O6-Methylguanine-DNA Methyltransferase Leu84Phe and Ile143Val Polymorphisms and Risk of Colorectal Cancer in the Nurses’ Health Study and Physicians’ Health Study (United States)
- 183 Downloads
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.
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.
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.
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.
KeywordsColorectal cancer O6-Methylguanine-DNA methyltransferase Genetic polymorphism Estrogen receptor
Nurses’ Health Study
Health Professionals Follow-Up Study
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.
- 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 60:2368–2371PubMedGoogle 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 61:4689–4692PubMedGoogle 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 500:75–87PubMedGoogle 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 12:1389–1394PubMedGoogle 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. CarcinogenesisGoogle 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 MetabGoogle Scholar
- 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 63:3133–3137PubMedGoogle Scholar
- 40.Giovannucci E (2003) Diet, body weight, and colorectal cancer: a summary of the epidemiologic evidence. J Womens Health (Larchmt) 12:173–182Google 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 11:255–264PubMedGoogle 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. CarcinogenesisGoogle 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 35:12259–12266CrossRefPubMedGoogle Scholar