Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu, Korea.
BK21 Plus KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, Korea.
Ann Surg Oncol. 2019 Oct;26(11):3756-3764. doi: 10.1245/s10434-019-07614-2. Epub 2019 Jul 16.
We evaluated the association between genetic variants in the Notch pathway and survival outcomes of patients with surgically resected NSCLC.
Sixty-four single nucleotide polymorphisms (SNPs) in the Notch pathway genes were evaluated in the discovery study (n = 354) and two sequential validation studies (n = 772 and n = 746, respectively). The association of genotype with overall survival (OS) and disease-free survival (DFS) was evaluated.
Of the 64 SNPs analyzed in the discovery study, 9 were significantly associated with OS or DFS. Among them, the association remained significant only for Deltex-1 (DTX1) rs1732786A>G in the first validation study. The second validation study confirmed again the association between DTX1 rs1732786A>G and survival outcomes. In the combined analysis, rs1732786A>G was significantly associated with better OS and DFS (adjusted HR ·aHR· for OS, 0.75; 95% CI 0.64-0.87; P = 0.0002; aHR for DFS, 0.79; 95% CI 0.71-0.89; P = 0.0001). In vitro luciferase assay showed that the rs1732786G allele was associated with higher promoter activity compared to rs1732786A allele. Consistently, relative mRNA expression level of DTX1 showed significant positive correlation with rs1732786 A-to-G change (P = 0.02) in tumor tissues.
These results suggest that DTX1 rs1732786 is a potential prognostic factor that may have clinical utility in the management of early stage NSCLC.
我们评估了 Notch 通路中的遗传变异与接受手术切除的 NSCLC 患者生存结局之间的关联。
在发现研究（n=354）和两个连续的验证研究（n=772 和 n=746）中，评估了 Notch 通路基因中的 64 个单核苷酸多态性（SNP）。评估了基因型与总生存期（OS）和无病生存期（DFS）的关系。
在发现研究中分析的 64 个 SNP 中，有 9 个与 OS 或 DFS 显著相关。其中，仅在第一个验证研究中 Deltex-1（DTX1）rs1732786A>G 仍存在显著相关性。第二个验证研究再次证实了 DTX1 rs1732786A>G 与生存结局之间的关联。在合并分析中，rs1732786A>G 与更好的 OS 和 DFS 显著相关（OS 的调整 HR·aHR·，0.75；95%CI 0.64-0.87；P=0.0002；DFS 的 aHR，0.79；95%CI 0.71-0.89；P=0.0001）。体外荧光素酶检测显示，与 rs1732786A 等位基因相比，rs1732786G 等位基因与更高的启动子活性相关。一致地，肿瘤组织中 DTX1 的相对 mRNA 表达水平与 rs1732786 A 到 G 的变化呈显著正相关（P=0.02）。
这些结果表明，DTX1 rs1732786 是一个潜在的预后因素，在早期 NSCLC 的治疗中可能具有临床应用价值。
