title: Genetic variants in inflammation-related genes are associated with radiation-induced toxicity following treatment for non-small cell lung cancer.
abstract: Treatment of non-small cell lung cancer (NSCLC) with radiotherapy or chemoradiotherapy is often accompanied by the development of esophagitis and pneumonitis. Identifying patients who might be at increased risk for normal tissue toxicity would help in determination of the optimal radiation dose to avoid these events. We profiled 59 single nucleotide polymorphisms (SNPs) from 37 inflammation-related genes in 173 NSCLC patients with stage IIIA/IIIB (dry) disease who were treated with definitive radiation or chemoradiation. For esophagitis risk, nine SNPs were associated with a 1.5- to 4-fold increase in risk, including three PTGS2 (COX2) variants: rs20417 (HR:1.93, 95% CI:1.10-3.39), rs5275 (HR:1.58, 95% CI:1.09-2.27), and rs689470 (HR:3.38, 95% CI:1.09-10.49). Significantly increased risk of pneumonitis was observed for patients with genetic variation in the proinflammatory genes IL1A, IL8, TNF, TNFRSF1B, and MIF. In contrast, NOS3:rs1799983 displayed a protective effect with a 45% reduction in pneumonitis risk (HR:0.55, 95% CI:0.31-0.96). Pneumonitis risk was also modulated by polymorphisms in anti-inflammatory genes, including genetic variation in IL13. rs20541 and rs180925 each resulted in increased risk (HR:2.95, 95% CI:1.14-7.63 and HR:3.23, 95% CI:1.03-10.18, respectively). The cumulative effect of these SNPs on risk was dose-dependent, as evidenced by a significantly increased risk of either toxicity with an increasing number of risk genotypes (P<0.001). These results suggest that genetic variations among inflammation pathway genes may modulate the development of radiation-induced toxicity and, ultimately, help in identifying patients who are at an increased likelihood for such events.
authors.affiliation: Department of Epidemiology, The University of Texas MD Anderson Cancer Center, Houston, Texas, United States of America.
authors.forename: Michelle A T
authors.initials: MA
authors.lastname: Hildebrandt
authors.forename: Ritsuko
authors.initials: R
authors.lastname: Komaki
authors.forename: Zhongxing
authors.initials: Z
authors.lastname: Liao
authors.forename: Jian
authors.initials: J
authors.lastname: Gu
authors.forename: Joe Y
authors.initials: JY
authors.lastname: Chang
authors.forename: Yuanqing
authors.initials: Y
authors.lastname: Ye
authors.forename: Charles
authors.initials: C
authors.lastname: Lu
authors.forename: David J
authors.initials: DJ
authors.lastname: Stewart
authors.forename: John D
authors.initials: JD
authors.lastname: Minna
authors.forename: Jack A
authors.initials: JA
authors.lastname: Roth
authors.forename: Scott M
authors.initials: SM
authors.lastname: Lippman
authors.forename: James D
authors.initials: JD
authors.lastname: Cox
authors.forename: Waun Ki
authors.initials: WK
authors.lastname: Hong
authors.forename: Margaret R
authors.initials: MR
authors.lastname: Spitz
authors.forename: Xifeng
authors.initials: X
authors.lastname: Wu
mesh_terms: D000483:Alleles; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics* / Q000532:radiotherapy*; D004941:Esophagitis / Q000209:etiology / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D007249:Inflammation / Q000235:genetics*; D008175:Lung Neoplasms / Q000235:genetics* / Q000532:radiotherapy*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011832:Radiation Injuries / Q000209:etiology / Q000235:genetics*; D017564:Radiation Pneumonitis / Q000209:etiology / Q000235:genetics; D016019:Survival Analysis
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