffery H, Luben RN, Lentjes MA, Khaw KT, Rodwell SA (2010) MGMT Ile143Val polymorphism, dietary factors and the risk of breast, colorectal and prostate cancer in the European prospective investigation into cancer and nutrition (EPIC)-Norfolk study. DNA Repair 9(4):421–428

    CAS  Article  Google Scholar 

  13. 13.

    Loh YH, Mitrou PN, Wood A, Luben RN, McTaggart A, Khaw KT, Rodwell SA (2011) SMAD7 and MGMT genotype variants and cancer incidence in the European prospective investigation into Cancer and nutrition (EPIC)-Norfolk study. Cancer Epidemiol 35(4):369–374

    CAS  Article  Google Scholar 

  14. 14.

    Matullo G, Dunning AM, Guarrera S, Baynes C, Polidoro S, Garte S, Autrup H, Malaveille C, Peluso M, Airoldi L, Veglia F, Gormally E, Hoek G, Krzyzanowski M, Overvad K, Raaschou-Nielsen O, Clavel-Chapelon F, Linseisen J, Boeing H, Trichopoulou A, Palli D, Krogh V, Tumino R, Panico S, Bueno-De-Mesquita HB, Peeters PH, Lund E, Pera G, Martinez C, Dorronsoro M, Barricarte A, Tormo MJ, Quiros JR, Day NE, Key TJ, Saracci R, Kaaks R, Riboli E, Vineis P (2006) DNA repair polymorphisms and cancer risk in non-smokers in a cohort study. Carcinogenesis 27(5):997–1007

    CAS  Article  Google Scholar 

  15. 15.

    Ritchey JD, Huang WY, Chokkalingam AP, Gao YT, Deng J, Levine P, Stanczyk FZ, Hsing AW (2005) Genetic variants of DNA repair genes and prostate cancer: a population-based study. Cancer Epidem Biomar 14(7):1703–1709

    CAS  Article  Google Scholar 

  16. 16.

    Chuang LY, Chang HW, Lin MC, Yang CH (2012) Chaotic particle swarm optimization for detecting SNP-SNP interactions for CXCL12-related genes in breast cancer prevention. European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation (ECP) 21(4):336–342

    CAS  Article  Google Scholar 

  17. 17.

    Goodman JE, Mechanic LE, Luke BT, Ambs S, Chanock S, Harris CC (2006) Exploring SNP-SNP interactions and colon cancer risk using polymorphism interaction analysis. Int J Cancer 118(7):1790–1797

    CAS  Article  Google Scholar 

  18. 18.

    Schwender H, Selinski S, Blaszkewicz M, Marchan R, Ickstadt K, Golka K, Hengstler JG (2012) Distinct SNP combinations confer susceptibility to urinary bladder cancer in smokers and non-smokers. PLoS One 7(12):e51880

    CAS  Article  Google Scholar 

  19. 19.

    Hu Z, Wang H, Shao M, Jin G, Sun W, Wang Y, Liu H, Wang Y, Ma H, Qian J, Jin L, Wei Q, Lu D, Huang W, Shen H (2007) Genetic variants in MGMT and risk of lung cancer in southeastern Chinese: a haplotype-based analysis. Hum Mutat 28(5):431–440

    CAS  Article  Google Scholar 

  20. 20.

    Huang J, Ye F, Chen H, Lu W, Xie X (2007) Amino acid substitution polymorphisms of the DNA repair gene MGMT and the susceptibility to cervical carcinoma. Carcinogenesis 28(6):1314–1322

    CAS  Article  Google Scholar 

  21. 21.

    Krzesniak M, Butkiewicz D, Samojedny A, Chorazy M, Rusin M (2004) Polymorphisms in TDG and MGMT genes - epidemiological and functional study in lung cancer patients from Poland. Ann Hum Genet 68(Pt 4):300–312

    CAS  Article  Google Scholar 

  22. 22.

    Li C, Liu J, Li A, Qian L, Wang X, Wei Q, Zhou J, Zhang Z (2005) Exon 3 polymorphisms and haplotypes of O6-methylguanine-DNA methyltransferase and risk of bladder cancer in southern China: a case-control analysis. Cancer Lett 227(1):49–57

    CAS  Article  Google Scholar 

  23. 23.

