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Clark C. Chen - One of the best experts on this subject based on the ideXlab platform.
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Glioblastomas located in proximity to the subventricular zone (SVZ) exhibited enrichment of gene expression profiles associated with the cancer stem cell state
Journal of Neuro-Oncology, 2020Co-Authors: Tyler C. Steed, Jeffrey M Treiber, Kunal S. Patel, Anders M Dale, Bob S Carter, Birra Taha, Hannah Carter, H. Billur Engin, Clark C. ChenAbstract:Introduction Conflicting results have been reported in the association between Glioblastoma proximity to the subventricular zone (SVZ) and enrichment of cancer stem cell properties. Here, we examined this hypothesis using magnetic resonance (MR) images derived from 217 The Cancer Imaging Archive (TCIA) Glioblastoma subjects. Methods Pre-operative MR images were segmented automatically into contrast enhancing (CE) tumor volumes using Iterative Probabilistic Voxel Labeling (IPVL). Distances were calculated from the centroid of CE tumor volumes to the SVZ and correlated with gene expression profiles of the corresponding Glioblastomas. Correlative analyses were performed between SVZ distance, gene expression patterns, and clinical survival. Results Glioblastoma located in proximity to the SVZ showed increased mRNA expression patterns associated with the cancer stem-cell state, including CD133 (P = 0.006). Consistent with the previous observations suggesting that Glioblastoma stem cells exhibit increased DNA repair capacity, Glioblastomas in proximity to the SVZ also showed increased expression of DNA repair genes, including MGMT (P = 0.018). Reflecting this enhanced DNA repair capacity, the genomes of Glioblastomas in SVZ proximity harbored fewer single nucleotide polymorphisms relative to those located distant to the SVZ (P = 0.003). Concordant with the notion that Glioblastoma stem cells are more aggressive and refractory to therapy, patients with Glioblastoma in proximity to SVZ exhibited poorer progression free and overall survival (P
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Glioblastomas located in proximity to the subventricular zone svz exhibited enrichment of gene expression profiles associated with the cancer stem cell state
Journal of Neuro-oncology, 2020Co-Authors: Tyler Steed, Jeffrey M Treiber, Kunal S. Patel, Anders M Dale, Bob S Carter, Birra Taha, Billur H Engin, Hannah Carter, Clark C. ChenAbstract:Conflicting results have been reported in the association between Glioblastoma proximity to the subventricular zone (SVZ) and enrichment of cancer stem cell properties. Here, we examined this hypothesis using magnetic resonance (MR) images derived from 217 The Cancer Imaging Archive (TCIA) Glioblastoma subjects. Pre-operative MR images were segmented automatically into contrast enhancing (CE) tumor volumes using Iterative Probabilistic Voxel Labeling (IPVL). Distances were calculated from the centroid of CE tumor volumes to the SVZ and correlated with gene expression profiles of the corresponding Glioblastomas. Correlative analyses were performed between SVZ distance, gene expression patterns, and clinical survival. Glioblastoma located in proximity to the SVZ showed increased mRNA expression patterns associated with the cancer stem-cell state, including CD133 (P = 0.006). Consistent with the previous observations suggesting that Glioblastoma stem cells exhibit increased DNA repair capacity, Glioblastomas in proximity to the SVZ also showed increased expression of DNA repair genes, including MGMT (P = 0.018). Reflecting this enhanced DNA repair capacity, the genomes of Glioblastomas in SVZ proximity harbored fewer single nucleotide polymorphisms relative to those located distant to the SVZ (P = 0.003). Concordant with the notion that Glioblastoma stem cells are more aggressive and refractory to therapy, patients with Glioblastoma in proximity to SVZ exhibited poorer progression free and overall survival (P < 0.01). An unbiased analysis of TCIA suggests that Glioblastomas located in proximity to the SVZ exhibited mRNA expression profiles associated with stem cell properties, increased DNA repair capacity, and is associated with poor clinical survival.
