Identification and characterization of ADAR1 mutations and changes in gene expression in human cancers

IF 1.4 4区 医学 Q4 GENETICS & HEREDITY Cancer Genetics Pub Date : 2024-11-01 DOI:10.1016/j.cancergen.2024.10.007
Anna Valentine , Korey Bosart , Wesley Bush , Renee A. Bouley , Ruben C. Petreaca
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Abstract

ADAR1 (Adenosine deaminase action on RNA1) is involved in post-transcriptional RNA editing. ADAR1 mutations have been identified in many cancers but its role in tumor formation is still not well understood. Here we used available cancer genomes deposited on CSOMIC and cBioPortal to identify and characterize mutations and changes in ADAR1 expression in cancer cells. We identify several high frequency substitutions including one at R767 which is located in one of the dsRNA interacting domains. In silico protein structure analysis suggest the R767 mutations affect the protein stability and are likely to destabilize interaction with dsRNA. Gene expression analysis shows that in samples with under-expressed ADAR1, there is a statistically significant increase in expression of BLCAP (Bladder Cancer Associated Protein). Although BLCAP was initially identified in bladder cancers, more recent evidence shows that it is a tumor suppressor and BLCAP mutations have been detected in many cancer cells. Epistatic analysis using the cBioPortal mutual exclusivity calculator for the TCGA pan-cancer data shows that co-mutations between ADAR1 and other genes regulated by it are likely in cancer cells except for PTEN, AKT1 and BLCAP. This suggests that when ADAR1 function is impaired, PTEN, AKT1 and BLCAP become essential for survival of cancer cells. We also identified several samples with high mutation burden between ADAR1 and other genes regulated primarily in endometrial cancers. Finally, we show that the deaminase domain is highly conserved in metazoans and mutations within conserved residues do occur in human cancers suggesting that destabilization of the enzyme function is contributing to cancer development.
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人类癌症中 ADAR1 基因突变和基因表达变化的鉴定与特征描述。
ADAR1(Adenosine deaminase action on RNA1)参与转录后 RNA 编辑。在许多癌症中都发现了 ADAR1 突变,但人们对其在肿瘤形成中的作用仍不甚了解。在这里,我们利用保存在 CSOMIC 和 cBioPortal 上的现有癌症基因组来鉴定和描述癌细胞中 ADAR1 的突变和表达变化。我们发现了几个高频置换,包括位于dsRNA相互作用结构域之一的R767。硅学蛋白质结构分析表明,R767 突变影响了蛋白质的稳定性,很可能会破坏与 dsRNA 的相互作用。基因表达分析表明,在 ADAR1 表达不足的样本中,BLCAP(膀胱癌相关蛋白)的表达有显著的统计学增长。虽然 BLCAP 最初是在膀胱癌中发现的,但最近的证据表明它是一种肿瘤抑制因子,而且在许多癌细胞中都发现了 BLCAP 突变。使用 cBioPortal 互斥性计算器对 TCGA 泛癌症数据进行的外显分析表明,除了 PTEN、AKT1 和 BLCAP 外,ADAR1 和受其调控的其他基因之间很可能在癌细胞中发生共突变。这表明,当 ADAR1 功能受损时,PTEN、AKT1 和 BLCAP 成为癌细胞存活的必要条件。我们还发现一些样本中 ADAR1 与其他主要受子宫内膜癌调控的基因之间存在高突变负荷。最后,我们发现脱氨酶结构域在类人猿中高度保守,而保守残基的突变确实发生在人类癌症中,这表明酶功能的不稳定性导致了癌症的发生。
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来源期刊
Cancer Genetics
Cancer Genetics ONCOLOGY-GENETICS & HEREDITY
CiteScore
3.20
自引率
5.30%
发文量
167
审稿时长
27 days
期刊介绍: The aim of Cancer Genetics is to publish high quality scientific papers on the cellular, genetic and molecular aspects of cancer, including cancer predisposition and clinical diagnostic applications. Specific areas of interest include descriptions of new chromosomal, molecular or epigenetic alterations in benign and malignant diseases; novel laboratory approaches for identification and characterization of chromosomal rearrangements or genomic alterations in cancer cells; correlation of genetic changes with pathology and clinical presentation; and the molecular genetics of cancer predisposition. To reach a basic science and clinical multidisciplinary audience, we welcome original full-length articles, reviews, meeting summaries, brief reports, and letters to the editor.
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