一项识别前列腺癌风险因素与药物靶点的多组学研究

A multi-omics study to identify risk factors and drug targets of prostate cancer

摘要

目的 使用多组学分析方法系统鉴定与前列腺癌诊断相关的关键风险生物分子，并探究潜在的药物干预靶点。方法 本研究基于前列腺癌全基因组关联研究、GTEx v8基因表达数量性状位点数据以及癌症基因组图谱数据库，通过转录组插补、基于汇总数据的孟德尔随机化（SMR）分析、共定位分析以及差异表达分析等方法筛选与前列腺癌发病相关的差异基因。对所得差异基因进行基因本体论分析、单细胞RNA测序分析以及免疫细胞浸润水平相关性分析。采用孟德尔随机化（MR）探究与前列腺癌诊断相关的免疫通路和循环代谢物。并通过SMR分析筛选前列腺癌的潜在药物靶点。结果 综合鉴定出4个与前列腺癌相关的差异基因，其中BHLHA15（OR=1.08）首次发现与前列腺癌发病风险相关。MR分析发现免疫细胞表面分子及炎症因子白介素-17A（IL-17A）（OR=1.25）是前列腺癌发病的危险因素。通过MR分析发现较高水平的癸二酸盐（OR=1.05）、半胱甘氨酸二硫化物（OR=1.11）与前列腺癌的发病风险升高存在关联。药物靶点分析筛选出14个潜在靶点基因，其中OPRL1的高表达与前列腺癌患者较差的无病生存期显著相关（HR=2.00，P=0.024）。结论 本研究通过多组学分析鉴定出了与前列腺癌发病相关的生物分子，有助于深化临床对前列腺癌致病机制的理解，并揭示其潜在的药物靶点。

Abstract

Objective To systematically identify key risk biomolecules associated with the diagnosis of prostate cancer using multi-omics analysis methods，and to explore potential drug intervention targets. Methods Based on prostate cancer genome-wide association study data，GTEx v8 expression quantitative trait locus data，and The Cancer Genome Atlas database，this study screened for differentially expressed genes associated with prostate cancer pathogenesis through transcriptome imputation，summary data-based Mendelian randomization（SMR）analysis，colocalization analysis，and differential expression analysis.The identified differentially expressed genes were subjected to gene ontology analysis，single-cell RNA sequencing analysis，and correlation analysis with immune cell infiltration levels.Mendelian randomization（MR）was employed to investigate immune pathways and circulating metabolites associated with prostate cancer diagnosis.Potential drug targets for prostate cancer were screened using SMR analysis. Results Four differentially expressed genes associated with prostate cancer were identified，among which BHLHA15（OR=1.08）was found to be associated with prostate cancer risk for the first time.MR analysis revealed that immune cell surface molecules and the inflammatory cytokine interleukin-17A（IL-17A）（OR=1.25）were risk factors for prostate cancer.MR analysis also indicated that higher levels of sebacate（OR=1.05）and cystine disulfide（OR=1.11）were associated with an increased risk of prostate cancer.Drug target analysis screened 14 potential target genes，among which high expression of OPRL1 was significantly correlated with poorer disease-free survival in prostate cancer patients（HR=2.00，P=0.024）. Conclusion This study identified biomolecules associated with prostate cancer pathogenesis through multi-omics analysis，which may help deepen the clinical understanding of the pathogenic mechanisms underlying prostate cancer and reveal potential drug targets.

关键词

前列腺癌 / 多组学 / 生物分子 / 药物靶点

Key words

prostate cancer / multi-omics / biomolecule / drug target

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