Emerging evidence suggests that the prognosis of patients with lung adenocarcinoma can be determined from germline variants and transcript levels in nontumoral lung tissue. Gene expression data from noninvolved lung tissue of 483 lung adenocarcinoma patients were tested for correlation with overall survival using multivariable Cox proportional hazard and multivariate machine learning models. For genes whose transcript levels are associated with survival, we used genotype data from 414 patients to identify germline variants acting as cis-expression quantitative trait loci (eQTLs). Associations of eQTL variant genotypes with gene expression and survival were tested. Levels of four transcripts were inversely associated with survival by Cox analysis (CLCF1, hazard ratio [HR] = 1.53; CNTNAP1, HR = 2.17; DUSP14, HR = 1.78; and MT1F: HR = 1.40). Machine learning analysis identified a signature of transcripts associated with lung adenocarcinoma outcome that was largely overlapping with the transcripts identified by Cox analysis, including the three most significant genes (CLCF1, CNTNAP1, and DUSP14). Pathway analysis indicated that the signature is enriched for ECM components. We identified 32 cis-eQTLs for CNTNAP1, including 6 with an inverse correlation and 26 with a direct correlation between the number of minor alleles and transcript levels. Of these, all but one were prognostic: the six with an inverse correlation were associated with better prognosis (HR < 1) while the others were associated with worse prognosis. Our findings provide supportive evidence that genetic predisposition to lung adenocarcinoma outcome is a feature already present in patients' noninvolved lung tissue.

中文翻译：

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肺腺癌结果的遗传易感性是患者未受累肺组织中已经存在的特征

新出现的证据表明，肺腺癌患者的预后可以根据非肿瘤肺组织中的种系变异和转录水平来确定。使用多变量 Cox 比例风险和多变量机器学习模型测试来自 483 名肺腺癌患者未受累肺组织的基因表达数据与总生存期的相关性。对于转录水平与生存相关的基因，我们使用来自 414 名患者的基因型数据来鉴定作为顺式表达数量性状基因座 (eQTL) 的种系变异。测试了 eQTL 变异基因型与基因表达和存活的关联。通过 Cox 分析，四种转录本的水平与生存率呈负相关（CLCF1，风险比 [HR] = 1.53；CNTNAP1 , HR = 2.17; DUSP14，HR = 1.78；和MT1F：HR = 1.40)。机器学习分析确定了与肺腺癌结果相关的转录本特征，该特征在很大程度上与 Cox 分析确定的转录本重叠，包括三个最重要的基因（CLCF1、CNTNAP1和DUSP14）。通路分析表明 ECM 组件的特征得到了丰富。我们为CNTNAP1鉴定了 32 个顺式-eQTL，包括 6 个负相关和 26 个与次要等位基因数量和转录水平之间的直接相关。其中，除 1 项外，其余均具有预后意义：6 项负相关与较好的预后相关 (HR < 1)，而其他与较差的预后相关。我们的研究结果提供了支持性证据，表明肺腺癌结果的遗传易感性是患者未受累肺组织中已经存在的特征。