Skip to main content

Advertisement

Log in

O6-Methylguanine-DNA Methyltransferase Leu84Phe and Ile143Val Polymorphisms and Risk of Colorectal Cancer in the Nurses’ Health Study and Physicians’ Health Study (United States)

  • Original Paper
  • Published:
Cancer Causes & Control Aims and scope Submit manuscript

Abstract

Objective

O6-methylguanine-DNA methyltransferase (MGMT) removes mutagenic adducts from the O6-position of guanine in DNA. Unrepaired O6-methylguanines result in G:C to A:T transitions in mutated K-ras and p53 in colorectal tumors. Two non-synonymous MGMT coding region variants, Leu84Phe and Ile143Val, lie in close proximity to the reactive 145Cys residue and to a conserved estrogen receptor interacting helix.

Methods

We assessed the association between the MGMT Leu84Phe and Ile143Val polymorphisms and risk of colorectal cancer in two nested case–control studies: one each in the Nurses’ Health Study (NHS) and the Physicians’ Health Study (PHS) cohorts.

Results

Among 197 female cases and 2,500 controls from the NHS, the variant 143Val allele was significantly associated with reduced risk of colorectal cancer [odds ratio (OR)=0.52, 95% confidence interval (CI) 0.33–0.80]. In women, statistically significant gene-environment interactions were found between the Leu84Phe polymorphism and alcohol intake (P=0.03), BMI (P=0.04) and postmenopausal hormone use (P=0.03). The Leu84Phe and Ile143Val polymorphisms were not significantly associated with risk of colorectal cancer among 271 male cases and 451 controls from the PHS.

Conclusions

Our results suggest that the common Leu84Phe and Ile143Val polymorphisms in MGMT influence risk of colorectal cancer in women possibly through modulating estrogen receptor-dependent transcriptional activation, which has previously been shown to occur in response to DNA alkylation damage.

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

Access this article

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

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

NHS:

Nurses’ Health Study

HPFS:

Health Professionals Follow-Up Study

MGMT:

O6-methylguanine-DNA methyltransferase

NNN:

N′-nitrosonornicotine

NNK:

4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone

NDMA:

N-nitrosodimethylamine

References

  1. Pegg AE (2000) Repair of O(6)-alkylguanine by alkyltransferases. Mutat Res 462:83–100

    CAS  PubMed  Google Scholar 

  2. Lindahl T, Demple B, Robins P (1982) Suicide inactivation of the E. coli O6-methylguanine-DNA methyltransferase. EMBO J 1:1359–1363

    CAS  PubMed  Google Scholar 

  3. Lindahl T, Sedgwick B, Sekiguchi M, Nakabeppu Y (1988) Regulation and expression of the adaptive response to alkylating agents. Annu Rev Biochem 57:133–157

    Article  CAS  PubMed  Google Scholar 

  4. Jackson PE, Hall CN, O’Connor PJ, Cooper DP, Margison GP, Povey AC (1997) Low O6-alkylguanine DNA-alkyltransferase activity in normal colorectal tissue is associated with colorectal tumours containing a GC–>AT transition in the K-ras oncogene. Carcinogenesis 18:1299–1302

    Article  CAS  PubMed  Google Scholar 

  5. Esteller M, Toyota M, Sanchez-Cespedes M, Capella G, Peinado MA, Watkins DN, Issa JP, Sidransky D, Baylin SB, Herman JG (2000) Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is associated with G to A mutations in K-ras in colorectal tumorigenesis. Cancer Res 60:2368–2371

    CAS  PubMed  Google Scholar 

  6. Esteller M, Risques RA, Toyota M, Capella G, Moreno V, Peinado MA, Baylin SB, Herman JG (2001) Promoter hypermethylation of the DNA repair gene O(6)-methylguanine-DNA methyltransferase is associated with the presence of G:C to A:T transition mutations in p53 in human colorectal tumorigenesis. Cancer Res 61:4689–4692

    CAS  PubMed  Google Scholar 

  7. Esteller M, Hamilton SR, Burger PC, Baylin SB, Herman JG (1999) Inactivation of the DNA repair gene O6-methylguanine-DNA methyltransferase by promoter hypermethylation is a common event in primary human neoplasia. Cancer Res 59:793–797

