Polymorphisms in BMP2/BMP4, with estimates of mean lung dose, predict radiation pneumonitis among patients receiving definitive radiotherapy for non-small cell lung cancer
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Ju Yang1,2, Ting Xu1, Daniel R. Gomez1, Xianglin Yuan3, Quynh-Nhu Nguyen1, Melenda Jeter1, Yipeng Song4, Stephen Hahn1 and Zhongxing Liao1
1Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA
2The Comprehensive Cancer Center of Drum Tower Hospital, Medical School of Nanjing University and Clinical Cancer Institute of Nanjing University, Nanjing, 210008, China
3Department of Oncology, Tongji Hospital, Huazhong University of Science and Technology, Wuhan, Hubei, 430030, China
4Department of Radiation Oncology, Yuhuangding Hospital, Shandong, 264000, China
Zhongxing Liao, email: firstname.lastname@example.org
Keywords: NSCLC, BMP2, radiation pneumonitis, polymorphism
Received: February 28, 2017 Accepted: April 07, 2017 Published: May 17, 2017
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.
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