Inflammation-related genetic variants predict toxicities following definitive-radiotherapy for lung cancer

Definitive radiotherapy improves locoregional control and survival in inoperable non-small cell lung cancer (NSCLC) patients. However, radiation-induced toxicities (pneumonitis/esophagitis) are common dose-limiting inflammatory conditions. We therefore conducted a pathway-based analysis to identify inflammation-related SNPs associated with radiation-induced pneumonitis or esophagitis. 11,930 SNPs were genotyped in 201 stage I-III NSCLC patients treated with definitive radiotherapy. Validation was performed in an additional 220 NSCLC cases. After validation, 19 SNPs remained significant. A polygenic risk score (PRS) was generated to summarize the effect from validated SNPs. Significant improvements in discriminative ability were observed by adding the PRS into the clinical/epidemiological variable-based model. We then used 277 lymphoblastoid cell-lines to assess radiation sensitivity and eQTL relationships of the identified SNPs. Three genes (PRKCE,DDX58 and TNFSF7) were associated with radiation sensitivity. We concluded that inflammation-related genetic variants could contribute to the development of radiation-induced toxicities. These loci could assist in predicting those unfavorable events.