The Transcriptomic and Gene Fusion Landscape of Pleomorphic Salivary Gland Adenomas.

IF 3.1 2区 医学 Q2 GENETICS & HEREDITY Genes, Chromosomes & Cancer Pub Date : 2025-01-01 DOI:10.1002/gcc.70023
Maryam Kakay Afshari, Paloma Tejera Nevado, André Fehr, Junchi Huang, Fredrik Jäwert, Jonas A Nilsson, Göran Stenman, Mattias K Andersson
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Abstract

Pleomorphic adenoma (PA) is the most common salivary gland tumor. PAs are characterized by chromosomal rearrangements of 8q12 and 12q14-15, leading to gene fusions involving the PLAG1 and HMGA2 oncogenes. Here, we performed the first comprehensive study of the transcriptomic and gene fusion landscape of 38 cytogenetically characterized PAs. RNA-seq identified PLAG1 or HMGA2 fusions in 33/38 cases (87%), of which 15 were novel fusions. Fusions were found also in tumors with normal karyotype, demonstrating that they are generated by cryptic rearrangements. PLAG1 was mainly activated by promoter swapping and HMGA2 by truncation of its 3'-part. RNA-seq revealed upregulation of genes involved in extracellular matrix production, WNT-signaling, and epithelial-mesenchymal transition in PA compared to normal salivary tissue. Principal component analysis identified two PA subclusters characterized by PLAG1- and HMGA2-activation, respectively, that differed in expression of genes involved in the immune system, cell adhesion, and microenvironment remodeling. Moreover, comparative analyses of PA and salivary carcinomas revealed that PA resembles myoepithelial carcinoma. Our study reveals new oncogenic gene fusions and expands our knowledge about the molecular underpinnings of PA.

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多形性唾液腺腺瘤的转录组学和基因融合研究。
多形性腺瘤(PA)是唾液腺最常见的肿瘤。PAs的特征是8q12和12q14-15的染色体重排,导致涉及PLAG1和HMGA2癌基因的基因融合。在这里,我们首次对38种具有细胞遗传学特征的PAs的转录组学和基因融合景观进行了全面研究。RNA-seq鉴定出33/38例(87%)的PLAG1或HMGA2融合,其中15例为新融合。在核型正常的肿瘤中也发现了融合,表明它们是由隐式重排产生的。PLAG1主要通过启动子交换激活,HMGA2主要通过截断其3'部分激活。RNA-seq显示,与正常唾液组织相比,PA中参与细胞外基质产生、wnt信号传导和上皮-间质转化的基因上调。主成分分析鉴定出两个PA亚簇,分别以PLAG1-和hmga2活化为特征,它们在免疫系统、细胞粘附和微环境重塑相关基因的表达上存在差异。此外,PA和唾液腺癌的比较分析显示PA类似于肌上皮癌。我们的研究揭示了新的致癌基因融合,并扩大了我们对前列腺癌分子基础的认识。
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来源期刊
Genes, Chromosomes & Cancer
Genes, Chromosomes & Cancer 医学-遗传学
CiteScore
7.00
自引率
8.10%
发文量
94
审稿时长
4-8 weeks
期刊介绍: Genes, Chromosomes & Cancer will offer rapid publication of original full-length research articles, perspectives, reviews and letters to the editors on genetic analysis as related to the study of neoplasia. The main scope of the journal is to communicate new insights into the etiology and/or pathogenesis of neoplasia, as well as molecular and cellular findings of relevance for the management of cancer patients. While preference will be given to research utilizing analytical and functional approaches, descriptive studies and case reports will also be welcomed when they offer insights regarding basic biological mechanisms or the clinical management of neoplastic disorders.
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