Potentially functional polymorphisms of EXO1 and risk of lung cancer in a Chinese population: A case-control analysis☆
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.
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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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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).
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These authors contribute equally to this work.