Polymorphisms in BMP2/BMP4, with estimates of mean lung dose, predict radiation pneumonitis among patients receiving definitive radiotherapy for non-small cell lung cancer

Abstract

Single nucleotide polymorphisms (SNPs) in TGFβ1 can predict the risk of radiation pneumonitis (RP) in patients with non-small cell lung cancer (NSCLC) after definitive radiotherapy. Here we investigated whether SNPs in TGFβ superfamily members BMP2 and BMP4 are associated with RP in such patients. In total, we retrospectively analyzed 663 patients given ≥ 60 Gy for NSCLC. We randomly assigned 323 patients to the training cohort and 340 patients to the validation cohort. Potentially functional and tagging SNPs of BMP2 (rs170986, rs1979855, rs1980499, rs235768, rs3178250) and BMP4 (rs17563, rs4898820, rs762642) were genotyped. The median of mean lung dose (MLD) was 17.9 Gy (range, 0.15-32.74 Gy). Higher MLD was strongly associated with increased risk of grade ≥ 2 RP (hazard ratio [HR]=2.191, 95% confidence interval [CI] = 1.680-2.856, P < 0.001) and grade ≥ 3 RP (HR = 4.253, 95% CI = 2.493-7.257, P < 0.001). In multivariate analyses, BMP2 rs235768 AT/TT was associated with higher risk of grade ≥ 2 RP (HR = 1.866, 95% CI = 1.221-2.820, P = 0.004 vs. AA) both in training cohort and validation cohort. Similar results were observed for BMP2 rs1980499. BMP2 rs3178250 CT/TT was associated with lower risk of grade ≥ 3 RP (HR = 0.406, 95% CI = 0.175-0.942, P = 0.036 vs. CC) in the pooled analysis. Adding the rs235768 and rs1980499 SNPs to a model comprising age, performance status, and MLD raised the Harrell's C for predicting grade ≥ 2 RP from 0.6117 to 0.6235 (P = 0.0105). SNPs in BMP2 can predict grade ≥ 2 or 3 RP after radiotherapy for NSCLC and improve the predictive power of MLD model. Validation is underway through an ongoing prospective trial.