McInerney Caitríona E, Lynn Joanna A, Gilmore Alan R, Flannery Tom, Prise Kevin M
Patrick G. Johnson Centre for Cancer Research, Queen's University Belfast, 97 Lisburn Rd, Belfast BT9 7AE, Northern Ireland, UK.
Department of Neurosurgery, Royal Victoria Hospital, Belfast Health & Social Care Trust, Belfast BT9 7AB, Northern Ireland, UK.
Curr Issues Mol Biol. 2022 Jul 2;44(7):2982-3000. doi: 10.3390/cimb44070206.
Adult brain tumors (glioma) represent a cancer of unmet need where standard-of-care is non-curative; thus, new therapies are urgently needed. It is unclear whether isocitrate dehydrogenases (IDH1/2) when not mutated have any role in gliomagenesis or tumor growth. Nevertheless, IDH1 is overexpressed in glioblastoma (GBM), which could impact upon cellular metabolism and epigenetic reprogramming. This study characterizes IDH1 expression and associated genes and pathways. A novel biomarker discovery pipeline using artificial intelligence (evolutionary algorithms) was employed to analyze IDH-wildtype adult gliomas from the TCGA LGG-GBM cohort. Ninety genes whose expression correlated with IDH1 expression were identified from: (1) All gliomas, (2) primary GBM, and (3) recurrent GBM tumors. Genes were overrepresented in ubiquitin-mediated proteolysis, focal adhesion, mTOR signaling, and pyruvate metabolism pathways. Other non-enriched pathways included O-glycan biosynthesis, notch signaling, and signaling regulating stem cell pluripotency (PCGF3). Potential prognostic (TSPYL2, JAKMIP1, CIT, TMTC1) and two diagnostic (MINK1, PLEKHM3) biomarkers were downregulated in GBM. Their gene expression and methylation were negatively and positively correlated with IDH1 expression, respectively. Two diagnostic biomarkers (BZW1, RCF2) showed the opposite trend. Prognostic genes were not impacted by high frequencies of molecular alterations and only one (TMTC1) could be validated in another cohort. Genes with mechanistic links to IDH1 were involved in brain neuronal development, cell proliferation, cytokinesis, and O-mannosylation as well as tumor suppression and anaplerosis. Results highlight metabolic vulnerabilities and therapeutic targets for use in future clinical trials.
成人脑肿瘤（胶质瘤）是一种尚未满足治疗需求的癌症，其标准治疗方法无法治愈；因此，迫切需要新的治疗方法。目前尚不清楚未发生突变的异柠檬酸脱氢酶（IDH1/2）在胶质瘤发生或肿瘤生长中是否起作用。然而，IDH1在胶质母细胞瘤（GBM）中过度表达，这可能会影响细胞代谢和表观遗传重编程。本研究对IDH1的表达以及相关基因和通路进行了表征。采用一种使用人工智能（进化算法）的新型生物标志物发现流程，分析了来自TCGA低级别胶质瘤-胶质母细胞瘤（LGG-GBM）队列的IDH野生型成人胶质瘤。从以下三个方面鉴定出了90个与IDH1表达相关的基因：（1）所有胶质瘤，（2）原发性GBM，（3）复发性GBM肿瘤。这些基因在泛素介导的蛋白水解、粘着斑、mTOR信号传导和丙酮酸代谢途径中过度富集。其他未富集的途径包括O-聚糖生物合成、Notch信号传导和调节干细胞多能性的信号传导（PCGF3）。潜在的预后生物标志物（TSPYL2、JAKMIP1、CIT、TMTC1）和两个诊断生物标志物（MINK1、PLEKHM3）在GBM中表达下调。它们的基因表达和甲基化分别与IDH1表达呈负相关和正相关。两个诊断生物标志物（BZW1、RCF2）表现出相反的趋势。预后基因不受高频分子改变的影响，只有一个（TMTC1）可以在另一个队列中得到验证。与IDH1有机制联系的基因参与脑神经元发育、细胞增殖、胞质分裂和O-甘露糖基化以及肿瘤抑制和回补反应。研究结果突出了未来临床试验中可利用的代谢脆弱性和治疗靶点。
