Elsevier

Cancer Epidemiology

Volume 35, Issue 4, August 2011, Pages 369-374
Cancer Epidemiology

SMAD7 and MGMT genotype variants and cancer incidence in the European Prospective Investigation into Cancer and Nutrition (EPIC)-Norfolk Study

https://doi.org/10.1016/j.canep.2010.09.011Get rights and content

Abstract

Purpose: The SMAD7 gene was recently identified to be associated with colorectal cancer risk. Smad7 protein is a known inhibitor of TGF-β signalling pathway which has a prominent role in tumorigenesis. MGMT gene regulates the direct damage reversal repair pathway, preventing DNA damage and potential cancer development. This exploratory study aims to investigate the association between SMAD7 (rs4464148, rs4939827) and MGMT (rs12917, rs2308321) genotype variants, and all-cancer incidence. Methods: Our study population was a sub-cohort of the EPIC-Norfolk study, a prospective cohort of approximately 25,000 men and women aged 40–79. Between recruitment 1993–1997 and follow-up to 2006, 192 incident cases and 1155 non-cases with genotype data were identified. Baseline 7-day food diary and health/lifestyle questionnaire data were analysed. Results: SMAD7 rs4464148 variant genotype was associated with increased cancer incidence [HR = 1.34, 95%CI = 1.00–1.80] but no overall association for SMAD7 rs4939827 or MGMT genotypes. Participants with variant genotypes in both SMAD7 SNPs had a higher cancer incidence compared to those without any (HR = 2.74, 95%CI = 1.10–6.79) (P = 0.03; Ptrend = 0.01). Amongst the younger age participants (<mean 62 years), SMAD7 rs4464148 variant genotype group had higher HR of 1.71 (95%CI = 1.03–2.83) compared to the non-variant genotype group. Conclusions: These findings suggest that SMAD7 rs4464148 common variant genotype is associated with cancer incidence but not SMAD7 rs4939827, MGMT rs12917 or MGMT rs2308321. A combination of variants of the SMAD7 SNPs may be associated with increased cancer risk in this study population. However, these findings need to be replicated in larger studies and in studies of specific cancer sites.

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.

References (30)

  • R.J. Akhurst

    TGF beta signaling in health and disease

    Nat Genet

    (2004)
  • J. Massague

    TGF-beta signal transduction

    Annu Rev Biochem

    (1998)
  • O. Korchynskyi et al.

    Expression of Smad proteins in human colorectal cancer

    Int J Cancer

    (1999)
  • X. Yan et al.

    Regulation of TGF-beta signaling by Smad7

    Acta Biochim Biophys Sin (Shanghai)

    (2009)
  • A. Tenesa et al.

    Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21

    Nat Genet

    (2008)
  • Cited by (0)

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