Reconstructing the Molecular Life History of Gliomas

Barthel, Floris P.; Wesseling, Pieter; Verhaak, Roel G.W.

doi:10.1101/192369

Cited by 11 publications

(15 citation statements)

References 234 publications

(204 reference statements)

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“…Gliomas are the largest group of intrinsic brain tumours with age adjusted incidence rates ranging from 4.67 to 5.73 per 100,000, causing more years of life lost compared with other cancers [1,2]. Glioblastoma (GBM) is the most malignant glioma and is classified molecularly as IDH-wildtype and IDH-mutant GBM [3][4][5][6][7][8][9][10]. During gliomagenesis, an array of genetic alterations may cause the dysregulation of cell growth signalling and cell cycle pathways [6,[11][12][13][14][15].…”

Section: Introductionmentioning

confidence: 99%

“…Neural stem cells in the subventricular zone may harbour recurrent driver somatic mutations that are shared with the tumour bulk (e.g., P53, PTEN, EGFR, and TERT) [17]. Telomerase (reactivation or reexpression) can occur in IDH wildtype and mutant GBMs driven either by telomerase reverse transcriptase (TERT) promoter mutations or other mechanisms [8,18]. e current standard-of-care for glioblastomas remains as maximal safe surgical resection with concurrent radiotherapy and temozolomide (TMZ) chemotherapy (Stupp protocol) [19,20].…”

Section: Introductionmentioning

confidence: 99%

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Clinically Actionable Insights into Initial and Matched Recurrent Glioblastomas to Inform Novel Treatment Approaches

Ellis

McInerney

Schrimpf

et al. 2019

Journal of Oncology

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Glioblastoma is the most common primary adult brain tumour, and despite optimal treatment, the median survival is 12–15 months. Patients with matched recurrent glioblastomas were investigated to try to find actionable mutations. Tumours were profiled using a validated DNA-based gene panel. Copy number variations (CNVs) and single nucleotide variants (SNVs) were examined, and potentially pathogenic variants and clinically actionable mutations were identified. The results revealed that glioblastomas were IDH-wildtype (IDHWT; n = 38) and IDH-mutant (IDHMUT; n = 3). SNVs in TSC2, MSH6, TP53, CREBBP, and IDH1 were variants of unknown significance (VUS) that were predicted to be pathogenic in both subtypes. IDHWT tumours had SNVs that impacted RTK/Ras/PI(3)K, p53, WNT, SHH, NOTCH, Rb, and G-protein pathways. Many tumours had BRCA1/2 (18%) variants, including confirmed somatic mutations in haemangioblastoma. IDHWT recurrent tumours had fewer pathways impacted (RTK/Ras/PI(3)K, p53, WNT, and G-protein) and CNV gains (BRCA2, GNAS, and EGFR) and losses (TERT and SMARCA4). IDHMUT tumours had SNVs that impacted RTK/Ras/PI(3)K, p53, and WNT pathways. VUS in KLK1 was possibly pathogenic in IDHMUT. Recurrent tumours also had fewer pathways (p53, WNT, and G-protein) impacted by genetic alterations. Public datasets (TCGA and GDC) confirmed the clinical significance of findings in both subtypes. Overall in this cohort, potentially actionable variation was most often identified in EGFR, PTEN, BRCA1/2, and ATM. This study underlines the need for detailed molecular profiling to identify individual GBM patients who may be eligible for novel treatment approaches. This information is also crucial for patient recruitment to clinical trials.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Clinically Actionable Insights into Initial and Matched Recurrent Glioblastomas to Inform Novel Treatment Approaches

Ellis

McInerney

Schrimpf

et al. 2019

Journal of Oncology

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“…Within the same patient, though different subtypes of cells shared many commonalities in CNV changes and regulon network, there were differences to some degree. We found that the non‐GSCs, which shared more common features in CNV or regulon network with a specific GSC, were derived from this GSC by trajectory analysis, suggesting that the differentiation or evolution of tumor cells is a gradual process with mutation accumulation 26 . We also identified the subclones of the same subtype in the same patient.…”

