Mutational analysis reveals the origin and therapy-driven evolution of recurrent glioma (original) (raw)
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Nature Genetics, 2013
nature genetics advance online publication 1 a r t i c l e s Recurrent and oncogenic gene fusions are hallmarks of hematological malignancies and have also been uncovered in solid tumors . We recently reported that a small subset of GBMs harbor FGFR-TACC gene fusions and provided data to suggest that individuals with FGFR-TACCpositive tumors would benefit from targeted FGFR kinase inhibition 9 . It remains unknown whether gene fusions involving other receptor tyrosine kinase (RTK)-coding genes exist and produce oncogene addiction in GBM. Here we analyze a large RNA-sequencing (RNA-seq) data set of primary GBMs and glioma sphere cultures (GSCs) and report the global landscape of in-frame gene fusions in human GBM.
Genomic profiles of low-grade murine gliomas evolve during progression to glioblastoma
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Gliomas are diverse neoplasms with multiple molecular subtypes. How tumor-initiating mutations relate to molecular subtypes as these tumors evolve during malignant progression remains unclear. We used genetically engineered mouse models, histopathology, genetic lineage tracing, expression profiling, and copy number analyses to examine how genomic tumor diversity evolves during the course of malignant progression from low- to high-grade disease. Knockout of all 3 retinoblastoma (Rb) family proteins was required to initiate low-grade tumors in adult mouse astrocytes. Mutations activating mitogen-activated protein kinase signaling, specifically KrasG12D, potentiated Rb-mediated tumorigenesis. Low-grade tumors showed mutant Kras-specific transcriptome profiles but lacked copy number mutations. These tumors stochastically progressed to high-grade, in part through acquisition of copy number mutations. High-grade tumor transcriptomes were heterogeneous and consisted of 3 subtypes that mimi...
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Frontiers in Oncology
Glioma are the most common type of malignant brain tumor, with glioblastoma (GBM) representing the most common and most lethal type of glioma. Surgical resection followed by radiotherapy and chemotherapy using the alkylating agent Temozolomide (TMZ) remain the mainstay of treatment for glioma. While this multimodal regimen is sufficient to temporarily eliminate the bulk of the tumor mass, recurrence is inevitable and often poses major challenges for clinical management due to treatment resistance and failure to respond to targeted therapies. Improved tumor profiling capacity has enabled characterization of the genomic landscape of gliomas with the overarching goal to identify clinically relevant subtypes and inform treatment decisions. Increased tumor mutational load has been shown to correlate with higher levels of neoantigens and is indicative of the potential to induce a durable response to immunotherapy. Following treatment with TMZ, a subset of glioma has been identified to recur with increased tumor mutational load. These hypermutant recurrent glioma represent a subtype of recurrence with unique molecular vulnerabilities. In this review, we will elaborate on the current knowledge regarding the evolution of hypermutation in gliomas and the potential therapeutic opportunities that arise with TMZ-induced hypermutation in gliomas.
Adult diffuse glioma are a diverse group of intracranial neoplasms associated with a disproportional large number of productive life years lost, thus imposing a highly emotional and significant financial burden on society. Patient death is the result of an aggressive course of disease following diagnosis. The Cancer Genome Atlas and similar projects have provided a comprehensive understanding of the somatic alterations and molecular subtypes of glioma at diagnosis. However, gliomas undergo significant molecular evolution during the malignant transformation. We review current knowledge on genomic, epigenomic and transcriptomic abnormalities before and after disease recurrence. We outline an effort to systemically catalogue the longitudinal changes in gliomas, the Glioma Longitudinal Analysis Consortium. The GLASS initiative will provide essential insights into the evolution of glioma towards a lethal phenotype with the potential to reveal targetable vulnerabilities, and ultimately, i...
