Background/Objectives: Lung cancer remains a global health concern, with substantial variation in patient survival. Despite advances in detection and treatment, the genetic basis for the divergent outcomes is not understood. We investigated germline polymorphisms that modulate overall survival in 1464 surgically resected lung adenocarcinoma patients. Methods: A multivariable Cox proportional hazard model was used to assess the association of more than seven million polymorphisms with overall survival at the 60-month follow-up, considering age, sex, pathological stage, decade of surgery and principal components as covariates. Genes in which variants were identified were studied in silico to investigate functional roles. Results: Six germline variants passed the genome-wide significance threshold. These single nucleotide polymorphisms were mapped to non-coding (intronic) regions on chromosomes 2, 3, and 5. The minor alleles of rs13000315, rs151212827, and rs190923216 (chr. 2, 3 and 5, respectively) were found to be independent negative prognostic factors. All six variants have been reported to regulate the expression of nine genes, seven of which are protein-coding, in different tissues. Survival-associated variants on chromosomes 2 and 3 were already reported to regulate the expression ofNT5DC2andNAGK, with high expression associated with the minor alleles. HighNT5DC2andNAGKexpression in lung adenocarcinoma tissue was already shown to correlate with poor overall survival. Conclusions: This study highlights a potential regulatory role of the identified polymorphisms in influencing outcome and suggests a mechanistic link between these variants, gene expression regulation, and lung adenocarcinoma prognosis. Validation and functional studies are warranted to elucidate the mechanisms underlying these associations.
背景/目的：肺癌仍是全球性健康问题，患者生存率存在显著差异。尽管检测与治疗手段不断进步，导致不同预后的遗传学基础尚未明确。本研究通过对1464例手术切除肺腺癌患者的分析，探讨了影响总生存期的种系多态性。方法：采用多变量Cox比例风险模型评估超过七百万个多态性位点与60个月随访期总生存期的关联性，并将年龄、性别、病理分期、手术年代及主成分作为协变量纳入分析。通过生物信息学方法对变异位点所在基因进行功能研究。结果：六个种系变异位点达到全基因组显著性阈值。这些单核苷酸多态性定位于2、3、5号染色体的非编码区（内含子区域）。研究发现rs13000315、rs151212827和rs190923216（分别位于2、3、5号染色体）的次要等位基因是独立的负面预后因素。所有六个变异位点均被报道可调控九个基因在不同组织中的表达，其中七个为蛋白质编码基因。既往研究已证实2号和3号染色体上的生存相关变异可调控NT5DC2和NAGK基因表达，其高表达与次要等位基因相关。肺腺癌组织中NT5DC2和NAGK的高表达已被证实与不良总生存期相关。结论：本研究揭示了所发现多态性位点在影响预后中的潜在调控作用，并提示这些变异位点、基因表达调控与肺腺癌预后之间存在机制性关联。需通过验证性研究和功能实验阐明这些关联的内在机制。
Germline Polymorphisms Associated with Overall Survival in Lung Adenocarcinoma: Genome-Wide Analysis
肿瘤(癌症)患者之家