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Differential localization of Glioblastoma subtype: implications on Glioblastoma pathogenesis
Oncotarget, 2016Co-Authors: Tyler Steed, Valya Ramakrishnan, Alexander Merk, Jeffrey M Treiber, Kunal S. Patel, Amanda Smith, Lionel M.l. Chow, Anders M Dale, Bob S Carter, Clark C. ChenAbstract:// Tyler C. Steed 1 , Jeffrey M. Treiber 1 , Kunal Patel 1,2 , Valya Ramakrishnan 1 , Alexander Merk 3 , Amanda R. Smith 3 , Bob S. Carter 1 , Anders M. Dale 4,5 , Lionel M. L. Chow 3 and Clark C. Chen 3 1 Center for Theoretical and Applied Neuro-Oncology, Division of Neurosurgery, Moores Cancer Center, University of California, San Diego, La Jolla, CA, USA 2 Weill-Cornell Medical College, New York Presbyterian Hospital, New York, NY, USA 3 Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA 4 Multimodal Imaging Laboratory, University of California San Diego, La Jolla, CA, USA 5 Department of Radiology, University of California San Diego, La Jolla, CA, USA Correspondence to: Clark C. Chen, email: // Keywords : Glioblastoma, MR imaging, subventricular zone, subtypes, automatic tumor segmentation Received : February 23, 2016 Accepted : March 26, 2016 Published : April 01, 2016 Abstract Introduction: The subventricular zone (SVZ) has been implicated in the pathogenesis of Glioblastoma. Whether molecular subtypes of Glioblastoma arise from unique niches of the brain relative to the SVZ remains largely unknown. Here, we tested whether these subtypes of Glioblastoma occupy distinct regions of the cerebrum and examined Glioblastoma localization in relation to the SVZ. Methods: Pre-operative MR images from 217 Glioblastoma patients from The Cancer Imaging Archive were segmented automatically into contrast enhancing (CE) tumor volumes using Iterative Probabilistic Voxel Labeling (IPVL). Probabilistic maps of tumor location were generated for each subtype and distances were calculated from the centroid of CE tumor volumes to the SVZ. Glioblastomas that arose in a Genetically Modified Murine Model (GEMM) model were also analyzed with regard to SVZ distance and molecular subtype. Results: Classical and mesenchymal Glioblastomas were more diffusely distributed and located farther from the SVZ. In contrast, proneural and neural Glioblastomas were more likely to be located in closer proximity to the SVZ. Moreover, in a GFAP-CreER ; Pten loxP/loxP ; Trp53 loxP/loxP ; Rb1 loxP/loxP ; Rbl1 -/- GEMM model of Glioblastoma where tumor can spontaneously arise in different regions of the cerebrum, tumors that arose near the SVZ were more likely to be of proneural subtype ( p < 0.0001). Conclusions: Glioblastoma subtypes occupy different regions of the brain and vary in proximity to the SVZ. These findings harbor implications pertaining to the pathogenesis of Glioblastoma subtypes.
Paul Guilhamon - One of the best experts on this subject based on the ideXlab platform.
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fate mapping of human Glioblastoma reveals an invariant stem cell hierarchy
Nature, 2017Co-Authors: Xiaoyang Lan, David J Jorg, Florence M G Cavalli, Laura M Richards, Long V Nguyen, Robert Vanner, Paul GuilhamonAbstract:Human Glioblastomas harbour a subpopulation of Glioblastoma stem cells that drive tumorigenesis. However, the origin of intratumoural functional heterogeneity between Glioblastoma cells remains poorly understood. Here we study the clonal evolution of barcoded Glioblastoma cells in an unbiased way following serial xenotransplantation to define their individual fate behaviours. Independent of an evolving mutational signature, we show that the growth of Glioblastoma clones in vivo is consistent with a remarkably neutral process involving a conserved proliferative hierarchy rooted in Glioblastoma stem cells. In this model, slow-cycling stem-like cells give rise to a more rapidly cycling progenitor population with extensive self-maintenance capacity, which in turn generates non-proliferative cells. We also identify rare 'outlier' clones that deviate from these dynamics, and further show that chemotherapy facilitates the expansion of pre-existing drug-resistant Glioblastoma stem cells. Finally, we show that functionally distinct Glioblastoma stem cells can be separately targeted using epigenetic compounds, suggesting new avenues for Glioblastoma-targeted therapy.
Hiroko Ohgaki - One of the best experts on this subject based on the ideXlab platform.