    CAS  PubMed  Google Scholar 

  8. Navasumrit P, Ward TH, O’Connor PJ, Nair J, Frank N, Bartsch H (2001) Ethanol enhances the formation of endogenously and exogenously derived adducts in rat hepatic DNA. Mutat Res 479:81–94

    CAS  PubMed  Google Scholar 

  9. Wilson DM 3rd, Tentler JJ, Carney JP, Wilson TM, Kelley MR (1994) Acute ethanol exposure suppresses the repair of O6-methylguanine DNA lesions in castrated adult male rats. Alcohol Clin Exp Res 18:1267–1271

    Article  CAS  PubMed  Google Scholar 

  10. Jokelainen K, Siitonen A, Jousimies-Somer H, Nosova T, Heine R, Salaspuro M (1996) In vitro alcohol dehydrogenase-mediated acetaldehyde production by aerobic bacteria representing the normal colonic flora in man. Alcohol Clin Exp Res 20:967–972

    CAS  PubMed  Google Scholar 

  11. Teo AK, Oh HK, Ali RB, Li BF (2001) The modified human DNA repair enzyme O(6)-methylguanine-DNA methyltransferase is a negative regulator of estrogen receptor-mediated transcription upon alkylation DNA damage. Mol Cell Biol 21:7105–7114

    Article  CAS  PubMed  Google Scholar 

  12. Povey AC, Badawi AF, Cooper DP, Hall CN, Harrison KL, Jackson PE, Lees NP, O’Connor PJ, Margison GP (2002) DNA alkylation and repair in the large bowel: animal and human studies. J Nutr 132:3518S–3521S

    CAS  PubMed  Google Scholar 

  13. Lijinsky W (1999) N-Nitroso compounds in the diet. Mutat Res 443:129–138

    CAS  PubMed  Google Scholar 

  14. Hecht SS (1999) DNA adduct formation from tobacco-specific N-nitrosamines. Mutat Res 424:127–142

    CAS  PubMed  Google Scholar 

  15. Knekt P, Jarvinen R, Dich J, Hakulinen T (1999) Risk of colorectal and other gastro-intestinal cancers after exposure to nitrate, nitrite and N-nitroso compounds: a follow-up study. Int J Cancer 80:852–856

    CAS  PubMed  Google Scholar 

  16. Souliotis VL, Henneman JR, Reed CD, Chhabra SK, Diwan BA, Anderson LM, Kyrtopoulos SA (2002) DNA adducts and liver DNA replication in rats during chronic exposure to N-nitrosodimethylamine (NDMA) and their relationships to the dose-dependence of NDMA hepatocarcinogenesis. Mutat Res 500:75–87

    CAS  PubMed  Google Scholar 

  17. Pegg AE (1990) Mammalian O6-alkylguanine-DNA alkyltransferase: regulation and importance in response to alkylating carcinogenic and therapeutic agents. Cancer Res 50:6119–6129

    CAS  PubMed  Google Scholar 

  18. Vahakangas K, Trivers GE, Plummer S, Hayes RB, Krokan H, Rowe M, Swartz RP, Yeager H Jr, Harris CC (1991) O(6)-methylguanine-DNA methyltransferase and uracil DNA glycosylase in human broncho-alveolar lavage cells and peripheral blood mononuclear cells from tobacco smokers and non-smokers. Carcinogenesis 12:1389–1394

    CAS  PubMed  Google Scholar 

  19. Margison GP, Povey AC, Kaina B, Santibanez Koref MF (2003) Variability and regulation of O6-alkylguanine-DNA alkyltransferase. Carcinogenesis 24:625–635

    Article  CAS  PubMed  Google Scholar 

  20. Margison GP, Heighway J, Pearson S, McGown G, Thorncroft MR, Watson AJ, Harrison KL, Lewis SJ, Rohde K, Barber PV et al (2005) Quantitative trait locus analysis reveals two intragenic sites that influence O6-alkylguanine-DNA alkyltransferase activity in peripheral blood mononuclear cells. Carcinogenesis

