A polymorphism in the DNA repair domain of APEX1 is associated with the radiation-induced pneumonitis risk among lung cancer patients after radiotherapy

Abstract

Objective: To examine the association of tag single nucleotide polymorphisms (tagSNPs) (rs1130409, rs1760944, rs2307486 and rs3136817) in APEX1 with the risk of severe radiation-induced pneumonitis (RP) after radiotherapy among Han Chinese patients with lung cancer.

Methods: A total of 168 patients with lung cancer who were receiving radiotherapy were prospectively recruited. RP was evaluated according to the Radiation Therapy Oncology Group. A case-control study was performed. The case group included patients with RP grade of ≥3, while the control group comprised patients with RP grades <3. Four tagSNPs of APEX1 were genotyped in 126 patients with complete follow-up by multi-SNaPshot® (Genesky Biotechnologies Inc., Shanghai, China) genotyping assays. RESULTS were assessed by a logistic regression model for RP risk and Mantal-Cox log-rank test for the cumulative RP probability by the genotypes.

Results: rs1130409 was associated with severe RP. GT genotype of rs1130409 was significantly higher in patients with RP than in those of the control group [68.8% vs 41.8%; p = 0.025; resulting odds ratio (OR), 5.98]. Patients with lung cancer bearing the G allele had a 5.83-fold higher risk of RP than those with the wild TT genotype [OR = 5.83; 95% confidence interval (CI), 1.27-26.90; p = 0.024], and this was further confirmed by the binary regression adjusted by some confounding factors, including Karnofsky performance scale, concurrent chemotherapy-radiotherapy and lung volume receiving >30 Gy (OR = 6.96; 95% CI, 1.36-35.77; p = 0.02). rs1130409 was also associated with the time to occurrence of severe RP (p = 0.04). Three-dimensional model APEX1 protein showed that rs1130409 is located in the random coil structure corresponding to the DNA repair function region.

Advances in knowledge: rs1130409 of APEX1 can be a predictor of RP grades ≥3 among patients with lung cancer.

Figure 1.

Percentage of grade ≥3 radiation-induced pneumonitis (RP) in 126 patients with lung cancer as a function of time from the start of radiation therapy and by tag single nucleotide polymorphism (tagSNP) genotype: (a) rs1130409, (b) rs1760944, (c) rs2307486 and (d) rs3136817. In each tagSNP, the solid line represents the wild homozygous genotype and the dashed lines represents the mutant homozygous genotype.

Figure 2.

Comparison of rs1130409 site and the active sites of the APEX1 protein on the sequence and three-dimensional model. (A) rs1130409 is indicated by a black arrow. The DNA binding sites, active sites, metal-binding sites and putative catalytic sites of the APEX1 protein are shown as red triangles. Non-synonymous single nucleotide polymorphisms (SNPs) are shown as green triangles, and synonymous SNPs are shown as yellow triangles. (B) Different secondary structures of APEX1 are shown in different colours: α-helices are shown in green, strands are shown in brown and random coils are shown in blue. Arrowheads indicate the N-to-C direction of the protein backbone. The SNP rs1130409 is highlighted in light yellow. Pink balls indicate the molecular structure of DNA. (a) rs1130409 on the APEX1 3D protein model. (b–d) are the APEX1 structures bound to DNA viewed from different angles: side, top and bottom. For colour image see online www.birpublications.org/doi/abs/10.1259/bjr.20140093.