Elsevier

Lung Cancer

Volume 60, Issue 3, June 2008, Pages 340-346
Lung Cancer

Potentially functional polymorphisms of EXO1 and risk of lung cancer in a Chinese population: A case-control analysis

https://doi.org/10.1016/j.lungcan.2007.11.003Get rights and content

Summary

Exonuclease 1 (EXO1) is an important nucleases involved in mismatch repair system that contributes to maintain genomic stability, to modulate DNA recombination, and to mediate cell cycle arrest. Potentially functional polymorphisms in EXO1 may alter cancer risks by influencing the repair activity of EXO1. Therefore, we hypothesized that single nucleotide polymorphisms (SNPs) in EXO1 were associated with risk of lung cancer. To test this hypothesis, we genotyped five common SNPs (rs1776177A/G, rs1047840G/A (Glu589Lys), rs1776148G/A (Gly670Glu), rs9350C/T (Leu757Pro) and rs851797T/C) that tag eight SNPs located at exon regions of EXO1 by using the Illumina high-throughput genotyping platform in 500 incident lung cancer cases and 517 cancer-free controls in a Chinese population. Significant differences of allele and genotype distributions were observed in Glu589Lys (rs1047840) of EXO1 between the cases and controls (P = 0.028 and 0.025 for allele and genotype distributions, respectively). Logistic regression analyses revealed that individuals carrying the variant 589Lys allele (589Glu/Lys or 589Lys/Lys) had a significantly increased risk of lung cancer [adjusted odds ratio (OR) = 1.41, 95% confidential interval (CI) = 1.09–1.84] compared with those who carried the wild-type homozygote (589Glu/Glu). Furthermore, we found that haplotype AAGTT was more frequent in cases than in controls (P < 0.001 for both two-sided χ2-test and 1000 times permutation tests). These results suggest that the EXO1 Glu589Lys polymorphism and its surrounding regions might be genetic susceptibility markers for lung cancer in this study population.

Introduction

Lung cancer is the leading cause of cancer-related deaths in the world [1]. In China, the incidence and mortality rates have been increasing rapidly in the last two decades and accumulating tobacco use was considered as the most important cause for lung cancer [2], [3], [4]. More than 60 carcinogens were detected in tobacco smoke and these carcinogens could form adducts or induce oxidative damages on DNA, resulting in mutations and/or genome instability [5]. Exonuclease 1 (EXO1; MIM #606063) is a member of the RAD2 nuclease family and functions in DNA replication, repair, and recombination by removing mispaired bases in mismatch repair system [6], [7]. Mismatch repair is one of the major DNA repair pathways in human beings, maintaining genomic stability, modulating DNA recombination, and mediating cell cycle arrest [8]. The deficiency of mismatch repair system results in numerous mutations that lead to the development of multiple tumors, including lung cancer [9], [10], [11].

The EXO1 gene has been mapped to chromosome 1q42-q43, spanning 42 kb and containing 1 untranslated exon followed by 13 translated exons [12], [13], [14]. EXO1 protein (846-amino acids) participates in mismatch-provoked excision repair, forming a ternary complex of EXO1-MLH1-PMS2 (EXO1-MutSα) or EXO1-MSH2-MSH6 (EXO1-MutLα) [15]. EXO1-null mice were characterized as having reduced survival time and increased susceptibility to the development of lymphoma [16]. Bardwell et al. showed that mice lacking exon 6 of EXO1 exhibited defective mismatch repair [17]. By screening a set of colon cancer families, Wu et al. detected 9 different mutations in EXO1 in 14 hereditary non-polyposis colorectal cancer (HNPCC) patients who did not carry mutations in MSH2, MLH1, or MSH6[18]; however, five of these nine mutations were considered polymorphisms because they were also observed in controls with similar frequencies [19] and the association with HNPCC was not in consistence with another study [20].

Recently, Yamamoto et al. explored the association between two single nucleotide polymorphisms (SNPs) at exon 10 (Thr439Met) and exon 14 (Leu757Pro) of EXO1 with the development of colorectal cancer in a Japanese population, and found that both SNPs were associated with altered risk of colorectal cancer [21]. Zienolddiny et al. [22] also evaluated the association of one non-synonymous polymorphism Glu589Lys of EXO1 with risk of non-small cell lung cancer in a case-control study of 343 cases and 413 controls in a Norway population but failed to find a significant association. Because only one SNP might not represent genetic variation in the gene, it is biologically plausible that multiple SNPs, especially in the exon regions with amino acid changes, might play a role in susceptibility to carcinogenesis. Therefore, we tested the hypothesis that multiple potentially functional SNPs in exons of EXO1 gene were associated individually or jointly with risk of lung cancer in a case-control study of lung cancer with moderate sample size (500 cases and 517 controls) in a Chinese population.

Section snippets

Study subjects

This study was approved by the Institutional Review Board of Nanjing Medical University. Characteristics of the study subjects have been described elsewhere [23]. In brief, a total of 500 incident cases with histopathologically confirmed lung cancer and 517 cancer-free controls frequency matched to the cases by age (±5 years) and gender were recruited from Nanjing and surrounding regions, Jiangsu Province, China, during the same time period. After a written informed consent was obtained, each

Results

Demographic characteristics of both lung cancer cases and cancer-free controls were presented previously [23]. Briefly, there was no significant difference in the distribution of age (P = 0.661) and gender (P = 1.000) between the lung cancer patients and the controls. Smokers had a 1.89-fold (95% CI = 1.46–2.43) increased risk of lung cancer compared with non-smokers, and a dose–response effect on the risk was evident as the cumulative smoking dose increased (OR = 1.39, 95% CI = 1.04–1.87 for less than

Discussion

In this study, we selected five potentially functional SNPs of the EXO1 gene to investigate their associations with the risk of lung cancer in a Chinese population with a moderate sample size of 500 lung cancer cases and 517 cancer-free controls. We found that variant genotypes of Glu589Lys (589Glu/Lys or 589Lys/Lys) were significantly associated with increased risk of lung cancer and the joint effect with smoking was also evident. Furthermore, haplotype AAGTT with 589Lys allele was more

Conflict of interest statement

None declared.

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      It is, therefore, clear that EXO1 stability is probably regulated by an interplay of post-translational modifications (PTM)–phosphorylation, SUMOylation, and ubiquitination–but the exact choreography of these PTMs and the exact roles of specific modifications in EXO1 regulation still need to be elucidated. Regulatory mechanisms impinging on EXO1 are of significance from a cancer standpoint, as multiple SNPs in EXO1 have been identified in patients with colorectal cancers (89–91), and a specific polymorphism, K589E (rs1047840), has been linked with an increased risk of breast (92), gastric (93), oral (94), lung (95), and brain (96) cancer development. Another polymorphism, N279S (rs4149909), was recently linked to an increased risk of breast cancer in a genome-wide association analysis of >120,000 individuals (97).

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    This work was supported in part by National Outstanding Youth Science Foundation of China 30425001 (to H. Shen) and 30625019 (to W. Huang), the China National Key Basic Research Program Grants 2002CB512902 (to D. Lu and H. Shen), 2006AA020706, 2004CB518605, 06XD14015 and 05DZ22201 (to W. Huang), and National “211” Environmental Genomics Grant (to D. Lu).

    1

    These authors contribute equally to this work.

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