  21. Egyhazi S, Ma S, Smoczynski K, Hansson J, Platz A, Ringborg U (2002) Novel O6-methylguanine-DNA methyltransferase SNPs: a frequency comparison of patients with familial melanoma and healthy individuals in Sweden. Hum Mutat 20:408–409

    CAS  PubMed  Google Scholar 

  22. Kaur TB, Travaline JM, Gaughan JP, Richie JP Jr, Stellman SD, Lazarus P (2000) Role of polymorphisms in codons 143 and 160 of the O6-alkylguanine DNA alkyltransferase gene in lung cancer risk. Cancer Epidemiol Biomarkers Prev 9:339–342

    CAS  PubMed  Google Scholar 

  23. Crone TM, Goodtzova K, Pegg AE (1996) Amino acid residues affecting the activity and stability of human O6-alkylguanine-DNA alkyltransferase. Mutat Res 363:15–25

    CAS  PubMed  Google Scholar 

  24. Crone TM, Pegg AE (1993) A single amino acid change in human O6-alkylguanine-DNA alkyltransferase decreasing sensitivity to inactivation by O6-benzylguanine. Cancer Res 53:4750–4753

    CAS  PubMed  Google Scholar 

  25. Chen J, Giovannucci E, Hankinson SE, Ma J, Willett WC, Spiegelman D, Kelsey KT, Hunter DJ (1998) A prospective study of methylenetetrahydrofolate reductase and methionine synthase gene polymorphisms, and risk of colorectal adenoma. Carcinogenesis 19:2129–2132

    CAS  PubMed  Google Scholar 

  26. Hankinson SE, Willett WC, Manson JE, Hunter DJ, Colditz GA, Stampfer MJ, Longcope C, Speizer FE (1995) Alcohol, height, and adiposity in relation to estrogen and prolactin levels in postmenopausal women. J Natl Cancer Inst 87:1297–1302

    CAS  PubMed  Google Scholar 

  27. Hunter DJ, Hankinson SE, Hough H, Gertig DM, Garcia-Closas M, Spiegelman D, Manson JE, Colditz GA, Willett WC, Speizer FE et al (1997) A prospective study of NAT2 acetylation genotype, cigarette smoking, and risk of breast cancer. Carcinogenesis 18:2127–2132

    Article  CAS  PubMed  Google Scholar 

  28. Stampfer MJ, Malinow MR, Willett WC, Newcomer LM, Upson B, Ullmann D, Tishler PV, Hennekens CH (1992) A prospective study of plasma homocyst(e)ine and risk of myocardial infarction in US physicians. JAMA 268:877–881

    Article  CAS  PubMed  Google Scholar 

  29. Deng C, Xie D, Capasso H, Zhao Y, Wang LD, Hong JY (1999) Genetic polymorphism of human O6-alkylguanine-DNA alkyltransferase: identification of a missense variation in the active site region. Pharmacogenetics 9:81–87

    CAS  PubMed  Google Scholar 

  30. Imai Y, Oda H, Nakatsuru Y, Ishikawa T (1995) A polymorphism at codon 160 of human O6-methylguanine-DNA methyltransferase gene in young patients with adult type cancers and functional assay. Carcinogenesis 16:2441–2445

    CAS  PubMed  Google Scholar 

  31. Giovannucci E, Stampfer MJ, Colditz GA, Hunter DJ, Fuchs C, Rosner BA, Speizer FE, Willett WC (1998) Multivitamin use, folate, and colon cancer in women in the Nurses’ Health Study. Ann Intern Med 129:517–524

    CAS  PubMed  Google Scholar 

  32. Daniels DS, Tainer JA (2000) Conserved structural motifs governing the stoichiometric repair of alkylated DNA by O(6)-alkylguanine-DNA alkyltransferase. Mutat Res 460:151–163

    CAS  PubMed  Google Scholar 

  33. Inoue R, Abe M, Nakabeppu Y, Sekiguchi M, Mori T, Suzuki T (2000) Characterization of human polymorphic DNA repair methyltransferase. Pharmacogenetics 10:59–66

