Shen Sipeng, Wei Yongyue, Li Yi, Duan Weiwei, Dong Xuesi, Lin Lijuan, You Dongfang, Tardon Adonina, Chen Chu, Field John K, Hung Rayjean J, Liu Geoffrey, Zhu Dakai, Amos Christopher I, Su Li, Zhao Yang, Hu Zhibin, Shen Hongbing, Zhang Ruyang, Chen Feng, Christiani David C
Department of Biostatistics, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
State Key Laboratory of Reproductive Medicine, Nanjing Medical University, Nanjing, 211166, Jiangsu, China.
NPJ Precis Oncol. 2021 May 17;5(1):39. doi: 10.1038/s41698-021-00182-3.
The genetic architecture of non-small cell lung cancer (NSCLC) is relevant to smoking status. However, the genetic contribution of long-term smoking cessation to the prognosis of NSCLC patients remains largely unknown. We conducted a genome-wide association study primarily on the prognosis of 1299 NSCLC patients of long-term former smokers from independent discovery (n = 566) and validation (n = 733) sets, and used in-silico function prediction and multi-omics analysis to identify single nucleotide polymorphisms (SNPs) on prognostics with NSCLC. We further detected SNPs with at least moderate association strength on survival within each group of never, short-term former, long-term former, and current smokers, and compared their genetic similarity at the SNP, gene, expression quantitative trait loci (eQTL), enhancer, and pathway levels. We identified two SNPs, rs34211819 at 7p12.3 (P = 3.90 × 10) and rs1143149 at 7p14.2 (P = 9.75 × 10), were significantly associated with survival of NSCLC patients who were long-term former smokers. Both SNPs had significant interaction effects with years of smoking cessation (rs34211819: P = 8.0 × 10; rs1143149: P = 0.003). In addition, in silico function prediction and multi-omics analysis provided evidence that these QTLs were associated with survival. Moreover, comparison analysis found higher genetic similarity between long-term former smokers and never-smokers, compared to short-term former smokers or current smokers. Pathway enrichment analysis indicated a unique pattern among long-term former smokers that was related to immune pathways. This study provides important insights into the genetic architecture associated with long-term former smoking NSCLC.
非小细胞肺癌（NSCLC）的遗传结构与吸烟状况相关。然而，长期戒烟对NSCLC患者预后的遗传贡献仍 largely 未知。我们主要对来自独立发现（n = 566）和验证（n = 733）集的1299例长期既往吸烟者的NSCLC患者的预后进行了全基因组关联研究，并使用计算机功能预测和多组学分析来识别与NSCLC预后相关的单核苷酸多态性（SNP）。我们进一步在从不吸烟者、短期既往吸烟者、长期既往吸烟者和当前吸烟者的每组中检测了与生存具有至少中等关联强度的SNP，并在SNP、基因、表达数量性状位点（eQTL）、增强子和通路水平上比较了它们的遗传相似性。我们鉴定出两个SNP，7p12.3处的rs34211819（P = 3.90×10）和7p14.2处的rs1143149（P = 9.75×10），与长期既往吸烟者的NSCLC患者生存显著相关。两个SNP均与戒烟年限具有显著的交互作用（rs34211819：P = 8.0×10；rs1143149：P = 0.003）。此外，计算机功能预测和多组学分析提供了证据表明这些QTL与生存相关。而且，比较分析发现，与短期既往吸烟者或当前吸烟者相比，长期既往吸烟者与从不吸烟者之间具有更高的遗传相似性。通路富集分析表明长期既往吸烟者中存在与免疫通路相关的独特模式。本研究为与长期既往吸烟的NSCLC相关的遗传结构提供了重要见解。
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