Abstract 4582: Genome-wide association study of toxicity following definitive radiotherapy in non-small cell lung cancer patients.
Authors: Pu Xia , Skinner Heath D. , Ye Yuanqing , Hildebrandt Michelle AT , Chang Joe Y. , Lu Charles , Komaki Ritsuko , Minna John D. , Roth Jack A. , Wu Xifeng 
Published: August 2014

Abstract
Radiation therapy in combination with chemotherapy is the primary treatment for lung cancer patients with surgically unresectable tumors or locally advanced diseases. Unfortunately, about one third of these patients develop clinically significant toxicities. This not only severely limits the dosage of radiation that can be delivered, but also negatively impacts patients’ quality of life. Commonly used clinical variables are insufficient to predict the occurrence of these toxicities prior to treatment. This has led to interest in examining the influence of genetic variability in patient toxicity following radiotherapy. Several small scale association studies with only limited samples and markers have provided evidence of genetic contribution to the risk of developing radiation-induced toxicity, while most lack validation. To identify reliable genetic variants associated with risk of developing clinically significant radiation-induced toxicities, we conducted a genome wide scan of 300,977 single-nucleotide polymorphisms (SNPs) in 393 non-small cell lung cancer (NSCLC) Caucasian patients who received definitive radiation therapy at the University of Texas MD Anderson Cancer Center (discovery phase). We assessed the association of each SNP with the two major forms of radiation-induced toxicities (pneumonitis and esophagitis) via a multivariate logistic regression model. A total of 30,474 SNPs were significantly associated with pneumonitis (651 SNPs reached P&lt;10−3, 45 SNPs reached P&lt;10−4) and 31,086 with esophagitis (687 SNPs reached P&lt;10−3, 59 SNPs reached P&lt;10−4). The most significant SNPs for pneumonitis and esophagitis were located in chromosome 10q (OR=3.24, 95%CI=2.06-5.08, P=3.18×10−7) and chromosome 4p (OR=0.17, 95%CI=0.08-0.37, P=9.42×10−6), respectively. The results from discovery phase showed no evidence for inflation of the test statistics (inflation factor of dominant model =1.065 for both outcomes). We then performed classification and regression tree (CART) analysis to explore high-order gene-gene interactions among top SNPs (P&lt;10−3) in modulating toxicities. Four SNPs for pneumonitis and four SNPs for esophagitis were identified by CART to have significant interactions in modulating the risk of developing toxicities. A validation phase for the most significant SNPs in an additional 275 NSCLC patients treated in a similar fashion is currently ongoing. To our knowledge, this is the first genome-wide association study to identify SNPs associated with toxicities resulting from definitive radiation therapy in NSCLC patients. With this relatively large sample size, we expect to identify novel susceptibility loci that may play a significant role in contributing to the development of radiation-induced toxicities. This will assist in the development of more personalized radiotherapy delivery and symptom management.
Citation Format: Xia Pu, Heath D. Skinner, Yuanqing Ye, Michelle AT Hildebrandt, Joe Y. Chang, Charles Lu, Ritsuko Komaki, John D. Minna, Jack A. Roth, Xifeng Wu. Genome-wide association study of toxicity following definitive radiotherapy in non-small cell lung cancer patients. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4582. doi:10.1158/1538-7445.AM2013-4582