Identification of genomic biomarkers and their pathway crosstalks for deciphering mechanistic links in glioblastoma

IF 16.4 1区 化学 Q1 CHEMISTRY, MULTIDISCIPLINARY
Darrak Moin Quddusi, Naim Bajcinca
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引用次数: 0

Abstract

Glioblastoma is a grade IV pernicious neoplasm occurring in the supratentorial region of brain. As its causes are largely unknown, it is essential to understand its dynamics at the molecular level. This necessitates the identification of better diagnostic and prognostic molecular candidates. Blood-based liquid biopsies are emerging as a novel tool for cancer biomarker discovery, guiding the treatment and improving its early detection based on their tumour origin. There exist previous studies focusing on the identification of tumour-based biomarkers for glioblastoma. However, these biomarkers inadequately represent the underlying pathological state and incompletely illustrate the tumour because of non-recursive nature of this approach to monitor the disease. Also, contrary to the tumour biopsies, liquid biopsies are non-invasive and can be performed at any interval during the disease span to surveil the disease. Therefore, in this study, a unique dataset of blood-based liquid biopsies obtained primarily from tumour-educated blood platelets (TEP) is utilised. This RNA-seq data from ArrayExpress is acquired comprising human cohort with 39 glioblastoma subjects and 43 healthy subjects. Canonical and machine learning approaches are applied for identification of the genomic biomarkers for glioblastoma and their crosstalks. In our study, 97 genes appeared enriched in 7 oncogenic pathways (RAF-MAPK, P53, PRC2-EZH2, YAP conserved, MEK-MAPK, ErbB2 and STK33 signalling pathways) using GSEA, out of which 17 have been identified participating actively in crosstalks. Using PCA, 42 genes are found enriched in 7 pathways (cytoplasmic ribosomal proteins, translation factors, electron transport chain, ribosome, Huntington's disease, primary immunodeficiency pathways, and interferon type I signalling pathway) harbouring tumour when altered, out of which 25 actively participate in crosstalks. All the 14 pathways foster well-known cancer hallmarks and the identified DEGs can serve as genomic biomarkers, not only for the diagnosis and prognosis of Glioblastoma but also in providing a molecular foothold for oncogenic decision making in order to fathom the disease dynamics. Moreover, SNP analysis for the identified DEGs is performed to investigate their roles in disease dynamics in an elaborated manner. These results suggest that TEPs are capable of providing disease insights just like tumour cells with an advantage of being extracted anytime during the course of disease in order to monitor it.

Abstract Image

鉴定基因组生物标志物及其通路串串,以破译胶质母细胞瘤的机制联系
胶质母细胞瘤是一种发生在大脑幕上区域的四级恶性肿瘤。由于其原因在很大程度上是未知的,因此有必要在分子水平上了解其动力学。这就需要确定更好的诊断和预后分子候选物。基于血液的液体活检正在成为发现癌症生物标志物的新工具,指导治疗并改善基于肿瘤起源的早期检测。先前的研究主要集中在胶质母细胞瘤肿瘤生物标志物的鉴定上。然而,这些生物标志物不能充分代表潜在的病理状态,也不能完全说明肿瘤,因为这种方法监测疾病的非递归性质。此外,与肿瘤活组织检查相反,液体活组织检查是非侵入性的,可以在疾病期间的任何间隔进行,以监测疾病。因此,在本研究中,使用了主要来自肿瘤诱导血小板(TEP)的基于血液的液体活检的独特数据集。该RNA-seq数据来自ArrayExpress,包括39名胶质母细胞瘤患者和43名健康受试者。规范化和机器学习方法应用于鉴定胶质母细胞瘤及其串串的基因组生物标志物。在我们的研究中,使用GSEA发现97个基因在7个致癌通路(RAF-MAPK、P53、PRC2-EZH2、YAP保守、MEK-MAPK、ErbB2和STK33信号通路)中富集,其中17个已被鉴定为积极参与串音。利用PCA,发现42个基因在7条通路(细胞质核糖体蛋白、翻译因子、电子传递链、核糖体、亨廷顿病、原发性免疫缺陷通路和干扰素I型信号通路)发生改变时富集,其中25个积极参与串串。所有这14条通路都形成了众所周知的癌症标志,所鉴定的deg可以作为基因组生物标志物,不仅可以用于胶质母细胞瘤的诊断和预后,还可以为致癌决策提供分子立足点,以了解疾病动态。此外,对鉴定的deg进行SNP分析,以详细的方式研究它们在疾病动力学中的作用。这些结果表明,TEPs能够像肿瘤细胞一样提供疾病洞察,其优势是在疾病过程中随时提取以监测疾病。
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来源期刊
Accounts of Chemical Research
Accounts of Chemical Research 化学-化学综合
CiteScore
31.40
自引率
1.10%
发文量
312
审稿时长
2 months
期刊介绍: Accounts of Chemical Research presents short, concise and critical articles offering easy-to-read overviews of basic research and applications in all areas of chemistry and biochemistry. These short reviews focus on research from the author’s own laboratory and are designed to teach the reader about a research project. In addition, Accounts of Chemical Research publishes commentaries that give an informed opinion on a current research problem. Special Issues online are devoted to a single topic of unusual activity and significance. Accounts of Chemical Research replaces the traditional article abstract with an article "Conspectus." These entries synopsize the research affording the reader a closer look at the content and significance of an article. Through this provision of a more detailed description of the article contents, the Conspectus enhances the article's discoverability by search engines and the exposure for the research.
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