Lung cancer susceptibility and prognosis associated with polymorphisms in the nonhomologous end-joining pathway genes: a multiple genotype-phenotype study.
BACKGROUND
Nonsmall cell lung cancer (NSCLC) frequently exhibits genomic instability, such as high fractional allelic loss (FAL). Genomic instability may result from unrepaired or misrepaired double-strand breaks (DSBs). The authors of this report postulated that polymorphisms in genes of the nonhomologous end-joining (NHEJ) pathway, which is the major DSB repair pathway in mammalian cells, may modulate lung cancer susceptibility and prognosis.


METHODS
Patients with NSCLC (n = 152) and a group of appropriate age-matched and sex-matched controls (n = 162) were subjected to genotype analysis of the NHEJ pathway genes x-ray repair complementing defective repair in Chinese hamster cells 6 (Ku70) (reference single nucleotide polymorphism number [rs] 2267437), x-ray repair complementing defective repair in Chinese hamster cells 5 (Ku80) (rs3835), x-ray repair complementing defective repair in Chinese hamster cells 4 (XRCC4) (rs1805377), and DNA ligase IV (LIG4) (rs1805388). The gene-gene interaction (joint effect), genotype-environmental (ie, smoking) correlation, and genotype-phenotype (ie, FAL) correlation were examined. The Kaplan-Meier method and log-rank tests were used to assess the prognostic effect.


RESULTS
There was a significant association between the XRCC4 and LIG4 genotypes with NSCLC risk in an analysis of individual polymorphism associations, and the risk of NSCLC increased further in a combined analysis of multiple polymorphisms (adjusted odds ratio [OR], 8.74). The patients who had a homozygous variant guanine/guanine genotype of the XRCC4 gene had a poorer prognosis compared with other patients (P = .015). There was a significant difference between the patient smokers and controls for XRCC4 (adjusted OR, 2.67) and LIG4 (adjusted OR, 2.04). In addition, polymorphisms in XRCC4 and LIG4 were linked significantly with patients who had high FAL (adjusted OR, 2.03-3.84).


CONCLUSIONS
To the authors' knowledge, this is the first nested case-control study to demonstrate a significant association between the polymorphisms of genes in the NHEJ pathway and lung cancer susceptibility and prognosis. The results may be useful for risk assessment and disease monitoring of patients with NSCLC.
Tseng
Ruo-Chia
RC
Department of Pharmacology, College of Medicine, National Cheng Kung University, Tainan, Taiwan.
Hsieh
Feng-Jen
FJ
Shih
Chuen-Ming
CM
Hsu
Han-Shui
HS
Chen
Chih-Yi
CY
Wang
Yi-Ching
YC
D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000401:mortality; D016022:Case-Control Studies; D053903:DNA Breaks, Double-Stranded; D045643:DNA Repair Enzymes / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D042822:Genomic Instability; D005838:Genotype; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics* / Q000401:mortality; D008297:Male; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis; D012306:Risk; D012907:Smoking
D004268:DNA-Binding Proteins; D045643:DNA Repair Enzymes