A Telomere-Maintenance Three-Gene Model for the Prognostic Prediction in Intrahepatic Cholangiocarcinoma and Multi-Cohort Validation.

IF 4.1 4区医学 Q2 GENETICS & HEREDITY

Current gene therapy Pub Date : 2026-05-30 DOI:10.2174/0115665232492924260525110747

Lihua Wang, Wenjing Zhao, Zhongfeng Cui, Guangming Li

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引用次数: 0

Abstract

Introduction: Intrahepatic cholangiocarcinoma (iCCA) is characterized by heterogeneity and poor survival. It remains unclear how telomere maintenance programs influence the prognosis and immune microenvironment in iCCA, and clinically applicable, telomere‑anchored transcriptomic tools are currently lacking.

Methods: Transcriptomes and survival data from TCGA-CHOL, GSE107943, and E-MTAB-6389 cohorts were integrated (n=135). Telomere maintenance gene (TMG) scores were calculated using GSVA and subsequently used for WGCNA module identification. Functional enrichment was analyzed with clusterProfiler (FDR-adjusted P < 0.05). A prognostic model was constructed using univariate Cox and LASSO-Cox regression analyses, and validated by Kaplan-Meier (KM) curve and time-dependent ROC. Immune features were inferred by MCPcounter, CIBERSORT, and ssGSEA algorithms. Drug sensitivity was predicted by pRRophetic, and the resulting IC50 estimates were then correlated with the RiskScore.

Results: The TMG score was inversely correlated with the ESTIMATE score (Spearman ρ=-0.2439, P=0.0044). WGCNA identified a TMG-associated module enriched for cellcycle/ mitotic and microtubule functions. Three key TMGs (PTTG1, TSPYL5, PLLP) were integrated to develop a RiskScore that can consistently stratify overall survival (OS) in both the integrated set and all external cohorts, demonstrating a robust accuracy for 1-, 3-, and 5-year prognostic prediction. High-RiskScore tumors exhibited reduced immune infiltration across multiple deconvolution frameworks. The RiskScore was negatively correlated with predicted IC50 for several agents (e.g., pyrimethamine, GNF-2, NSC-87877, CGP-082996, KIN001-135), suggesting higher drug sensitivity in high-risk cases.

Discussion: We identified a three-gene, telomere-related risk score for iCCA, which can effectively predict patients' survival and distinguish immune-cold, high-proliferation phenotypes. Potential targeted drugs for high-risk patients were predicted and supported by mechanistic validation.

Conclusion: A compact telomere-anchored three-gene RiskScore was developed to predict the prognosis, immune contexture, and therapy sensitivity for iCCA.

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端粒维持三基因模型用于肝内胆管癌的预后预测及多队列验证。

肝内胆管癌（iCCA）具有异质性和生存率差的特点。目前尚不清楚端粒维持计划如何影响iCCA的预后和免疫微环境，并且目前缺乏临床应用的端粒锚定转录组学工具。方法：整合来自TCGA-CHOL、GSE107943和E-MTAB-6389队列的转录组和生存数据（n=135）。使用GSVA计算端粒维持基因（TMG）评分，随后用于WGCNA模块鉴定。功能富集用clusterProfiler分析（fdr校正P < 0.05）。采用单因素Cox和LASSO-Cox回归分析建立预后模型，并采用Kaplan-Meier （KM）曲线和随时间变化的ROC进行验证。免疫特征通过MCPcounter、CIBERSORT和ssGSEA算法推断。药物敏感性由prorophetic预测，所得IC50估计值随后与RiskScore相关联。结果：TMG评分与ESTIMATE评分呈负相关（Spearman ρ=-0.2439， P=0.0044）。WGCNA鉴定了一个与tmg相关的模块，该模块丰富了细胞周期/有丝分裂和微管功能。三个关键的TMGs （PTTG1, TSPYL5， PLLP）被整合成一个RiskScore，可以在整合组和所有外部队列中一致地对总生存（OS）进行分层，显示出1年，3年和5年预后预测的强大准确性。高风险评分的肿瘤在多个反褶积框架中表现出免疫浸润减少。RiskScore与几种药物（如乙胺嘧啶、GNF-2、NSC-87877、CGP-082996、KIN001-135）的预测IC50呈负相关，提示高危病例的药物敏感性较高。讨论：我们确定了iCCA的三基因端粒相关风险评分，该评分可以有效预测患者的生存并区分免疫冷，高增殖表型。通过机制验证预测并支持高危患者的潜在靶向药物。结论：一种紧凑的端粒锚定的三基因风险评分可以预测iCCA的预后、免疫状况和治疗敏感性。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Current gene therapy 医学-遗传学

CiteScore

6.70

自引率

2.80%

发文量

期刊介绍： Current Gene Therapy is a bi-monthly peer-reviewed journal aimed at academic and industrial scientists with an interest in major topics concerning basic research and clinical applications of gene and cell therapy of diseases. Cell therapy manuscripts can also include application in diseases when cells have been genetically modified. Current Gene Therapy publishes full-length/mini reviews and original research on the latest developments in gene transfer and gene expression analysis, vector development, cellular genetic engineering, animal models and human clinical applications of gene and cell therapy for the treatment of diseases. Current Gene Therapy publishes reviews and original research containing experimental data on gene and cell therapy. The journal also includes manuscripts on technological advances, ethical and regulatory considerations of gene and cell therapy. Reviews should provide the reader with a comprehensive assessment of any area of experimental biology applied to molecular medicine that is not only of significance within a particular field of gene therapy and cell therapy but also of interest to investigators in other fields. Authors are encouraged to provide their own assessment and vision for future advances. Reviews are also welcome on late breaking discoveries on which substantial literature has not yet been amassed. Such reviews provide a forum for sharply focused topics of recent experimental investigations in gene therapy primarily to make these results accessible to both clinical and basic researchers. Manuscripts containing experimental data should be original data, not previously published.