Alternative polyadenylation shapes the molecular and clinical features of lung adenocarcinoma.

IF 3.1 2区生物学 Q3 BIOCHEMISTRY & MOLECULAR BIOLOGY

Human molecular genetics Pub Date : 2024-11-02 DOI:10.1093/hmg/ddae150

Yipeng Gao, Vikram R Shaw, Christopher I Amos

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引用次数: 0

Abstract

Alternative polyadenylation (APA) is a major mechanism of post-transcriptional regulation that affects mRNA stability, localization and translation efficiency. Previous pan-cancer studies have revealed that APA is frequently disrupted in cancer and is associated with patient outcomes. Yet, little is known about cancer type-specific APA alterations. Here, we integrated RNA-sequencing data from a Korean cohort (GEO: GSE40419) and The Cancer Genome Atlas (TCGA) to comprehensively analyze APA alterations in lung adenocarcinomas (LUADs). Comparing expression levels of core genes involved in polyadenylation, we find that overall, the set of 28 of 31 genes are upregulated, with CSTF2 particularly upregulated. We observed broad and recurrent APA changes in LUAD growth-promoting genes. In addition, we find enrichment of APA events in genes associated with known LUAD pathways and an increased heterogeneity in polyadenylation (polyA) site usage of proliferation-associated genes. Upon further investigation, we report smoking-specific APA changes are also highly relevant to LUAD development. Overall, our in-depth analysis reveals APA as an important driver for the molecular and clinical features of lung adenocarcinoma.

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交替多腺苷酸化决定了肺腺癌的分子和临床特征。

替代多腺苷酸化（APA）是转录后调控的一种主要机制，它影响 mRNA 的稳定性、定位和翻译效率。以往的泛癌症研究表明，APA 在癌症中经常发生紊乱，并与患者的预后有关。然而，人们对癌症类型特异性的 APA 改变知之甚少。在这里，我们整合了来自韩国队列（GEO：GSE40419）和癌症基因组图谱（TCGA）的RNA测序数据，全面分析了肺腺癌（LUADs）中APA的改变。通过比较参与多聚腺苷酸化的核心基因的表达水平，我们发现总体而言，31 个基因中有 28 个基因上调，其中 CSTF2 上调尤为明显。我们在 LUAD 生长促进基因中观察到了广泛且反复出现的 APA 变化。此外，我们还发现与已知 LUAD 通路相关的基因中也存在 APA 事件，而且增殖相关基因的多聚腺苷酸（polyA）位点使用的异质性也有所增加。经过进一步研究，我们发现吸烟特异性 APA 变化也与 LUAD 的发展高度相关。总之，我们的深入分析揭示了 APA 是肺腺癌分子和临床特征的重要驱动因素。

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

Human molecular genetics 生物-生化与分子生物学

CiteScore

6.90

自引率

2.90%

发文量

294

审稿时长

2-4 weeks

期刊介绍： Human Molecular Genetics concentrates on full-length research papers covering a wide range of topics in all aspects of human molecular genetics. These include: the molecular basis of human genetic disease developmental genetics cancer genetics neurogenetics chromosome and genome structure and function therapy of genetic disease stem cells in human genetic disease and therapy, including the application of iPS cells genome-wide association studies mouse and other models of human diseases functional genomics computational genomics In addition, the journal also publishes research on other model systems for the analysis of genes, especially when there is an obvious relevance to human genetics.