Functional polymorphisms of base excision repair genes XRCC1 and APEX1 predict risk of radiation pneumonitis in patients with non-small cell lung cancer treated with definitive radiation therapy

Abstract

Purpose: To explore whether functional single nucleotide polymorphisms (SNPs) of base-excision repair genes are predictors of radiation treatment-related pneumonitis (RP), we investigated associations between functional SNPs of ADPRT, APEX1, and XRCC1 and RP development.

Methods and materials: We genotyped SNPs of ADPRT (rs1136410 [V762A]), XRCC1 (rs1799782 [R194W], rs25489 [R280H], and rs25487 [Q399R]), and APEX1 (rs1130409 [D148E]) in 165 patients with non-small cell lung cancer (NSCLC) who received definitive chemoradiation therapy. Results were assessed by both Logistic and Cox regression models for RP risk. Kaplan-Meier curves were generated for the cumulative RP probability by the genotypes.

Results: We found that SNPs of XRCC1 Q399R and APEX1 D148E each had a significant effect on the development of Grade ≥2 RP (XRCC1: AA vs. GG, adjusted hazard ratio [HR] = 0.48, 95% confidence interval [CI], 0.24-0.97; APEX1: GG vs. TT, adjusted HR = 3.61, 95% CI, 1.64-7.93) in an allele-dose response manner (Trend tests: p = 0.040 and 0.001, respectively). The number of the combined protective XRCC1 A and APEX1 T alleles (from 0 to 4) also showed a significant trend of predicting RP risk (p = 0.001).

Conclusions: SNPs of the base-excision repair genes may be biomarkers for susceptibility to RP. Larger prospective studies are needed to validate our findings.

Fig. 1

Cumulative probability of grade ≥ 2 radiation pneumonitis in 165 patients with NSCLC as a function of time from the start of radiation therapy by genotypes. (a) XRCC1 Q399R; (b) APEX1 D148E; (c) ADPRT V762A; (d) XRCC1 399A and APEX1 148T combined alleles.

Fig. 2

Classification and regression tree analysis for predictors of grade ≥ 2 radiation pneumonitis in 165 patients with NSCLC. SNPs were classified as wild type (W) and variant genotype (V).