Department of Radiation Oncology, Navy General Hospital, Beijing, People's Republic of China; Department of Radiation Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas.
Duke Cancer Institute, Duke University Medical Center, Durham, North Carolina; Department of Population Health Sciences, Duke University School of Medicine, Durham, North Carolina.
J Thorac Oncol. 2018 May;13(5):660-675. doi: 10.1016/j.jtho.2018.01.028. Epub 2018 Feb 15.
Autophagy not only plays an important role in the progression of cancer but is also involved in tissue inflammatory response. However, few published studies have investigated associations between functional genetic variants of autophagy-related genes and radiation pneumonitis (RP) as well as clinical outcomes in patients with NSCLC after definitive radiotherapy.
We genotyped nine potentially functional single-nucleotide polymorphisms (SNPs) in four autophagy-related genes (autophagy related 2B gene [ATG2B], autophagy related 10 gene [ATG10], autophagy related 12 gene [ATG12], and autophagy related 16 like 2 gene [ATG16L2]) in 393 North American patients with NSCLC treated by definitive radiotherapy and assessed their associations with RP, local recurrence-free survival (LRFS), progression-free survival (PFS), and overall survival (OS) in multivariable Cox proportional hazard regression analyses.
We found that patients with the ATG16L2 rs10898880 CC variant genotype had a better LRFS, PFS, and OS (adjusted hazard ratio = 0.59, 0.64, and 0.64; 95% confidence interval: 0.45-0.79, 0.48-0.84, and 0.48-0.86; p = 0.0004, 0.002, and 0.003, respectively), but a greater risk for development of severe RP (adjusted hazard ratio = 1.80, 95% confidence interval: 1.04-3.12, p = 0.037) than did patients with AA/AC genotypes. Further functional analyses suggested that the ATG16L2 rs10898880 C variant allele modulated expression of the ATG16L2 gene.
This is the first report that one potentially functional SNP rs10898880 in ATG16L2 may be a predictor of RP, LRFS, PFS, and OS in patients with NSCLC after definitive radiotherapy. Additional larger, prospective studies are needed to confirm these findings.
自噬不仅在癌症的进展中起着重要作用，而且还参与组织炎症反应。然而，很少有发表的研究调查自噬相关基因的功能遗传变异与非小细胞肺癌（NSCLC）患者接受根治性放疗后放射性肺炎（RP）以及临床结局之间的关系。
我们对 393 名接受根治性放疗的北美 NSCLC 患者的四个自噬相关基因（自噬相关 2B 基因[ATG2B]、自噬相关 10 基因[ATG10]、自噬相关 12 基因[ATG12]和自噬相关 16 样 2 基因[ATG16L2]）中的九个潜在功能单核苷酸多态性（SNP）进行了基因分型，并在多变量 Cox 比例风险回归分析中评估了它们与 RP、局部无复发生存（LRFS）、无进展生存期（PFS）和总生存期（OS）的关系。
我们发现，ATG16L2 rs10898880 CC 变异基因型患者的 LRFS、PFS 和 OS 更好（调整后的危险比分别为 0.59、0.64 和 0.64；95%置信区间分别为 0.45-0.79、0.48-0.84 和 0.48-0.86；p=0.0004、0.002 和 0.003），但发生严重 RP 的风险更高（调整后的危险比为 1.80；95%置信区间为 1.04-3.12；p=0.037）比 AA/AC 基因型患者。进一步的功能分析表明，ATG16L2 rs10898880 C 变异等位基因调节了 ATG16L2 基因的表达。
这是第一项报告表明，ATG16L2 中的一个潜在功能 SNP rs10898880 可能是 NSCLC 患者接受根治性放疗后 RP、LRFS、PFS 和 OS 的预测因子。需要进一步进行更大的前瞻性研究来证实这些发现。
