SMAD7 and MGMT genotype variants and cancer incidence in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk Study
Introduction
There are many underlying mechanisms and pathways in the initiation, development and progression of cancer. Genetic variation of genes linked to these pathways, for example the transforming growth factor-beta (TGF-β) signalling and DNA repair pathways have been shown to play a role in carcinogenesis [1], [2].
The TGF-β signalling pathway has been considered as both a tumour suppressor pathway and a promoter of tumour progression and invasion [3]. In human cancers, it is also one of the most commonly altered cellular signalling pathways [4], [5] and appropriate regulation of TGF-β signalling is vital for the pathway's diverse cellular responses including cell proliferation, differentiation and apoptosis [6], [7]. The signalling is mediated by receptors and intracellular signal transducers known as the Smads [8]. Based on their functions, Smad proteins are divided into three groups – the receptor-activated Smads, the common-mediator and the inhibitors [9]. Inactivating mutations of Smad proteins have been found in human cancers [9] and overexpression of the inhibitor, Smad7 protein has been shown to antagonize TGF-β-mediated fibrosis, carcinogenesis and inflammation [10]. Recently, genome-wide scans have identified the SMAD7 gene (18q21) as a locus associated with a modest but highly significant increase in colorectal cancer risk [1], [11]. Broderick et al. [1] identified common variant alleles of SMAD7 rs12953717, rs4464148 and rs4939827 to influence colorectal cancer risk. Independent studies replicated this association [11], [12] and a recent case–control study also linked these common variants to colon cancer risk [13].
The MGMT gene regulates the direct damage reversal pathway, a DNA repair pathway crucial in preventing DNA damage and potential cancer development. The O6-methylguanine-DNA methyltransferase or MGMT protein acts by removing DNA alkyl adducts formed by alkylating agents such as cigarette smoking and N-nitroso compounds from the diet. If left unrepaired, modifications introduced into the DNA may lead to an accumulation of mutations in genomic DNA and eventually cancer development [14]. Thus, this has led to studies investigating the association between MGMT polymorphisms and cancer risk at various cancer sites including lung, breast and colorectal [15], [16], [17], with a recent prospective study investigating a series of DNA repair genes including the MGMT gene in relation to cancer incidence [18]. Overall, the findings are not very clear and inconsistent.
This exploratory study aims to investigate the association between (i) SMAD7 genotype variants (rs4464148 and rs4939827), (ii) MGMT genotype variants (rs12917 and rs2308321) and cancer incidence. We also assessed lifestyle factors which may influence the relationship between these variants and cancer incidence in this sub-cohort study.
Section snippets
Study population
The EPIC-Norfolk study is a prospective cohort of 25,639 men and women aged 40–79 years, recruited between 1993 and 1997 in Norfolk, East Anglia, United Kingdom (UK) and followed up to present. Participants for the present study are from a sub-cohort study consisting of 2566 individuals randomly selected from the total EPIC-Norfolk cohort for genome-wide scans using a random selection algorithm [19]. After excluding participants who did not have baseline health examination and food diaries
Results
A total of 1347 participants were available for analyses comprising 709 men and 638 women (mean age at recruitment approximately 62 years) and 192 incident cancer cases (111 men and 81 women) after mean follow-up of 10.1 years. The four types of cancer in the order of the highest incidence were prostate (n = 35), breast (n = 34), colorectal (n = 33) and lung (n = 21). Table 1 presents baseline characteristics in cancer cases and non-cases. Cancer cases were generally older and less active than
Discussion
The present study showed that the SMAD7 rs4464148 variant genotype was associated with a significant increase in all-cancer risk. There was no evidence of associations between cancer risk and SMAD7 rs4939827, MGMT rs12917 or MGMT rs2308321 variant genotype. There was evidence for increased cancer risk when combining variant genotypes in both of the SMAD7 SNPs. Participants carrying both the variant genotypes had higher relative risk estimates compared to those with non-variant genotypes in both
Conflict of interest statement
The authors declare that there are no conflicts of interest.
Role of the funding source
EPIC-Norfolk is funded by the Medical Research Council and Cancer Research UK.
Y.H. Loh was supported by the Singapore Health Services.
Acknowledgements
We thank the EPIC-Norfolk participants and EPIC staff.
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