Sensitivity to<i>BUB1B</i>Inhibition Defines an Alternative Classification of Glioblastoma

Lee, Eunjee; Pain, Margaret; Wang, Huaien; Herman, Jacob; Toledo, Chad M.; DeLuca, Jennifer G.; Yong, Raymund L.; Paddison, Patrick J.; Zhu, Jun

doi:10.1158/0008-5472.can-17-0736

Cited by 37 publications

(35 citation statements)

References 55 publications

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“…Indeed, our signature contains crucial regulators of this process, including PTTG1/ securin and the mitotic kinases AURKA, AURKB, CDK1 and PLK1, which have gained recent attention as therapeutical targets in GBM. Thus, in vitro and xenograft animal model studies have advocated the use of AURK inhibitors in combination with radiotherapy and temozolomide against GBM cells (52)(53)(54)(55). Our data suggest that, when used as single agents, mitotic kinase inhibitors may be particularly effective against G3-group tumors.…”

Section: Discussionmentioning

confidence: 75%

A DNA Repair and Cell-Cycle Gene Expression Signature in Primary and Recurrent Glioblastoma: Prognostic Value and Clinical Implications

Gobin

Nazarov²,

Warta

et al. 2019

Cancer Research

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Inevitable tumor recurrence and a poor median survival are frustrating reminders of the inefficacy of our current standard of care for patients with newly diagnosed glioblastoma (GBM), which includes surgery followed by radiotherapy and chemotherapy with the DNA alkylating agent temozolomide. Because resistance to genotoxic damage is achieved mainly through execution of the DNA damage response (DDR) and DNA repair pathways, knowledge of the changes in DNA repair and cell-cycle gene expression that occur during tumor development might help identify new targets and improve treatment. Here, we performed a gene expression analysis targeting components of the DNA repair and cell-cycle machineries in cohorts of paired tumor samples (i.e., biopsies from the same patient obtained at the time of primary tumor operation and at recurrence) from patients treated with radiotherapy or radiotherapy plus temozolomide. We identified and validated a 27gene signature that resulted in the classification of GBM specimens into three groups, two of which displayed inverse expression profiles. Each group contained primary and recurrent samples, and the tumor at relapse frequently displayed a gene expression profile different from that of the matched primary biopsy. Within the groups that exhibited opposing gene expression profiles, the expression pattern of the gene signature at relapse was linked to progression-free survival. We provide experimental evidence that our signature exposes group-specific vulnerabilities against genotoxicants and inhibitors of the cell cycle and DDR, with the prospect of personalized therapeutic strategies. Significance: These findings suggest that classification of GBM tumors based on a DNA repair and cell-cycle gene expression signature exposes vulnerabilities to standard-ofcare therapies and offers the potential for personalized therapeutic strategies.

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Section: Discussionmentioning

confidence: 75%

A DNA Repair and Cell-Cycle Gene Expression Signature in Primary and Recurrent Glioblastoma: Prognostic Value and Clinical Implications

Gobin

Nazarov²,

Warta

et al. 2019

Cancer Research

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“…This reaction provides a predictive marker. The BUB1BR/S classification of GBM tumors can predict the clinical course and sensitivity to drug treatment (16,17). The ZWINT gene is highly expressed in a variety of cancers, including esophageal cancer.…”

Section: Discussionmentioning

confidence: 99%

Gene set enrichment analysis and meta-analysis to identify six key genes regulating and controlling the prognosis of esophageal squamous cell carcinoma

