ZFHX4突变与肿瘤免疫治疗疗效相关性的生物信息学研究  

Association between ZFHX4 mutations and the efficacy of tumor immunotherapy

作　　者：李德周[1] 舒鹏 张永虎 李红山[3] LI Dezhou;SHU Peng;ZHANG Yonghu;LI Hongshan(Department of Infectious Diseases,Ningbo Second Hospital,Ningbo 315000,China)

机构地区：[1]宁波市第二医院急性感染科,315000 [2]宁波市北仑区人民医院分子实验室 [3]宁波市第二医院中西医结合肝病科

出　　处：《浙江医学》2025年第2期139-145,I0004,共8页Zhejiang Medical Journal

基　　金：宁波市省市共建医学重点学科项目(2016-S04);浙江省中医药创新团队建设项目(2022-16)。

摘　　要：目的探究锌指同源框蛋白4(ZFHX4)突变与肿瘤免疫检查点抑制剂(ICIs)治疗反应及肿瘤免疫微环境的关系。方法登陆cBioPortal数据库获取8组公开的ICIs治疗患者全外显子组测序队列,包含膀胱癌、头颈癌、黑色素瘤、非小细胞肺癌4种癌症共769例患者,评估ZFHX4突变与免疫治疗疗效及预后的关系。从Pan-Cancer图谱联盟获取癌症基因组图谱33种癌症的泛癌队列,分析ZFHX4突变与免疫微环境的关系。选择3组ICIs治疗患者(肝癌41例,膀胱癌348例,黑色素瘤110例)转录组测序队列,探究ZFHX4基因表达与ICIs治疗反应及预后的关系。结果769例ICIs治疗患者中,190例(32.8%)患者存在ZFHX4突变。与ZFHX4野生型患者相比,ZFHX4突变型患者无进展生存率(P=0.014)、总生存率(P=0.002)、客观反应率(P=0.030)和持久临床收益(P=0.007)均较高。肿瘤微环境综合分析发现,ZFHX4突变型患者免疫原性增强(P<0.001),抗肿瘤免疫细胞浸润增加(P<0.001),肿瘤突变负荷水平较高(P<0.001)。结论ZFHX4突变预示着较好的ICIs治疗疗效,可作为ICIs治疗疗效潜在的预测因子。Objective To investigate the relationship between zinc finger homeobox 4(ZFHX4)gene mutations and the response to cancer immune checkpoint inhibitors(ICIs)therapy.Methods Whole exome sequencing data from eight public ICIs-treated patient cohorts(769 patients in total)were obtained from the cBioPortal database,covering four cancer types:bladder cancer,head and neck cancer,melanoma,and non-small cell lung cancer.The association of ZFHX4 mutations with immunotherapy efficacy and prognosis of cancer patients was evaluated.Data from the Pan-Cancer Atlas,incorporating the Cancer Genome Atlas of 33 cancer types were used to analyze the relationship between ZFHX4 mutations and the immune microenvironment.Three transcriptome sequencing cohorts of ICIs-treated patients(41 cases of liver cancer,348 cases of bladder cancer,and 110 cases of melanoma)were selected to explore the association of ZFHX4 gene expression with the response to ICIs therapy and prognosis of patients.Results Among the 769 ICIs-treated patients,32.8%(190 patients)carried ZFHX4 gene mutations.Compared to patients with wild-type ZFHX4,patients with ZFHX4 mutanttions had significantly longer progression-free survival rate(P=0.014)and overall survival rate(P=0.002),higher objective response rate(P=0.030),and greater durable clinical benefit(P=0.007).Comprehensive analysis of the tumor microenvironment revealed that the ZFHX4-mutant patients exhibited enhanced immunogenicity(P<0.001),increased anti-tumor immune cell infiltration(P<0.001),and a higher tumor mutational burden(P<0.001).Conclusion ZFHX4 gene mutations are associated with better therapeutic efficacy of ICIs,which may serve as a potential predictive biomarker for ICIs treatment outcomes in cancer patients.

关 键 词：免疫检查点抑制剂 锌指同源框蛋白4 基因突变 生物标志物 

分 类 号：R73[医药卫生—肿瘤]