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.