    Article  CAS  PubMed  Google Scholar 

  34. Ma S, Egyhazi S, Ueno T, Lindholm C, Kreklau EL, Stierner U, Ringborg U, Hansson J (2003) O6-methylguanine-DNA-methyltransferase expression and gene polymorphisms in relation to chemotherapeutic response in metastatic melanoma. Br J Cancer 89:1517–1523

    Article  CAS  PubMed  Google Scholar 

  35. Onland-Moret NC, Peeters PH, van der Schouw YT, Grobbee DE, van Gils CH (2004) Alcohol and endogenous sex steroid levels in postmenopausal women: a cross-sectional study. J Clin Endocrinol Metab

  36. van Engeland M, Weijenberg MP, Roemen GM, Brink M, de Bruine AP, Goldbohm RA, van den Brandt PA, Baylin SB, de Goeij AF, Herman JG (2003) Effects of dietary folate and alcohol intake on promoter methylation in sporadic colorectal cancer: the Netherlands cohort study on diet and cancer. Cancer Res 63:3133–3137

    PubMed  Google Scholar 

  37. Espina N, Lima V, Lieber CS, Garro AJ (1988) In vitro and in vivo inhibitory effect of ethanol and acetaldehyde on O6-methylguanine transferase. Carcinogenesis 9:761–766

    CAS  PubMed  Google Scholar 

  38. Giovannucci E (2004) Alcohol, one-carbon metabolism, and colorectal cancer: recent insights from molecular studies. J Nutr 134:2475S–2481S

    CAS  PubMed  Google Scholar 

  39. Lin J, Zhang SM, Cook NR, Rexrode KM, Lee IM, Buring JE (2004) Body mass index and risk of colorectal cancer in women (United States). Cancer Causes Control 15:581–589

    Article  PubMed  Google Scholar 

  40. Giovannucci E (2003) Diet, body weight, and colorectal cancer: a summary of the epidemiologic evidence. J Womens Health (Larchmt) 12:173–182

    Google Scholar 

  41. Giovannucci E (2001) Insulin, insulin-like growth factors and colon cancer: a review of the evidence. J Nutr 131:3109S–3120S

    CAS  PubMed  Google Scholar 

  42. Giovannucci E, Colditz GA, Stampfer MJ, Willett WC (1996) Physical activity, obesity, and risk of colorectal adenoma in women (United States). Cancer Causes Control 7:253–263

    Article  CAS  PubMed  Google Scholar 

  43. Slattery ML, Ballard-Barbash R, Edwards S, Caan BJ, Potter JD (2003) Body mass index and colon cancer: an evaluation of the modifying effects of estrogen (United States). Cancer Causes Control 14:75–84

    CAS  PubMed  Google Scholar 

  44. Terry PD, Miller AB, Rohan TE (2002) Obesity and colorectal cancer risk in women. Gut 51:191–194

    Article  CAS  PubMed  Google Scholar 

  45. Key TJ, Allen NE, Verkasalo PK, Banks E (2001) Energy balance and cancer: the role of sex hormones. Proc Nutr Soc 60:81–89

    CAS  PubMed  Google Scholar 

  46. Kaaks R, Lukanova A, Kurzer MS (2002) Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Cancer Epidemiol Biomarkers Prev 11:1531–1543

    CAS  PubMed  Google Scholar 

  47. Powell DR, Suwanichkul A, Cubbage ML, DePaolis LA, Snuggs MB, Lee PD (1991) Insulin inhibits transcription of the human gene for insulin-like growth factor-binding protein-1. J Biol Chem 266:18868–18876

    CAS  PubMed  Google Scholar 

  48. Lee PD, Conover CA, Powell DR (1993) Regulation and function of insulin-like growth factor-binding protein-1. Proc Soc Exp Biol Med 204:4–29

    CAS  PubMed  Google Scholar 

  49. Giovannucci E (2002) Obesity, gender, and colon cancer. Gut 51:147

    Article  CAS  PubMed  Google Scholar 

  50. Bulun SE, Zeitoun K, Sasano H, Simpson ER (1999) Aromatase in aging women. Semin Reprod Endocrinol 17:349–358

    CAS  PubMed  Google Scholar 

  51. Grodstein F, Newcomb PA, Stampfer MJ (1999) Postmenopausal hormone therapy and the risk of colorectal cancer: a review and meta-analysis. Am J Med 106:574–582