Functional discovery of targetable dependencies in recurrent glioblastoma
Research Square (Research Square), 2022
Resistance to genotoxic therapies and tumor recurrence are hallmarks of glioblastoma (GBM), an aggressive brain tumor. Here, we explore the functional drivers of post-treatment recurrent GBM. By conducting genome-wide CRISPR-Cas9 screens in patient-derived GBM models, we uncover distinct genetic dependencies in recurrent tumor cells that were absent in their patient-matched primary predecessors, accompanied by increased mutational burden and differential transcript and protein expression. These analyses map a multilayered genetic response to drive tumor recurrence, identifying protein tyrosine phosphatase 4A2 (PTP4A2) as a novel modulator of self-renewal, proliferation and tumorigenicity at GBM recurrence. Mechanistically, genetic perturbation or small molecule inhibition of PTP4A2 represses axon guidance activity through a dephosphorylation axis with roundabout guidance receptor 1 (ROBO1), exploiting a functional dependency on ROBO signaling. Importantly, engineered anti-ROBO1 single-domain antibodies also mimic the effects of PTP4A2 inhibition. We conclude that functional reprogramming drives tumorigenicity and dependence on a multi-targetable PTP4A2-ROBO1 signaling axis at GBM recurrence. Full Text For decades, clinicians have administered radiation therapy and chemotherapy to treat cancer patients 1. In parallel, resistance to these genotoxic treatments and tumor recurrence have become an inevitable reality for aggressive tumors. However, despite the clinical relevance and applications, functional drivers of disease recurrence remain poorly understood. Glioblastoma (GBM) remains the most aggressive and prevalent malignant primary brain tumor in adults 2. Unchanged since 2005, standard of care (SoC) consists of surgical resection, followed by radiation therapy (RT) plus concurrent and adjuvant chemotherapy with temozolomide (TMZ) 3,4. Despite these therapeutic efforts, patients inevitably succumb to recurrent disease with a median overall survival of 14.6 months and a ve-year survival rate of 5.5-6.8% 2,3,5. Unbiased genome-wide functional genomic screens have provided insights into genes and pathways regulating tumor cell survival, invasion, and sensitivity to TMZ in primary pre-treatment tumor cells 6-9. However, these studies do not examine changes at post-treatment tumor recurrence, and thus cannot explain treatment failure in ~70% of GBM patients 10. Here, we conduct a genome-scale comparison between patient-matched pre-and post-treatment GBM cells at the functional, transcriptomic, and proteomic levels. We uncover a therapeutic vulnerability for protein tyrosine phosphatase 4A2 (PTP4A2) at tumor recurrence, and introduce a modulatory role for PTP4A2 on axonal guidance proteins. Comparing primary and recurrent GBM We derived a pair of patient-matched GBM cell lines, one from a tumor specimen obtained at initial diagnosis prior to chemoradiotherapy (BT594, primary tumor cells), and a second specimen obtained at rst disease recurrence post-therapy (BT972, recurrent tumor cells) (Figure 1A, Table S1). Consistent with previous observations 11,12 , recurrent tumor cells showed a 25-fold increase in in vitro self-renewal capacity (P = 5.0e-09
Neuro-oncology, 2018
Adult diffuse gliomas are a diverse group of brain neoplasms that inflict a high emotional toll on patients and their families. The Cancer Genome Atlas (TCGA) and similar projects have provided a comprehensive understanding of the somatic alterations and molecular subtypes of glioma at diagnosis. However, gliomas undergo significant cellular and molecular evolution during disease progression. We review the current knowledge on the genomic and epigenetic abnormalities in primary tumors and after disease recurrence, highlight the gaps in the literature, and elaborate on the need for a new multi-institutional effort to bridge these knowledge gaps and how the Glioma Longitudinal AnalySiS Consortium (GLASS) aims to systemically catalog the longitudinal changes in gliomas. The GLASS initiative will provide essential insights into the evolution of glioma toward a lethal phenotype, with the potential to reveal targetable vulnerabilities, and ultimately, improved outcomes for a patient popul...