Genetic variants in inflammation-related genes are associated with radiation-induced toxicity following treatment for non-small cell lung cancer.
Genetic variants in inflammation-related genes are associated with radiation-induced toxicity following treatment for non-small cell lung cancer.
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DOI：
10.1371/journal.pone.0012402
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发表时间：
2010-08-25
期刊：
影响因子：
3.7
通讯作者：
Wu X
中科院分区：
文献类型：
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作者：
Hildebrandt MA;Komaki R;Liao Z;Gu J;Chang JY;Ye Y;Lu C;Stewart DJ;Minna JD;Roth JA;Lippman SM;Cox JD;Hong WK;Spitz MR;Wu X
放射治疗或放化疗治疗非小细胞肺癌（NSCLC）常伴有食管炎和肺炎的发生。识别可能正常组织毒性风险增加的患者，将有助于确定最佳放射剂量以避免这些情况。我们对173例患有IIIA/IIIB期（干性）疾病且接受根治性放疗或放化疗的非小细胞肺癌患者的37个炎症相关基因中的59个单核苷酸多态性（SNPs）进行了分析。对于食管炎风险，9个单核苷酸多态性与1.5至4倍的风险增加相关，包括3个前列腺素内过氧化物合酶2（PTGS2，即COX2）变体：rs20417（风险比：1.93，95%置信区间：1.10 - 3.39）、rs5275（风险比：1.58，95%置信区间：1.09 - 2.27）和rs689470（风险比：3.38，95%置信区间：1.09 - 10.49）。在促炎基因白细胞介素1A（IL1A）、白细胞介素8（IL8）、肿瘤坏死因子（TNF）、肿瘤坏死因子受体超家族成员1B（TNFRSF1B）和巨噬细胞移动抑制因子（MIF）存在基因变异的患者中，观察到肺炎风险显著增加。相反，一氧化氮合酶3（NOS3）的rs1799983表现出保护作用，肺炎风险降低45%（风险比：0.55，95%置信区间：0.31 - 0.96）。肺炎风险也受到抗炎基因多态性的调节，包括白细胞介素13（IL13）的基因变异。rs20541和rs180925各自导致风险增加（风险比分别为2.95，95%置信区间：1.14 - 7.63和3.23，95%置信区间：1.03 - 10.18）。这些单核苷酸多态性对风险的累积效应是剂量依赖性的，随着风险基因型数量的增加，任一毒性的风险显著增加就证明了这一点（P<0.001）。这些结果表明，炎症通路基因之间的基因变异可能调节放射诱导的毒性的发生，并最终有助于识别发生此类情况可能性增加的患者。
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.
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