    Article  CAS  PubMed  Google Scholar 

  52. Di Domenico M, Castoria G, Bilancio A, Migliaccio A, Auricchio F (1996) Estradiol activation of human colon carcinoma-derived Caco-2 cell growth. Cancer Res 56:4516–4521

    CAS  PubMed  Google Scholar 

  53. English MA, Kane KF, Cruickshank N, Langman MJ, Stewart PM, Hewison M (1999) Loss of estrogen inactivation in colonic cancer. J Clin Endocrinol Metab 84:2080–2085

    Article  CAS  PubMed  Google Scholar 

  54. Fiorelli G, Picariello L, Martineti V, Tonelli F, Brandi ML (1999) Estrogen synthesis in human colon cancer epithelial cells. J Steroid Biochem Mol Biol 71:223–230

    Article  CAS  PubMed  Google Scholar 

  55. Smirnoff P, Liel Y, Gnainsky J, Shany S, Schwartz B (1999) The protective effect of estrogen against chemically induced murine colon carcinogenesis is associated with decreased CpG island methylation and increased mRNA and protein expression of the colonic vitamin D receptor. Oncol Res 11:255–264

    CAS  PubMed  Google Scholar 

  56. Schwartz B, Smirnoff P, Shany S, Liel Y (2000) Estrogen controls expression and bioresponse of 1,25-dihydroxyvitamin D receptors in the rat colon. Mol Cell Biochem 203:87–93

    Article  CAS  PubMed  Google Scholar 

  57. McMichael AJ, Potter JD (1980) Reproduction, endogenous and exogenous sex hormones, and colon cancer: a review and hypothesis. J Natl Cancer Inst 65:1201–1207

    CAS  PubMed  Google Scholar 

  58. Issa JP, Ottaviano YL, Celano P, Hamilton SR, Davidson NE, Baylin SB (1994) Methylation of the oestrogen receptor CpG island links ageing and neoplasia in human colon. Nat Genet 7:536–540

    Article  CAS  PubMed  Google Scholar 

  59. Carothers AM, Hughes SA, Ortega D, Bertagnolli MM (2002) 2-Methoxyestradiol induces p53-associated apoptosis of colorectal cancer cells. Cancer Lett 187:77–86

    Article  CAS  PubMed  Google Scholar 

  60. Javid SH, Moran AE, Carothers AM, Redston M, Bertagnolli MM (2004) Modulation of tumor formation and intestinal cell migration by estrogens in the ApcMin/+ mouse model of colorectal cancer. Carcinogenesis

  61. Weyant MJ, Carothers AM, Mahmoud NN, Bradlow HL, Remotti H, Bilinski RT, Bertagnolli MM (2001) Reciprocal expression of ERalpha and ERbeta is associated with estrogen-mediated modulation of intestinal tumorigenesis. Cancer Res 61:2547–2551

    CAS  PubMed  Google Scholar 

  62. Oh HK, Teo AK, Ali RB, Lim A, Ayi TC, Yarosh DB, Li BF (1996) Conformational change in human DNA repair enzyme O6-methylguanine-DNA methyltransferase upon alkylation of its active site by SN1 (indirect-acting) and SN2 (direct-acting) alkylating agents: breaking a “salt-link”. Biochemistry 35:12259–12266

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

We thank the participants of the Nurses’ Health Study and Physicians’ Health Study for their cooperation and participation. Supported by National Institutes of Health research grants CA70817, CA87969, CA34944, CA-40360, HL-26490 and HL-34595. G.J.T. is supported by training grant CA 09001–27 from the National Institutes of Health.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Gregory J. Tranah.

Additional information

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tranah, G.J., Bugni, J., Giovannucci, E. et al. O6-Methylguanine-DNA Methyltransferase Leu84Phe and Ile143Val Polymorphisms and Risk of Colorectal Cancer in the Nurses’ Health Study and Physicians’ Health Study (United States). Cancer Causes Control 17, 721–731 (2006). https://doi.org/10.1007/s10552-006-0005-y

Download citation

  • Received:

  • Accepted:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10552-006-0005-y

Keywords

Navigation