乳腺癌可选择性多聚腺苷酸化及其相关因素系统分析*

doi:10.3870/j.issn.1672-0741.25.01.013

摘要/Abstract

摘要： 目的旨在通过整合多组学和临床信息,全面分析乳腺癌(breast cancer,BRCA)中特异性可选择性多聚腺苷酸化(alternative polyadenylation,APA)的变化及其预后价值,并深入挖掘相关的关键上下游调控因素。方法整合来自TCGA和GTEx队列的多个组学数据集,以鉴定BRCA中失调的APA事件。进一步结合临床信息,并使用LASSO Cox回归分析,筛选与预后相关的APA事件。通过结合多元线性回归分析和LASSO回归分析,鉴定潜在调控预后APA事件的上游APA因子以及相关的体细胞突变。最后,基于miRNA-3′非翻译区(3′ untranslated regions,3′UTR)调控信息,分析APA伴随的下游miRNA结合位点的变化。结果通过对BRCA中APA谱的分析,揭示了广泛的APA失调现象,这些失调APA事件中77.37%为转录本缩短,且主要影响了癌症和免疫过程。筛选出112个与BRCA预后相关的APA事件,并基于其中10个核心APA事件,构建了总生存期(overall survival,OS)预测特征。进一步的分析表明,SNRNP70和PABPN1是APA失调的关键调控因子。其中SNRNP70的下调可能导致APA介导的STARD10转录本缩短。此外,体细胞突变与BRCA中82.44%的失调APA事件相关,可以通过改变基因功能来影响APA。通过构建BRCA的APA-miRNA网络,进一步发现STARD10的3′UTR缩短使其表达能够逃避miR-325-3p的抑制。结论研究发现了一系列与BRCA预后相关的APA事件及其关键上下游调控因素,研究结果将有助于APA调控机制的深入理解。

关键词: 可选择性多聚腺苷酸化, 乳腺癌, 预后分析, miRNA调控网络, 致癌基因

Abstract: Objective By integrating multi-omics and clinical information,we conducted a comprehensive analysis of specific alternative polyadenylation(APA)alterations and their prognostic significance in breast cancer(BRCA)and explored the key upstream and downstream regulatory factors involved. Methods Multiple omics datasets from the TCGA and GTEx cohorts were integrated to identify dysregulated APA events in BRCA.Clinical information and LASSO Cox regression analysis were used to identify APA events associated with prognosis.Potential upstream APA regulators and somatic mutations influencing prognostic APA events were identified through multivariate linear regression and LASSO regression analyses.Finally,changes in downstream miRNA binding sites associated with APA events were analyzed based on miRNA-3′untranslated regions(3′UTR) regulatory information. Results An in-depth and systematic analysis of APA profiles in BRCA revealed widespread APA dysregulation,with 77.37% of altered APA events involving transcript shortening,predominantly affecting cancer- and immune-related processes.A total of 112 prognosis-related APA events were identified,and an overall survival(OS)prediction signature was constructed on the basis of 10 core APA events.Further analysis pinpointed SNRNP70 and PABPN1 as crucial regulators of APA deregulation,with SNRNP70 downregulation potentially causing APA-mediated shortening of STARD10.Moreover,systematic analysis of APA-modulated somatic mutations revealed that they were associated with 82.44% of dysregulated APA events and may influence APA by altering gene function.The construction of an APA-miRNA network for BRCA further revealed that APA-oriented dysfunction in STARD10 arises from its evasion of miR-325-3p suppression. Conclusion This study identified a series of prognosis-related APA events and their critical upstream and downstream regulatory factors through an integrative multi-omics approach,providing insights into the regulatory mechanisms of APA in BRCA.

Key words: alternative polyadenylation, breast cancer, prognostic analysis, miRNA regulatory network, oncogenes

中图分类号:

R737.9

黄丽云, 覃柳宇, 蒋运, 牛晓辉, 杨健叶, 龚静. 乳腺癌可选择性多聚腺苷酸化及其相关因素系统分析^*[J]. 华中科技大学学报（医学版）, 2026, 55(1): 34-44.

Huang Liyun, Qin Liuyu, Jiang Yun et al. Comprehensive Analysis of Alternative Polyadenylation and Related Factors in Breast Cancer[J]. Acta Medicinae Universitatis Scientiae et Technologiae Huazhong, 2026, 55(1): 34-44.

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乳腺癌可选择性多聚腺苷酸化及其相关因素系统分析^*

Comprehensive Analysis of Alternative Polyadenylation and Related Factors in Breast Cancer

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