Background
Worldwide, lung cancer harbored the highest incidence and mortality rates among all malignant cancers [
1,
2]. Non-small cell lung cancer (NSCLC), as the most common type of lung cancer, accounts for 75–80 % of all lung cancer cases [
3]. The development of lung cancer was greatly affected by the environmental factors, such as cigarette smoking, alcohol drinking and air pollutants [
4‐
6]. However, evidence has showed that the genetic variants of cancer-related genes are associated with lung risk, which the important role of genetic factors in the development of lung cancer [
7‐
9].
Nucleotide excision repair (NER) is the major DNA repair pathway to remove bulky DNA lesions induced by UV light and environmental carcinogens [
10]. NER has two subpathways, global genome NER (GG-NER) and transcription coupling NER (TC-NER). TC-NER is involved in a rapid removal of the damages on the transcribed strands of active genes and a resumption of transcription [
11‐
13]. TC-NER is initiated by arresting RNA polymerase II at DNA lesion site on transcript strand. In the initiation of transcription coupling repair, the TC-NER specific proteins Cockayne syndrome complementation group A (CSA) and group B (CSB) are thought to play an important role in removing the stalled RNA polymorase II and recruiting other DNA repair proteins [
14]. Many studies have demonstrated that the decreased expression of CSA and CSB in lung cancer and the genetic variants in these two genes were associated with the lung cancer risk [
15‐
18].
Xeroderma pigmentosum group A (XPA)-binding protein 2 (XAB2), which located at 19p13.2, was first identified as an interacting protein with XPA and hence found to interact with CSA, CSB and RNA polymerase II to participant to TC-NER and transcription [
17,
19,
20].
In vitro, when cells treated with DNA-damaging agents, enhanced interaction of XAB2 with RNA polymerase II or XPA was observed, which suggesting DNA damage-responsive activity of the XAB2 [
19].
Due to the important role of XAB2 in the TC-NER, we proposed that the genetic variants in XAB2 genes might contribute to the risk of lung cancer. To verify this proposal, we conducted this case-control study to evaluate the role of XAB2 tagSNPs in the development of NSCLC.
Discussion
In this case-control study in a Chinese population, we found that two tag SNPs (rs794078 and rs4134816) in XAB2 were associated with significantly decreased risk of development non-small cell lung cancer. These findings indicated that XAB2 genetic variants might contribute to the susceptibility of lung cancer.
Nucleotide excision repair is the main mechanism for removing the bulky DNA adduct from damage DNA for preventing carcinogens-induced mutagenesis [
22,
23]. Several animal models, where individual NER genes were disrupted, had showed the importance of the integrity of NER pathway in preventing lung cancer [
24,
25].
TC-NER, as one of important sub-pathways in NER, only repairs the lesions in the transcribed strand in active genes. There are several major proteins involved in TC-NER in human cells, including CSA, CSB, XPA and XAB2. Studies have showed that the deficient of these nucleotide excision repair proteins contributed to the risk of various cancers. Animal experiments showed that the CSB played an important role in the cellular response to stress and CSB
−/− mice were increased susceptible to chemically induced skin cancer [
26]. A case-control study also found 12.2 and 12.5 % reduced RNA transcriptional levels of CSA and CSB in lung cancer patients than controls [
27].
XAB2 is a key factor in TC-NER, which is composed of 855 amino acids and contains 15 tetratricopeptide repeat motifs. By interacting with CSA, CSB, RNA polymerase II and XPA, XAB2 conducted the multiple functions in the process of transcription and TC-NER [
19,
20]. Microinjection of specific antibodies against XAB2 inhibits transcription and TC-NER, suggesting the key role of XAB2 in the process of transcription and TC-NER [
20]. Knockdown of XAB2 in HeLa cell resulted in a hypersensitivity to killing by UV light and a decreased recovery of RNA synthesis [
19]. Over expression of XAB2 was observed in HL60 cells treated with inhibited all-trans retinoic acid (ATRA) and inhibited XAB2 expression by small interfering RNA (siRNA) increased ATRA-sensitive cellular differentiation, which indicated that XAB2 was associated with the cellular differentiation [
28].
Studies have demonstrated that the polymorphisms, which located in NER genes or regulatory sequences, may affect DNA repair capacity and further increase likelihood of cancer development. In the present study of NSCLC in Chinese, we used a relatively comprehensive selection of SNPs and found the significant effects of
XAB2 variants on the risk of lung cancer. This is the first study to investigate the association of
XAB2 polymorphisms with the risk for developing cancer. There were several studies to evaluate the role of
XAB2 genetic variants in complex autoimmune disease. For example, Briggs et al. conducted a case-control study to evaluate the correlation between
XAB2 rs4134860 T > C variant and the risk of multiple sclerosis (MS) and found an increased risk of MS among rs4134860 CC genotype carriers [
29]. In this lung cancer case-control study, we didn’t find any association of
XAB2 rs4134860 T > C polymorphism with the risk of NSCLC. In another study, researchers analyzed the impact of several polymorphisms in DNA repair genes on the prognosis of colorectal cancer patients and didn’t find the association of
XAB2 rs794078 G > A variant with the cancer prognosis [
30]. In present study, individuals carrying
XAB2 rs794078 AA genotype had 88 % decreased risk of NSCLC.
As we know, the magnitude of the effect of smoking far outweighed all other factors leading to lung cancer [
31,
32]. Many studies have demonstrated that the strong association of smoking with lung cancer risk [
5,
33,
34]. Therefore, we further analyzed the role of
XAB2 polymorphisms in the development of NSCLC stratified by smoking status. We observed that a 49 % protective effect for
XAB2 rs4134816 variant was evident only for non-smokers, but not for smokers. The exact mechanism of how cigarette-smoking effects on DNA repair capacity posted by
XAB2 polymorphism is unknown. One possible explanation may be that the protective effect of
XAB2 variant allele might be evident in non-smokers with low levels of oxidative damage. Similar pattern of genetic effects have been observed for DNA repair gene XRCC1 (X-ray repair cross-complementation group 1) at low smoking exposure, but not at high smoking exposure [
35].
When stratified by gender, our study showed a 61 % protective effect of
XAB2 rs4134816 C genotype among men, but not among women. Genetic variants in NER genes are associated with variability of lung cancer risk. Letkova and his colleagues investigated the polymorphisms of selected DNA repair genes, including XPC, XPD, hOGG1 and XRCC1, and found the different risks of developing lung cancer when stratified by gender, which further supporting our current findings [
36]. Our present study also found that a 65 % protective effect for
XAB2 rs4134816 T > C genetic variant among subjects aged 60 years or younger. Using Cox proportional hazard model, Gauderman et al. estimated the age-specific genetic incidence rate and found that the estimated proportion of lung cancer patients with high-risk allele exceeds 90 % for cases with onset at age 60 years or less and decreases to approximately 10 % for cases with onset at age 80 years or older. These findings suggested the contribution of age in the development of cancer [
37]. The numbers of subjects in several of subgroups were very small, so some caution is needed when interpreting these findings.
Our study has its limitation. Due to the moderate sample size and the lack of related phenotypic and functional assays, large studies and functional evaluations are still need to be conducted in the future.
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Competing interests
The authors declare that they have no competing interests.
Authors’ contributions
NP drafted the article; NP, JY, LC and YL analyzed the data; JW, QS, JY and ZZ collected clinical data; XZ contributed to the research plan, approved the data and the final version of the manuscript. All authors read and approved the final manuscript.