1. Introduction 1 TP53 RB1 2 3 4 At least four pathways of DNA repair operate on specific types of damaged DNA. Base excision repair (BER) operates on small lesions, while the NER pathway repairs bulk lesions. Mismatch repair corrects replication errors. Double-strand DNA break repair (DSBR) actually consists of two pathways, homologous recombination (HR) and non-homologous end-joining (NHEJ). The NHEJ repair pathway involves direct ligation of the two double strand break ends, while HR is a process by which double-strand DNA breaks are repaired through the alignment of homologous sequences of DNA. The following sections review the literature on DNA repair genes in more detail, specifically those involved in the NER pathway. 5 6 7 de novo 6 XPD 8 The aim of this article is to review and evaluate associations between genes in the NER pathway and lung cancer risk, focusing on genes encoding five key enzymes in this pathway: XPA, ERCC1, ERCC2/XPD, ERCC4/XPF and ERCC5/XPG. 2. Materials and methods 2-1. Identification and eligibility of relevant studies 9 13 XPA 11 ERCC1 13 17 ERCC2 14 18 19 11 13 14 17 24 11 13 14 17 19 21 28 ERCC1 ERCC4/XPF ERCC4/XPF ERCC5/XPG ERCC5/XPG 2-2. Data extraction and assessment of study quality For each study, characteristics such as authors, year of publication, ethnic group of the study population, source of control population, number of genotyped cases and controls, crude odds ratio (OR) and the method for quality control of genotyping were noted. For studies including subjects of different ethnic groups, data were extracted separately for each ethnic group whenever possible. Methods for defining study quality in genetic studies are more clearly delineated than those for observational studies. We assessed the homogeneity of the study population (Caucasian or Asian). 2-3. Meta-analysis 29 29 30 31 32 33 34 34 3. Results 3-1. DNA repair capacity and lung cancer risk 35 36 37 38 39 40 XPA 41 42 43 44 XPA XPA 45 1 XPA  XPA XPA  46 XPA 10 9 10 11 12 13 1 1 9 10 13 9 10 13 11 9 XPA XPA ERCC1 ERCC1 47 ERCC1 ERCC1 48 ERCC1 ERCC1 For the T19007 C (Asn118Asn) polymorphism, although the T/T genotype generates the less commonly associated triplet codon sequence encoding the amino acid and has been termed the "variant" by convention, the T/T genotype indeed has been reported to occur at higher frequencies. Hence, the T/T genotype is used as reference in this paper. The C/C genotype of the C8092A polymorphism is used as reference on the same score. 13 14 15 16 17 2 15 16 16 13 15 15 ERCC1 ERCC2/XPD ERCC2/XPD ERCC2 49 ERCC2/XPD ERCC2/XPD ERCC2/XPD ERCC2/XPD 20 18 19 21 22 23 50 51 18 23 50 ERCC2/XPD 51 11 13 14 17 24 3 ERCC2/XPD 3 20 20 18 16 19 19 4 ERCC2 19 19 25 18 22 21 23 25 26 27 51 51 18 19 21 23 25 27 51 11 13 14 17 24 28 14 13 11 24 17 28 The summary frequency of the 751Lys allele among Caucasians (0.634, 95% CI = 0.614 - 0.655) was significantly lower than that among Asians (0.843, 95% CI = 0.763 - 0.924). A statistically significant ethnic difference was observed between Caucasians and Asians. Summary ORs for the Gln/Gln genotype and Lys/Gln genotype were 1.06 (95% CI = 0.97 - 1.16) and 1.30 (95% CI = 1.14 - 1.49), respectively. Evidence of publication bias was absent in all of the analyses. The effect of the Gln/Gln genotype on lung cancer risk was stronger in Caucasians (OR = 2.25, 95% CI = 0.97 - 5.23) than in Asians (OR = 1.02, 95% CI = 0.20 - 5.27). This may only be due to a difference in sample sizes. Reasons for this difference in risk among different ethnic populations are as yet unknown but, if real, may be related to other genetic or environmental factors. The Cochrane Q test for heterogeneity showed a statistical significance among Asian studies (P = 0.040, Gln/Gln genotype vs. Lys/Lys genotype). 14 19 26 27 13 26 27 ERCC2/XPD 19 20 21 ERCC2/XPD ERCC4/XPF 52 ERCC4/XPF Drosophila Saccharomyces cerevisiae S. pombe 53 ERCC4/XPF ERCC4/XPF  ERCC4/XPF ERCC4/XPF ERCC4/XPF 54 55 ERCC4/XPF 9 24 ERCC5/XPG ERCC5/XPG is responsible for a 1186 amino acid structure-specific endonuclease activity that is essential for the two incision steps in NER. The ERCC5/XPG nuclease has been suggested to act on the single-stranded region created as a result of the combined action of the XPB helicase and the ERCC2/XPD helicase at the DNA damage site. In human cells, ERCC5/XPG catalyses an incision approximately 5 nucleotides 3' to the site of damage but is also involved non-enzymatically in the subsequent 5' incision. It is further involved in the stabilization of a pre-incision complex on the damaged DNA. ERCC5/XPG EECC5/XPG 56 57 24 13 24 4. Discussion in vivo in vitro ERCC2/XPD ERCC2/XPD ERCC2/XPD 58 32 ERCC2/XPD 59 60 ERCC2/XPD ERCC2/XPD 22 XPG  61 AUG 62 63 62 XPA XPA 9 AUG XPA 64 XPA in vitro 10 XPA 65 66 67 68 ERCC2/XPD XPA 69