Genetic variants of the nonhomologous end joining gene LIG4 and severe radiation pneumonitis in nonsmall cell lung cancer patients treated with definitive radiotherapy

BACKGROUND: Nonhomologous end joining (NHEJ) is a pathway that repairs DNA double-strand breaks (DSBs) to maintain genomic stability in response to irradiation. The authors hypothesized that single nucleotide polymorphisms (SNPs) in NHEJ repair genes may affect clinical outcomes in patients with nonsmall cell lung cancer (NSCLC) who receive definitive radio(chemo)therapy. METHODS: The authors genotyped 5 potentially functional SNPs-x-ray repair complementing defective repair in Chinese hamster cells 4 (XRCC4) reference SNP (rs) number rs6869366 (-1394 guanine to thymine [-1394G -> T] change) and rs28360071 (intron 3, deletion/insertion), XRCC5 rs3835 (guanine to adenine [G -> A] change at nucleotide 2408), XRCC6 rs2267437 (-1310 cytosine to guanine [C -> G) change], and DNA ligase IV (LIG4) rs1805388 (threonine-to-isoleucine change at codon 9 [T9I])-and estimated their associations with severe radiation pneumonitis (RP) (grade >= 3) in 195 patients with NSCLC. RESULTS: A predictive role in radiation pneumonitis (RP) development was observed for the LIG4 SNP rs1805388 (adjusted hazard ratio, 2.08; 95% confidence interval, 1.04-4.12; P=.037 for the CT/TT genotype vs the CC genotype). In addition, men with the TT genotype of the XRCC4 rs6869366 SNP and women with AG + AA genotypes of the XRCC5 rs3835 SNP also were at increased risk of developing severe RP. CONCLUSIONS: The current results indicated that NHEJ genetic polymorphisms, particularly LIG4 rs1805388, may modulate the risk of RP in patients with NSCLC who receive definitive radio(chemo) therapy. Large studies will be needed to confirm these findings. Cancer 2012; 118: 528-35. (C) 2011 American Cancer Society.