    Liu Y, Scheurer ME, El-Zein R, Cao Y, Do KA, Gilbert M, Aldape KD, Wei Q, Etzel C, Bondy ML (2009) Association and interactions between DNA repair gene polymorphisms and adult glioma. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 18(1):204–214

    CAS  Article  Google Scholar 

  24. 24.

    Shen J, Terry MB, Gammon MD, Gaudet MM, Teitelbaum SL, Eng SM, Sagiv SK, Neugut AI, Santella RM (2005) MGMT genotype modulates the associations between cigarette smoking, dietary antioxidants and breast cancer risk. Carcinogenesis 26(12):2131–2137

    CAS  Article  Google Scholar 

  25. 25.

    Shen M, Purdue MP, Kricker A, Lan Q, Grulich AE, Vajdic CM, Turner J, Whitby D, Chanock S, Rothman N, Armstrong BK (2007) Polymorphisms in DNA repair genes and risk of non-Hodgkin's lymphoma in New South Wales, Australia. Haematologica 92(9):1180–1185

    CAS  Article  Google Scholar 

  26. 26.

    Huang WY, Chow WH, Rothman N, Lissowska J, Llaca V, Yeager M, Zatonski W, Hayes RB (2005) Selected DNA repair polymorphisms and gastric cancer in Poland. Carcinogenesis 26(8):1354–1359

    CAS  Article  Google Scholar 

  27. 27.

    Wang L, Liu H, Zhang Z, Spitz MR, Wei Q (2006) Association of genetic variants of O6-methylguanine-DNA methyltransferase with risk of lung cancer in non-Hispanic whites. Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology 15(12):2364–2369

    CAS  Article  Google Scholar 

  28. 28.

    Liu J, Zhang R, Chen F, Yu C, Sun Y, Jia C, Zhang L, Salahuddin T, Li X, Lang J, Song X (2013) MGMT Leu84Phe polymorphism contributes to cancer susceptibility: evidence from 44 case-control studies. PLoS One 8(9):e75367

    CAS  Article  Google Scholar 

  29. 29.

    Qiu ZX, Xue F, Shi XF, He X, Ma HN, Chen L, Chen PZ (2014) MGMT Leu84Phe gene polymorphism and lung cancer risk: a meta-analysis. Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine 35(5):4381–4387

    CAS  Article  Google Scholar 

  30. 30.

    Zhong Y, Huang Y, Huang Y, Zhang T, Ma C, Zhang S, Fan W, Chen H, Qian J, Lu D (2010) Effects of O6-methylguanine-DNA methyltransferase (MGMT) polymorphisms on cancer: a meta-analysis. Mutagenesis 25(1):83–95

    CAS  Article  Google Scholar 

  31. 31.

    Hirschhorn JN, Lohmueller K, Byrne E, Hirschhorn K (2002) A comprehensive review of genetic association studies. Genetics in medicine : official journal of the American College of Medical Genetics 4(2):45–61

    CAS  Article  Google Scholar 

  32. 32.

    Rodriguez C, Calle EE, Miracle-McMahill HL, Tatham LM, Wingo PA, Thun MJ, Heath CW Jr (1997) Family history and risk of fatal prostate cancer. Epidemiology (Cambridge, Mass) 8(6):653–657

    CAS  Article  Google Scholar 

Download references

Author information

Affiliations

Authors

Corresponding author

Correspondence to Yongliang Ma.

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

The study protocol has been approved by the local ethics committee.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Wei Zhang and Mingkai Liu are the Co-first author.

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Zhang, W., Liu, M., Li, Y. et al. The Role of O6-methylguanine-DNA Methyltransferase Polymorphisms in Prostate Cancer Susceptibility: a Meta-Analysis. Pathol. Oncol. Res. 26, 1201–1209 (2020). https://doi.org/10.1007/s12253-019-00672-7

Download citation

Keywords

  • MGMT
  • PCa
  • Prostate cancer
  • Risk
  • Meta-analysis