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Cancer Causes & Control
Published in: Cancer Causes & Control 5/2006

01-06-2006 | Original Paper

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

Authors: Gregory J. Tranah, James Bugni, Edward Giovannucci, Jing Ma, Charles Fuchs, Lisa Hines, Leona Samson, David J. Hunter

Published in: Cancer Causes & Control | Issue 5/2006

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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.
Literature
1.
Pegg AE (2000) Repair of O(6)-alkylguanine by alkyltransferases. Mutat Res 462:83–100PubMed
2.
Lindahl T, Demple B, Robins P (1982) Suicide inactivation of the E. coli O6-methylguanine-DNA methyltransferase. EMBO J 1:1359–1363PubMed
3.
Lindahl T, Sedgwick B, Sekiguchi M, Nakabeppu Y (1988) Regulation and expression of the adaptive response to alkylating agents. Annu Rev Biochem 57:133–157CrossRefPubMed
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 18:1299–1302CrossRefPubMed
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 60:2368–2371PubMed
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 61:4689–4692PubMed
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 59:793–797PubMed
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 479:81–94PubMed
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 18:1267–1271CrossRefPubMed
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 20:967–972PubMed
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 21:7105–7114CrossRefPubMed
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–3521SPubMed
13.
Lijinsky W (1999) N-Nitroso compounds in the diet. Mutat Res 443:129–138PubMed
14.
Hecht SS (1999) DNA adduct formation from tobacco-specific N-nitrosamines. Mutat Res 424:127–142PubMed
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 80:852–856PubMed
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 500:75–87PubMed
17.
Pegg AE (1990) Mammalian O6-alkylguanine-DNA alkyltransferase: regulation and importance in response to alkylating carcinogenic and therapeutic agents. Cancer Res 50:6119–6129PubMed
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 12:1389–1394PubMed
19.
Margison GP, Povey AC, Kaina B, Santibanez Koref MF (2003) Variability and regulation of O6-alkylguanine-DNA alkyltransferase. Carcinogenesis 24:625–635CrossRefPubMed
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 20:408–409PubMed
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 9:339–342PubMed
23.
Crone TM, Goodtzova K, Pegg AE (1996) Amino acid residues affecting the activity and stability of human O6-alkylguanine-DNA alkyltransferase. Mutat Res 363:15–25PubMed
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 53:4750–4753PubMed
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 19:2129–2132PubMed
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 87:1297–1302PubMed
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 18:2127–2132CrossRefPubMed
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 268:877–881CrossRefPubMed
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 9:81–87PubMed
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 16:2441–2445PubMed
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 129:517–524PubMed
32.
Daniels DS, Tainer JA (2000) Conserved structural motifs governing the stoichiometric repair of alkylated DNA by O(6)-alkylguanine-DNA alkyltransferase. Mutat Res 460:151–163PubMed
33.
Inoue R, Abe M, Nakabeppu Y, Sekiguchi M, Mori T, Suzuki T (2000) Characterization of human polymorphic DNA repair methyltransferase. Pharmacogenetics 10:59–66CrossRefPubMed
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 89:1517–1523CrossRefPubMed
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 63:3133–3137PubMed
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 9:761–766PubMed
38.
Giovannucci E (2004) Alcohol, one-carbon metabolism, and colorectal cancer: recent insights from molecular studies. J Nutr 134:2475S–2481SPubMed
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 15:581–589CrossRefPubMed
40.
Giovannucci E (2003) Diet, body weight, and colorectal cancer: a summary of the epidemiologic evidence. J Womens Health (Larchmt) 12:173–182
41.
Giovannucci E (2001) Insulin, insulin-like growth factors and colon cancer: a review of the evidence. J Nutr 131:3109S–3120SPubMed
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 7:253–263CrossRefPubMed
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 14:75–84PubMed
44.
45.
Key TJ, Allen NE, Verkasalo PK, Banks E (2001) Energy balance and cancer: the role of sex hormones. Proc Nutr Soc 60:81–89PubMed
46.
Kaaks R, Lukanova A, Kurzer MS (2002) Obesity, endogenous hormones, and endometrial cancer risk: a synthetic review. Cancer Epidemiol Biomarkers Prev 11:1531–1543PubMed
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 266:18868–18876PubMed
48.
Lee PD, Conover CA, Powell DR (1993) Regulation and function of insulin-like growth factor-binding protein-1. Proc Soc Exp Biol Med 204:4–29PubMed
49.
50.
Bulun SE, Zeitoun K, Sasano H, Simpson ER (1999) Aromatase in aging women. Semin Reprod Endocrinol 17:349–358PubMed
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 106:574–582CrossRefPubMed
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 56:4516–4521PubMed
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 84:2080–2085CrossRefPubMed
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 71:223–230CrossRefPubMed
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 11:255–264PubMed
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 203:87–93CrossRefPubMed
57.
McMichael AJ, Potter JD (1980) Reproduction, endogenous and exogenous sex hormones, and colon cancer: a review and hypothesis. J Natl Cancer Inst 65:1201–1207PubMed
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 7:536–540CrossRefPubMed
59.
Carothers AM, Hughes SA, Ortega D, Bertagnolli MM (2002) 2-Methoxyestradiol induces p53-associated apoptosis of colorectal cancer cells. Cancer Lett 187:77–86CrossRefPubMed
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 61:2547–2551PubMed
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 35:12259–12266CrossRefPubMed
Metadata
Title
O6-Methylguanine-DNA Methyltransferase Leu84Phe and Ile143Val Polymorphisms and Risk of Colorectal Cancer in the Nurses’ Health Study and Physicians’ Health Study (United States)
Authors
Gregory J. Tranah
James Bugni
Edward Giovannucci
Jing Ma
Charles Fuchs
Lisa Hines
Leona Samson
David J. Hunter
Publication date
01-06-2006
Publisher
Kluwer Academic Publishers
Published in
Cancer Causes & Control / Issue 5/2006
Print ISSN: 0957-5243
Electronic ISSN: 1573-7225
DOI
https://doi.org/10.1007/s10552-006-0005-y

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