Original articlePolymorphism of the DNA repair gene ERCC2 Lys751Gln and risk of lung cancer in a northeastern Chinese population
Introduction
DNA repair systems are essential for life. They are responsible for maintaining the integrity of the genome and play a critical role in protecting against mutations that can lead to cancer [1], [2], [3]. At least four pathways of DNA repair operate on specific types of damaged DNA. The nucleotide excision repair pathway (NER) repairs bulk lesions. DNA damage from big adducts is repaired mainly by the nucleotide excision repair pathway. ERCC2 (excision repair cross-complementing rodent repair deficiency, complementation group 2 [xeroderma pigmentosum D]) belongs to the NER pathway [4].
The ERCC2 gene comprises 23 exons. The ERCC2 protein is a 5′ or 3′ helicase consisting of 761 amino acids. Several polymorphisms have been identified in coding part of the ERCC2 gene, of which Ile199Met (C/G), His201Tyr (C/T), Asp312Asn (G/A), and Lys751Gln (A/C) result in amino acid changes, whereas codon Arg156Arg (C/A) and Asp711Asp (C/T) are silent polymorphisms. The lysine-to-glutamate substitution of the ERCC2 Lys751Gln polymorphism leads to a change of charge. The amino acid substitution is located in a domain which is involved in the interaction between ERCC2 and its helicase activator, p44 protein, inside the TFIIH complex [5], [6]. ERCC2 Lys751Gln is common among whites but rare among Asians [7], [8].
The functional significance of ERCC2 variants has not yet been elucidated, but some variants may be associated with reduced repair capacity [5], [8]. A number of studies have evaluated the potential role of ERCC2 Lys751Gln polymorphism on cancer, but the results have been conflicting across studies [4], [5].
The only study of head and neck cancer among whites reported that the CC genotype of ERCC2 Lys751Gln (A35931C) was associated with a borderline increased risk (CC versus AA+AC: adjusted odds ratio ORadj = 1.55, 95% CI = 0.96–2.52); odds ratios in this study were higher among older individuals and among those who smoked or drank alcohol at the time of the study [9]. Liang et al. [10] reported that the CC genotype of ERCC2 Lys751Gln was associated with increased risk of lung cancer in a Chinese population (CC versus AA: ORadj = 2.71, 95% CI = 1.01–7.24); the odds ratio was also significantly higher among cases with squamous cell carcinoma. Recently, Vogel et al. [11] reported that both CC and AC carriers of ERCC2 Lys751Gln were at significantly increased risk of lung cancer among Danes. Yu et al. [12] reported that the CC genotype of ERCC2 Lys751Gln was associated with an increased risk (OR = 6.71, 95% CI = 1.90–23.73) of esophageal squamous cell carcinoma in a Chinese population. Baccarelli et al. [13] reported that the C-allele of ERCC2 Lys751Gln was associated with increased melanoma risk among older subjects or subjects without dysplastic naevi. On the other hand, for a Danish white population Dybdahl et al. [14] suggested that a variant C-allele of ERCC2 Lys751Gln (A35931C) may be protective for development of basal cell carcinoma. But in a recent study of basal cell carcinoma in Danes, ERCC2 Lys751Gln polymorphism was not associated with cancer risk [15]. Tomescu et al. [16] reported that the A-allele of ERCC2 Lys751Gln was significantly overrepresented among melanoma cases in a British white population (A versus C: OR = 2.8, 95% CI = 1.2–7.0). Chen et al. [17] reported that the A-allele was associated with a significantly increased risk of lung cancer (AA+AC versus CC: OR = 3.19, 95% CI = 1.01–10.07) in a Chinese population. Other studies of basal cell carcinoma [18], melanoma [1], bladder cancer [19], [20], gliomas [21], and lung cancer [22], [23], [24], [25] did not observe any associations. In addition, the results of two meta-analyses were inconsistent: The results of Hu et al. [26] support the hypothesis that the ERCC2 751C is a risk allele and that individuals with the ERCC2 751CC genotype are at higher risk of developing lung cancer; the results of Benhamou and Sarasin [8], however, suggest that there is no clear association between ERCC2 Lys751Gln gene polymorphisms and lung cancer. Haplotype analysis or analysis of special combinations of variant alleles suggests that the C-allele of ERCC2 Lys751Gln is associated with increased risk of breast cancer [27], colorectal cancer [28], and lung cancer [29], [30].
Lung cancer is considered a polygenic disease [31]. Over the last decade, the incidence and mortality rates of lung cancer in China have increased significantly and constantly [32]. However, studies of ERCC2 SNPs and other DNA repair gene SNPs and lung cancer in a Chinese population are scarce. Although the association between ERCC2 Lys751Gln polymorphism and lung cancer has been evaluated in Chinese populations, conflicting results have been reported among three investigations [10], [17], [33].
We have recently reported in a case–control study that ERCC2 Arg156Arg (A22541C) contributed to the risk of developing lung cancer in a Chinese population [34]. In the present study, we explored the hypothesis that the ERCC2 polymorphism Lys751Gln may be a marker for lung cancer risk in a northeastern Chinese population.
Section snippets
Study population
This hospital-based case–control study consisted of 147 cases with lung cancer and 145 cancer-free controls. All subjects were unrelated ethnic Han Chinese from northeastern China. The cases with newly diagnosed primary lung cancer were recruited between March 2002 and August 2004 at Liaoning Tumor Hospital, Affiliated Eighth Hospital of Shenyang Medical College, and The General Hospital of Shenyang Military Region. All cases were previously untreated (i.e., enrolled in the study prior to
Results
As shown in Table 1, the analysis included 145 controls and 147 cases: squamous cell carcinoma, 6 (42%); adenocarcinoma, 63 (43%); and other lung cancer, 22 (15%). There was no statistically significant difference in mean age or gender between the cases and controls. There were more subjects with family history of lung cancer among cases (10%) than among controls (0.7%), (P < 0.001) and more subjects with a longer history of smoking among cases (42%) than among controls (23%), (P = 0.001). The
Discussion
In the present study, our main finding was that the C-allele of ERCC2 Lys751Gln (A35931C) was significantly overrepresented among lung cancer cases, and especially among patients with squamous cell carcinoma. This suggests that the C-allele of ERCC2 Lys751Gln (A35931C), or another nearby genetic variation linked to it, leads to an increased susceptibility to lung cancer. Our results therefore add to the notion that the C-allele of ERCC2 Lys751Gln is associated with an increased risk of lung
Acknowledgments
We thank Prof. Bjorn A. Nexo and Prof. Lars Bolund (Institute of Human Genetics, University of Aarhus, Denmark) for advice on the design of project. We thank our volunteers for donating their blood and collaborators for collection of blood sample and information. This study was approved by the Chinese Administration Office of Human Genetic Resources (no. [2001] 015) and was supported by grant no. 30571016 from National Nature Science Foundation of China, grants no. 1022043-1-05 and
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