Chen

Yuan

et al. 2018

J. Thorac. Dis

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Background: Esophageal squamous cell carcinoma (ESCC) is a common malignancy with high mortality. Because of the lack of clarity in the relevant genes and mechanisms involved, and the current difficulty for oncotherapy in providing therapeutic solutions, there is an urgent need to study this matter. While gene probe studies have been used to select the most virulent genes and pathways, paucity of case controls during gene screening and lack of conclusive results to expound the etiology and pathogenesis of the disease, have reduced study reliability. Methods: We chose six datasets from independent studies in the Gene Expression Omnibus (GEO) database and used gene set enrichment analysis and meta-analysis to select key genes and pathways. Results: We found four down-regulated and four up-regulated pathways through gene set enrichment analysis, and 406 differential genes through meta-analysis. Based on The Cancer Genome Atlas (TCGA), 995 differentially expressed genes were screened out. Comparing the 406 gene set with the 995 gene set, we found 19 common genes, of which 6 had a common pathway and were screened out as key genes regulating and controlling the prognosis of ESCC. Conclusions: Among the 19 genes, we found three genes that affect the chemotherapy of ESCC: BUB1B, BUB1, and TTK. Another three genes NDC1, NUP107, and NUP155 on the RNA transport pathway were also found. Altogether, these six genes are not only crucial in the development of ESCC, but also determine the prognosis of patients. The key genes and pathways identified in the present study will be used for the next stage in our study, which will involve gene elimination and other experimentation methods.

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“…e proteins encoded by genes BUB1, BUB1B, and TTK have the ability to phosphorylate serine and threonine residues in the substrates [14], while TTK can also phosphorylate tyrosine residues, acting on checkpoints during cell mitosis [15]. It has been found that numerous tumors, such as glioblastoma [16,17] and gastric adenocarcinoma [18], harbor expression changes in BUB1, BUB1B, and TTK as well as checkpoint dysfunction. Moreover, BUB1, BUB1B, and TTK were shown to be associated with malignant behaviors such as PCPG metastasis in TCGAbased studies [19,20].…”

Section: Discussionmentioning

confidence: 99%

Identification of Genes Associated with the Metastasis of Pheochromocytoma/Paraganglioma Based on Weighted Gene Coexpression Network Analysis

Ding

Zhang

et al. 2020

BioMed Research International

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Background. Pheochromocytoma/paraganglioma (PCPG) is a benign neuroendocrine neoplasm in most cases, but metastasis and other malignant behaviors can be observed in this tumor. The aim of this study was to identify genes associated with the metastasis of PCPG. Methods. The Cancer Genome Atlas (TCGA) expression profile data and clinical information were downloaded from the cbioportal, and the weighted gene coexpression network analysis (WGCNA) was conducted. The gene coexpression modules were extracted from the network through the WGCNA package of R software. We further extracted metastasis-related modules of PCPG. Enrichment analysis of Biological Process of Gene Ontology and Kyoto Encyclopedia of Genes and Genomes was carried out for important modules, and survival analysis of hub genes in the modules was performed. Results. A total of 168 PCPG samples were included in this study. The weighted gene coexpression network was constructed with 5125 genes of the top 25% variance among the 20501 genes obtained from the database. We identified 11 coexpression modules, among which the salmon module was associated with the age of PCPG patients at diagnosis, metastasis, and malignancy of the tumors. Conclusion. WGCNA was performed to identify the gene coexpression modules and hub genes in the metastasis-related gene module of PCPG. The findings in this study provide a new clue for further study of the mechanisms underlying the PCPG metastasis.

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Sensitivity toBUB1BInhibition Defines an Alternative Classification of Glioblastoma

Cited by 37 publications

References 55 publications

A DNA Repair and Cell-Cycle Gene Expression Signature in Primary and Recurrent Glioblastoma: Prognostic Value and Clinical Implications

A DNA Repair and Cell-Cycle Gene Expression Signature in Primary and Recurrent Glioblastoma: Prognostic Value and Clinical Implications

Gene set enrichment analysis and meta-analysis to identify six key genes regulating and controlling the prognosis of esophageal squamous cell carcinoma

Identification of Genes Associated with the Metastasis of Pheochromocytoma/Paraganglioma Based on Weighted Gene Coexpression Network Analysis

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