Section: Discussionmentioning

confidence: 78%

“…It indicated that some subclones were less affected by inter‐tumoral heterogeneity and we speculated that these subclones may be directly derived from driver mutations 30,31 . In patient BT_S4, ME_2 showed a tendency of transition to ME_1 subclones, and we thought that these two subclones possessed the same progenitor and were at different phases of glioma genesis of one consecutive evolution process 26 …”

Section: Discussionmentioning

confidence: 85%

Effect of intra‐ and inter‐tumoral heterogeneity on molecular characteristics of primary IDH‐wild type glioblastoma revealed by single‐cell analysis

Xiong

Yang

2020

CNS Neurosci Ther

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Aims To reveal the effects of intra‐ and inter‐tumoral heterogeneity on characteristics of primary IDH‐wild type glioblastoma cells. Methods Single‐cell RNA‐seq data were acquired from the GEO database, and bulk sample transcriptome data were downloaded from the TCGA database with clinical information. Neoplastic subtype and glioma stem‐like cells (GSCs) were identified by matching 5000 random virtual samples based on ssGSEA. CNV was inferred to compare the heterogeneity among patients and subtypes by infercnv. Transition direction was inferred by RNA velocity, and lineage trajectory was inferred by monocle. Regulon network of cells was analyzed by SCENIC, and cell communication was identified by CellPhoneDB. Results Glioblastoma (GBM) cells could be divided into four subtypes by Verhaak classifier. However, classification of three subtypes (except NE subtype) was more suitable for GBM cells, and Verhaak classifier has difficulty in distinguishing GSCs. GBM heterogeneity and GBM cells’ regulon network were mainly influenced by inter‐tumoral heterogeneity. Within the same patient, different subclones exist in the same subtype of cells whose transition direction could be predicted by regulon similarity. Apart from inter‐tumoral heterogeneity, different subtype of cells share common subtype‐specific cell‐cell communications. Conclusions Inter‐tumoral heterogeneity contributes mainly to GBM heterogeneity and cell molecular characteristics. However, the same subtype of cells shared cell communication similarities.

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“…The tumorprivate mutations in the tumor tissue might facilitate the development of a new targeted therapy. In addition, the anatomical location of those cells would mature the Big Bang theory 7,60) into the Firework theory of subventricular abnormal cells 43) .…”

Section: History : Progress Toward the Stem Cell Origin Of Gbmmentioning

confidence: 99%

Glioblastoma Cellular Origin and the Firework Pattern of Cancer Genesis from the Subventricular Zone

Yoon

Park

Jang

et al. 2020

J Korean Neurosurg Soc

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Glioblastoma (GBM) is a disease without any definite cure. Numerous approaches have been tested in efforts to conquer this brain disease, but patients invariably experience recurrence or develop resistance to treatment. New surgical tools, carefully chosen samples, and experimental methods are enabling discoveries at single-cell resolution. The present article reviews the cell-of-origin of isocitrate dehydrogenase (IDH)-wildtype GBM, beginning with the historical background for focusing on cellular origin and introducing the cancer genesis patterned on firework. The authors also review mutations associated with the senescence process in cells of the subventricular zone (SVZ), and biological validation of somatic mutations in a mouse SVZ model. Understanding GBM would facilitate research on the origin of other cancers and may catalyze the development of new management approaches or treatments against IDH-wildtype GBM.

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Reconstructing the Molecular Life History of Gliomas

Cited by 11 publications

References 234 publications

Clinically Actionable Insights into Initial and Matched Recurrent Glioblastomas to Inform Novel Treatment Approaches

Clinically Actionable Insights into Initial and Matched Recurrent Glioblastomas to Inform Novel Treatment Approaches

Effect of intra‐ and inter‐tumoral heterogeneity on molecular characteristics of primary IDH‐wild type glioblastoma revealed by single‐cell analysis

Glioblastoma Cellular Origin and the Firework Pattern of Cancer Genesis from the Subventricular Zone

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