PDGF基因表达和p53的改变对弥漫性星形细胞胶质瘤的生物学有贡献。

IF 4.7 2区 医学 Q1 GENETICS & HEREDITY NPJ Genomic Medicine Pub Date : 2023-02-25 DOI:10.1038/s41525-023-00351-2
Mehul Kumar, Mathieu Meode, Michael Blough, Gregory Cairncross, Pinaki Bose
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引用次数: 1

摘要

弥漫性、组织学级别较低的成人星形细胞瘤(LGAs)是根据异柠檬酸脱氢酶(IDH)基因的突变状态进行分类的。野生型(WT) LGAs通常迅速发展为胶质母细胞瘤(GBM),而突变型肿瘤通常遵循惰性过程。为了找到这些不同行为可能的影响因素,我们比较了它们各自的转录组。与突变型LGAs不同,血小板衍生生长因子(PDGF)信号在WT肿瘤中显著富集,PDGFA是该通路中最高的过表达基因。此外,PDGFA和PDGFD启动子的甲基化可能是它们在突变肿瘤中低表达的机制。WT病例中,7号染色体拷贝数增加与PDGFA高表达同时发生,PDGFA高表达与非整倍体、细胞外基质(ECM)相关的免疫抑制特征和不良预后相关。我们还注意到,在WT病例中,PDGFA的高表达与肿瘤分级无关,p53通路失活的多种机制伴随着PDGFA过表达的肿瘤进展为GBM。相反,TP53点突变是突变型LGAs的早期和恒定特征。我们的研究结果表明,PDGF基因家族的成员,与不同的p53通路改变一致,是LGA行为的基础。
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PDGF gene expression and p53 alterations contribute to the biology of diffuse astrocytic gliomas.

Diffuse, histologically lower grade astrocytomas of adults (LGAs) are classified based on the mutational status of the isocitrate dehydrogenase (IDH) genes. While wild-type (WT) LGAs often evolve quickly to glioblastoma (GBM), mutant tumors typically follow an indolent course. To find possible effectors of these different behaviors, we compared their respective transcriptomes. Unlike mutant LGAs, platelet-derived growth factor (PDGF) signaling was significantly enriched in WT tumors, and PDGFA was the top overexpressed gene in the pathway. Moreover, methylation of the PDGFA and PDGFD promoters emerged as a possible mechanism for their low expression in mutant tumors. Copy number gain of chromosome 7 co-occurred with high expression of PDGFA in WT cases, and high expression of PDGFA was associated with aneuploidy, extracellular matrix (ECM)-related immunosuppressive features and poor prognosis. We also noted that high PDGFA expression in WT cases occurred irrespective of tumor grade and that multiple mechanisms of p53 pathway inactivation accompanied progression to GBM in PDGFA-overexpressing tumors. Conversely, TP53 point mutations were an early and constant feature of mutant LGAs. Our results suggest that members of the PDGF gene family, in concert with different p53 pathway alterations, underlie LGA behaviors.

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来源期刊
NPJ Genomic Medicine
NPJ Genomic Medicine Biochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
9.40
自引率
1.90%
发文量
67
审稿时长
17 weeks
期刊介绍: npj Genomic Medicine is an international, peer-reviewed journal dedicated to publishing the most important scientific advances in all aspects of genomics and its application in the practice of medicine. The journal defines genomic medicine as "diagnosis, prognosis, prevention and/or treatment of disease and disorders of the mind and body, using approaches informed or enabled by knowledge of the genome and the molecules it encodes." Relevant and high-impact papers that encompass studies of individuals, families, or populations are considered for publication. An emphasis will include coupling detailed phenotype and genome sequencing information, both enabled by new technologies and informatics, to delineate the underlying aetiology of disease. Clinical recommendations and/or guidelines of how that data should be used in the clinical management of those patients in the study, and others, are also encouraged.
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