摘要
目的:分析补体激活通路基因遗传变异与非小细胞肺癌(non-small cell lung cancer,NSCLC)患者生存的相关性及其潜在的分子机制。方法:对连续招募的1531例NSCLC患者进行随机分组,分为发现集和验证集;收集所有患者的随访信息和临床资料,并进行全基因组关联芯片扫描;通过全基因组基因型填补,系统分析补体激活通路基因集的遗传变异与NSCLC患者总生存期(overall survival,OS)之间的相关性。采用多因素Cox回归和多重检验在发现集中评估74个基因上的3661个单核苷酸多态性位点(single-nucleotide polymorphisms,SNPs)与NSCLC患者生存的关联,通过多重检验的显著性SNPs在验证集中进行进一步验证,并对显著性关联位点和易感基因进行生物学功能预测。结果:识别出C6基因上9个具有连锁不平衡关联(r^(2)>0.6)的SNPs与NSCLC患者生存显著相关,其中P值最小的位点rs10512781可能对C6基因表达水平具有调控功能,C6基因表达在正常肺组织中较肺癌组织显著上调,且与更优的NSCLC患者预后和更高的免疫细胞浸润水平相关;进一步利用Lasso回归筛选得到8个影响患者生存的独立因素,构建的Cox预测模型对患者生存率具有良好的预测价值。结论:补体激活通路基因集中遗传变异rs10512781可能通过调控C6基因表达,从而影响NSCLC患者的生存,该研究为寻找预测肺癌生存的潜在生物标志物和易感基因提供了一定的依据。
Objective:To analyze the association between genetic variants of complement activation pathway genes and survival of patients with non-small cell lung cancer(NSCLC),and to explore the underlying molecular mechanism.Methods:A total of 1531 consecutively recruited NSCLC patients were randomized into a discovery set and a validation set.Follow-up information and clinical data of all patients were collected,and genome-wide association chip scanning was performed.We systematically analyzed the association between genetic variants in the complement activated pathway gene set and overall survival(OS)in NSCLC patients with genomic imputation.Multivariate Cox regression analysis with multiple testing was used to assess 3661 single nucleotide polymorphisms(SNPs)at 74 genes in the discovery set for association with survival in NSCLC patients,and the significant SNPs that passed the test were further verified in the validation set.Bioinformatics analysis were performed to assess the functions of the identified SNPs and gene.Results:We identified 9 SNPs with linkage disequilibrium in C6(r^(2)>0.6)that were significantly associated with survival of NSCLC patients,and rs10512781,the sentinel SNPs with the lowest P value,may regulate C6 gene expression level.The C6 gene was significantly overexpressed in normal tissues than in cancerous tissues and was associated with better prognosis and higher levels of immune cell infiltration in NSCLC patients.Eight independent factors affecting patient survival were selected by Lasso regression,and the model constructed by Cox regression showeda good predictive value for patients'overall survival.Conclusion:The genetic variation rs10512781 in the complement activation pathway may affect the OS of NSCLC patients by regulating C6 expression.This study provides the foundational basis for developing potential biomarkers for lung cancer survival prediction.
作者
柏宇舜
郑吉
李竞饶
张若昕
BAI Yushun;ZHENG Ji;LI Jingrao;ZHANG Ruoxin(Department of Epidemiology,School of Public Health,Key Laboratory of Public Health Safety of Ministry of Education,Fudan University,Shanghai 200032,China;Yiwu Research Institute of Fudan University,Zhejiang Yiwu 322000,China.)
出处
《现代肿瘤医学》
CAS
北大核心
2022年第15期2739-2743,共5页
Journal of Modern Oncology
基金
上海市公共卫生体系建设三年行动计划(编号:GWV-10.1-XK16,GWV-10.2-YQ42)。
关键词
非小细胞肺癌
补体通路
遗传变异
总生存期
non-small cell lung cancer
complement pathway
genetic variants
overall survival
作者简介
柏宇舜(1997—),男,安徽合肥人,硕士,主要从事肿瘤分子流行病学研究。E-mail:17333251374@163.com;通讯作者:张若昕(1985—),女,江苏南京人,副研究员,硕士生导师,主要从事肿瘤分子流行病学研究。E-mail:zhangruoxin@fudan.edu.cn。
