华东地区早发胃癌特异性分子标志物的多组学整合分析  

Integrated multi-omics approach to investigate biomarkers specific for early-onset gastric cancer in Eastern China

作　　者：李竞娆 丁诗韵 武文汇 毛嘉宁 郑吉 王梦筠[2] 张若昕 LI Jingrao;DING Shiyun;WU Wenhui;MAO Jianing;ZHENG Ji;WANG Mengyun;ZHANG Ruoxin(Department of Epidemiology,School of Public Health,Key Laboratory of Public Health of Ministry of Education,Fudan University,Shanghai 200032,China;Fudan University Cancer Institute,Cancer Hospital Affiliated to Fudan University,Shanghai 200032,China;Yiwu Research Institute Fudan University,Zhejiang Yiwu 322000,China)

机构地区：[1]复旦大学公共卫生学院流行病学教研室,公共卫生安全教育部重点实验室,上海200032 [2]复旦大学肿瘤研究所,复旦大学附属肿瘤医院,上海200032 [3]复旦大学义乌研究院,浙江义乌322000

出　　处：《现代肿瘤医学》2024年第11期2032-2039,共8页Journal of Modern Oncology

基　　金：上海市复旦大学义乌研究院复旦基地项目(编号:20-1-43);上海市加强公共卫生体系建设三年行动计划(2023-2025年)重点学科项目(编号:GWVI-11.1-23);复旦—嘉定公共卫生高质量发展重点学科项目(编号:GWGZLXK-2023-02)。

摘　　要：目的:寻找早发胃癌特异性标志基因,并探究标志基因遗传变异与华东地区早发胃癌发病风险的关联。方法:研究利用多个胃癌组学研究中东亚人群数据,从拷贝数变异(copy number aberrations,CNAs)和转录组差异表达(differentially expressed genes,DEGs)两个水平整合分析早发胃癌特异的候选基因。通过单因素和多因素Logistic回归评估候选基因表达与早发胃癌的关联,通过亚组分析评估不同亚型之间的关联强度。通过逐步回归筛选早发胃癌标志基因,以构建预测模型。收集华东地区原发性早发胃癌和癌旁组织的临床样本,并使用实时荧光定量PCR验证标志基因的表达差异。另外,使用华东地区1086例原发胃癌和1062例健康对照的全基因组关联芯片数据,通过多因素Logistic回归分别在早发组和晚发组中评估了早发胃癌标志基因区间及其上下游20 kb的单核苷酸多态性位点(single nucleotide polymorphisms,SNPs)与胃癌发病风险的关联,通过假阳性报告概率(false positive report probability,FPRP)检验筛选出显著关联的位点,并利用基因表达数量性状位点(expression quantitative trait loci,eQTL)分析SNPs对基因表达的顺势调控情况。结果:多组学数据整合CNAs和DEGs分析发现6个早发胃癌特异性的候选基因,其中BUD31、POLI和SETBP1的表达水平与胃癌早发相关。分层分析显示,这些关联在Ⅲ/Ⅳ期胃癌和印戒细胞癌中更显著。进一步的逐步回归分析表明,将POLI和SETBP1纳入预测模型显著优于仅纳入胃癌常见突变CDH1的模型(曲线下面积area under curve,AUC_(new)=0.733,AUC_(previous)=0.683,P=0.03)。qRT-PCR结果与前期一致,显示在早发胃癌组织中,POLI和SETBP1表达均显著低于癌旁组织(P_(POLI)=0.049,PSETBP1=0.002)。基因芯片关联研究结果显示,SETBP1 rs7235777 C>A变异与EOGC的风险升高相关(OR_(adj)=1.67,95%CI=1.21~2.13,P_(adj)=0.002,FPRP_(0.1)=0.059),但与晚发胃癌发病风险无�Objective:To identify specific marker genes for early-onset gastric cancer(EOGC),and investigate the association between genetic variations in these marker genes and EOGC risk in the Eastern China population.Methods:An integrative analysis of copy number aberrations(CNAs)and differentially expressed genes(DEGs)was conducted in the Eastern Asian populations to discover candidate genes specific for EOGC.Univariate and multivariate Logistic regression analyses were employed to assess the association between candidate gene expression and EOGC.Subgroup analysis was performed to evaluate the association strength in different subtypes.A stepwise regression approach was used to select EOGC marker genes to construct a prediction model.Gene expressions in EOGC tumor and_(adj)acent tissues were quantified by using quantitative real-time polymerase chain reactions(qRT-PCR)in clinically-derived samples.Genetic variants of the novel EOGC marker genes were investigated in a case-control study comprising 1086 primary GC cases and 1062 healthy controls from Eastern China.Multivariate Logistic regression models were conducted to assess the association between the genetic variants and EOGC risk,followed by false positive report probability(FPRP)testing to identify significant single nucleotide polymorphisms(SNPs).Expression quantitative trait loci(eQTL)analysis was used to study the cis-regulation of significant SNPs and target gene expression.Results:The integrative analysis of CNAs and DEGs identified 6 candidate genes specific for EOGC,among which the expression levels of 3 genes,BUD31,POLI and SETBP1,were associated with EOGC risk in univariable and multivariable Logistic regression analyses.Stratification analysis indicated that some of these associations were more pronounced in subgroups withⅢ/Ⅳstage gastric cancer and signet-ring cell carcinoma.After stepwise selection,POLI and SETBP1 were included to construct a prediction model for EOGC,the area under curve consisting of the novel markers(AUC_(new)=0.733)was higher tha

关 键 词：早发胃癌 标志基因 遗传易感性 

分 类 号：R735.2[医药卫生—肿瘤]