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

Abstract

O⁶-Methylguanine-DNA methyltransferase (MGMT) repairs DNA damage caused by alkylating agents including N-nitroso compounds from diet. MGMT Ile143Val polymorphism may lead to less DNA damage repair and increased cancer risk depending on the environmental exposures. We investigated interactions between dietary factors and the MGMT Ile143Val polymorphism in relation to breast, colorectal and prostate cancer risk. There were 276/1498, 273/2984 and 312/1486 cases/controls for the breast, colorectal and prostate cancer studies respectively; all nested within the EPIC-Norfolk study, a prospective cohort of approximately 25,000 men and women aged 40–79. Baseline 7-day food diary data were collected for dietary assessment. MGMT Ile143Val polymorphism was not overall associated with breast, colorectal and prostate cancer risk. There was a significant interaction between this polymorphism and intake of red and processed meat on colorectal cancer risk (P_interaction = 0.04) suggesting an increased risk among carriers of the variant genotype compared to the MGMT Ile143Ile common genotype. A lower colorectal cancer risk was seen with higher intake of vitamin E and carotene among the variant genotype group but not in the common genotype group (P_interaction = 0.009 and P_interaction = 0.005 for vitamin E and carotene, respectively). A higher prostate cancer risk was seen with higher alcohol intake among the variant genotype (OR = 2.08, 95% CI = 1.21–3.57, P_interaction = 0.0009) compared to the common genotype with lower alcohol intake. In this UK population, the MGMT Ile143Val polymorphism was not overall associated with breast, colorectal and prostate cancer risk. There was evidence for this polymorphism playing a role in modulating the risk of prostate cancer in presence of alcohol. For colorectal cancer, the MGMT Ile143Val polymorphism may confer increased or decreased risk depending on the dietary exposure.

Introduction

The evidence that red meat and processed meat intake are positively associated with colorectal cancer risk is generally accepted as convincing [1], [2], [3] whilst the evidence for meat intake increasing prostate and breast cancer risk is more inconsistent [4], [5], [6], [7], [8]. Red meat is a source of haem which induces the endogenous formation of N-nitroso compounds in the human gut [9] whilst nitrite-preserved meat is a source of exogenous N-nitroso compounds [10]. Many of these N-nitroso compounds are known alkylating agents and carcinogens [11], [12]. These alkylating agents form O⁶-alkylguanine adducts, and DNA alkylation at the O⁶ position of guanine is one of the most critical steps leading to mutation, cancer and cell death [13]. Dietary antioxidants which include vitamin C and vitamin E, may reduce this type of DNA alkylation damage susceptibility by acting as nitrosation inhibitors [14], [15].

The DNA repair protein responsible for the cellular defence against this alkylation damage in human cells is the O⁶-methylguanine-DNA methyltransferase or MGMT. MGMT repairs this damage in a single-step reaction by catalysing the transfer of alkyl adducts from guanine to the active site of an internal cysteine residue [16]. This minimises the mutagenic effects of alkylating agents because if left unrepaired or mis-repaired, modifications introduced into the DNA may lead to an accumulation of mutations in genomic DNA. O⁶-alkylguanine, notably O⁶-methylguanine and O⁶-ethylguanine, are mispairing lesions providing the main source of guanine:cytosine to adenine:thymine pairs (GC → AT) transition mutations [17] and alkylated O⁶-methylguanine-DNA adducts have been detected in human colonic tissue [18]. These mutations may eventually lead to cancer development [12].

The MGMT protein consists of 207 amino acids, coded by the human MGMT gene which is located in the chromosome band 10q26 [16], [19]. Polymorphisms in the MGMT gene may explain the differences in the MGMT enzyme activity levels [20], which in turn may lead to reduced DNA repair capacity and thus increased cancer risk. The three common MGMT single nucleotide polymorphisms (SNPs) which lead to alterations of the amino acid sequence of the protein are Leu84Phe, Ile143Val and Lys178Arg with the last two SNPs in almost perfect disequilibrium [21].

Epidemiological studies have examined the association between MGMT polymorphisms, mainly Leu84Phe and Ile143Val SNPs and risk of cancer at various sites but the association between the latter SNP and risk of breast, colorectal and prostate cancer have not been studied extensively [22], [23], [24], [25]. The Ile143Val polymorphism is of interest due to its close proximity to the reactive alkyl-acceptor cysteine which is located at position 145 [26]. Though the effect of MGMT Ile143Val polymorphism on enzyme activity is not clear, certain food constituents may influence DNA repair. However, very few studies have examined the interactive effects of MGMT Ile143Val polymorphism with dietary factors on breast, colorectal and prostate cancer risk [22], [24], [25].

In this study, we examined whether MGMT Ile143Val (rs2308321) gene polymorphism is associated with risk of breast, colorectal and prostate cancer in the European Prospective Investigation into Cancer and Nutrition [EPIC]-Norfolk study and we also tested the hypothesis that carriers of the MGMT 143 variant allele may confer increased or decreased cancer susceptibility due to differences in DNA repair of DNA-alkylating N-nitroso compounds in presence of increased red and processed meat intake. Additionally, we examined potential interactions between other dietary factors such as alcohol, fruit and vegetables, fibre and dietary antioxidants (vitamin C, vitamin E and carotene), and this polymorphism on risk of breast, colorectal or prostate cancer.