Abstract
BackgroundThe nucleotide excision repair (NER) protein, xeroderma pigmentosum C (XPC), participates in recognizing DNA lesions and initiating DNA repair in response to DNA damage. Because mutations in XPC cause a high risk of cancer in XP patients, we hypothesized that inherited sequence variations in XPC may alter DNA repair and thus susceptibility to cancer.MethodsIn this hospital-based case-control study, we investigated five XPC tagging, common single nucleotide polymorphisms (tagging SNPs) in 1,010 patients with newly diagnosed lung cancer and 1,011 matched cancer free controls in a Chinese population.ResultsIn individual tagging SNP analysis, we found that rs3731055AG+AA variant genotypes were associated with a significantly decreased risk of lung adenocarcinoma [adjusted odds ratio (OR), 0.71; 95% confidence interval (CI), 0.56–0.90] but an increased risk of small cell carcinomas [adjusted OR, 1.79; 95% CI, 1.05–3.07]. Furthermore, we found that haplotype ACCCA was associated with a decreased risk of lung adenocarcinoma [OR, 0.78; 95% CI, 0.62–0.97] but an increased risk of small cell carcinomas [OR, 1.68; 95% CI, 1.04–2.71], which reflected the presence of rs3731055A allele in this haplotype. Further stratified analysis revealed that the protective effect of rs3731055AG+AA on risk of lung adenocarcinoma was more evident among young subjects (age ≤ 60) and never smokers.ConclusionThese results suggest that inherited sequence variations in XPC may modulate risk of lung cancer, especially lung adenocarcinoma, in Chinese populations. However, these findings need to be verified in larger confirmatory studies with more comprehensively selected tagging SNPs.
Highlights
The nucleotide excision repair (NER) protein, xeroderma pigmentosum C (XPC), participates in recognizing DNA lesions and initiating DNA repair in response to DNA damage
The observed MAFs of all single nucleotide polymorphisms (SNPs) were very similar between the cases and controls, the observed MAFs of two non-synomynous SNPs (i.e., A499V and K939Q) from the controls (0.32 and 0.36, respectively) were close to that (0.30 and 0.38, respectively) for Chinese obtained in the HapMap database but higher than that (0.24 and 0.34, respectively) from the Environmental Genome Project (EGP) database
When the results were stratified by tumor histology, we found that compared with the rs3731055 GG genotype, the combined rs3731055 AG+AA genotype was associated with a significantly decrease risk of lung AC but an increase risk of the small cell lung carcinoma (SCLC) group
Summary
The nucleotide excision repair (NER) protein, xeroderma pigmentosum C (XPC), participates in recognizing DNA lesions and initiating DNA repair in response to DNA damage. Because mutations in XPC cause a high risk of cancer in XP patients, we hypothesized that inherited sequence variations in XPC may alter DNA repair and susceptibility to cancer. Considerable evidence suggests that NER capacity is crucial in maintaining normal cell functions, and variations the in DNA repair capacity (DRC) among individuals may contribute to differences in risk of cancers, including lung cancer [11]. The underlying molecular mechanisms of individual variation in cancer susceptibility are thought to be due to genetic polymorphisms, single nucleotide polymorphisms (SNPs) involved in cellular mechanisms, such as DNA repair, that maintain normal cell growth [12]. It is likely that inherited sequence variations of the NER genes mayaffect individual susceptibility to cancer as seen in the recessive genetic syndrome xeroderma pigmentosum (XP) [13]
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