The Thr300Ala variant of ATG16L1 is associated with decreased risk of brain metastasis in patients with non-small cell lung cancer
The Thr300Ala variant of ATG16L1 is associated with decreased risk of brain metastasis in patients with non-small cell lung cancer
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ATG16L1 的 Thr300Ala 变体与非小细胞肺癌患者脑转移风险降低相关
DOI：
10.1080/15548627.2017.1308997
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发表时间：
2017-01-01
期刊：
影响因子：
13.3
通讯作者：
Yuan, Xiang-lin
中科院分区：
文献类型：
--
作者：
Li, Qian-xia;Zhou, Xiao;Yuan, Xiang-lin
摘要 非小细胞肺癌 (NSCLC) 经常转移至大脑，但确定哪些患者会发生脑转移 (BM) 很困难。巨自噬/自噬对于癌症的发生和进展至关重要。我们假设自噬相关基因的遗传变异可能影响 NSCLC 患者的脑转移 (BM)。我们使用 323 名 NSCLC 患者血液样本中的 DNA 对 7 个自噬相关 (ATG) 基因（ATG3、ATG5、ATG7、ATG10、ATG12、ATG16L1 和 MAP1LC3/LC3）中的 16 个单核苷酸多态性 (SNP) 进行了基因分型。此外，我们评估了这些基因与随后的 BM 发育的潜在关联。建立了稳定转染ATG16L1:rs2241880(T300A)的肺癌细胞系。使用转染 ATG16L1–300T 或 ATG16L1–300A 的细胞开发小鼠脑转移模型。 ATG10: rs10036653 和 ATG16L1: rs2241880 与 BM 风险降低显着相关（各自的风险比 [HRs]=0.596，95% 置信区间 [CI] 0.398–0.894，P = 0.012；HR = 0. 655，95% CI分别为 0.438–0.978，P = 0.039）。 ATG12：rs26532 与 BM 风险增加显着相关（HR=1.644，95% CI 1.049–2.576，P = 0.030）。侵袭和迁移测定表明，ATG16L1–300T（相对于 300A）转染刺激了 A549 细胞的迁移。体内转移测定显示，转染 ATG16L1-300T（相对于 300A）显着增加脑转移。我们的结果表明，自噬相关基因的遗传变异可以预测 BM，并且基因组分析将有助于对 BM 预防试验的患者进行分层。
ABSTRACT Non-small cell lung cancer (NSCLC) often metastasizes to the brain, but identifying which patients will develop brain metastases (BM) is difficult. Macroautophagy/autophagy is critical for cancer initiation and progression. We hypothesized that genetic variants of autophagy-related genes may affect brain metastases (BM) in NSCLC patients. We genotyped 16 single nucleotide polymorphisms (SNPs) in 7 autophagy-related (ATG) genes (ATG3, ATG5, ATG7, ATG10, ATG12, ATG16L1, and MAP1LC3/LC3) by using DNA from blood samples of 323 NSCLC patients. Further, we evaluated the potential associations of these genes with subsequent BM development. Lung cancer cell lines stably transfected with ATG16L1: rs2241880 (T300A) were established. Mouse models of brain metastasis were developed using cells transfected with ATG16L1–300T or ATG16L1–300A. ATG10: rs10036653 and ATG16L1: rs2241880 were significantly associated with a decreased risk of BM (respective hazard ratios [HRs]=0.596, 95% confidence interval [CI] 0.398–0.894, P = 0.012; and HR = 0. 655, 95% CI 0.438–0.978, P = 0.039, respectively). ATG12: rs26532 was significantly associated with an increased risk of BM (HR=1.644, 95% CI 1.049–2.576, P = 0.030). Invasion and migration assays indicated that transfection with ATG16L1–300T (vs. 300A) stimulated the migration of A549 cells. An in vivo metastasis assay revealed that transfection with ATG16L1–300T (vs. 300A) significantly increased brain metastasis. Our results indicate that genetic variations in autophagy-related genes can predict BM and that genome analysis would facilitate stratification of patients for BM prevention trials.