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Germline MSH6 Mutation in a Patient With Two Independent Primary Glioblastomas.
Journal of Neuropathology and Experimental Neurology, 2017Co-Authors: Linda M. Forsström, Paul Kleihues, Hiroko Ohgaki, Koichiro Sumi, Markus J. Mäkinen, Ji Eun Oh, Riitta Herva, Lauri A. AaltonenAbstract:We previously reported a patient who had developed 2 Glioblastomas at the age of 54 and 64 years, respectively. The first Glioblastoma in the right frontal lobe was treated with surgery and radiotherapy. Ten years later, the patient developed a second, left frontal Glioblastoma. Discordant patterns of TP53 and PTEN mutations suggested that the second tumor was not a recurrence but an independently developed Glioblastoma. To determine the molecular mechanism underlying this enigmatic case with 10-year survival, we performed whole-exome sequencing. We found that both tumors were IDH-wildtype, excluding the possibility of secondary Glioblastomas that developed from a less malignant astrocytic precursor lesion. We here report that the patient carried a heterozygous germline mutation [c.3305_3306insT; p.1102-fs-insT(Gly1105/TrpfsX3)] in the MSH6 mismatch repair gene. Further sequencing revealed that in addition to the germline MSH6 mutation, the first Glioblastoma showed loss of the MSH6 wild-type allele, and the second Glioblastoma carried a somatic MSH6 mutation [c.1403G>A; p.Arg468His]. Our results indicate that both Glioblastomas had 2 hits in the MSH6 gene, and that loss of MSH6 function was the key event in the pathogenesis of these 2 independent primary Glioblastomas.
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The Definition of Primary and Secondary Glioblastoma
Clinical Cancer Research, 2012Co-Authors: Hiroko Ohgaki, Paul KleihuesAbstract:Glioblastoma is the most frequent and malignant brain tumor. The vast majority of Glioblastomas (∼90%) develop rapidly de novo in elderly patients, without clinical or histologic evidence of a less malignant precursor lesion (primary Glioblastomas). Secondary Glioblastomas progress from low-grade diffuse astrocytoma or anaplastic astrocytoma. They manifest in younger patients, have a lesser degree of necrosis, are preferentially located in the frontal lobe, and carry a significantly better prognosis. Histologically, primary and secondary Glioblastomas are largely indistinguishable, but they differ in their genetic and epigenetic profiles. Decisive genetic signposts of secondary Glioblastoma are IDH1 mutations, which are absent in primary Glioblastomas and which are associated with a hypermethylation phenotype. IDH1 mutations are the earliest detectable genetic alteration in precursor low-grade diffuse astrocytomas and in oligodendrogliomas, indicating that these tumors are derived from neural precursor cells that differ from those of primary Glioblastomas. In this review, we summarize epidemiologic, clinical, histopathologic, genetic, and expression features of primary and secondary Glioblastomas and the biologic consequences of IDH1 mutations. We conclude that this genetic alteration is a definitive diagnostic molecular marker of secondary Glioblastomas and more reliable and objective than clinical criteria. Despite a similar histologic appearance, primary and secondary Glioblastomas are distinct tumor entities that originate from different precursor cells and may require different therapeutic approaches. Clin Cancer Res; 19(4); 764–72. ©2012 AACR .
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The Definition of Primary and Secondary Glioblastoma
Clinical cancer research : an official journal of the American Association for Cancer Research, 2012Co-Authors: Hiroko Ohgaki, Paul KleihuesAbstract:Glioblastoma is the most frequent and malignant brain tumor. The vast majority of Glioblastomas (~90%) develop rapidly de novo in elderly patients, without clinical or histologic evidence of a less malignant precursor lesion (primary Glioblastomas). Secondary Glioblastomas progress from low-grade diffuse astrocytoma or anaplastic astrocytoma. They manifest in younger patients, have a lesser degree of necrosis, are preferentially located in the frontal lobe, and carry a significantly better prognosis. Histologically, primary and secondary Glioblastomas are largely indistinguishable, but they differ in their genetic and epigenetic profiles. Decisive genetic signposts of secondary Glioblastoma are IDH1 mutations, which are absent in primary Glioblastomas and which are associated with a hypermethylation phenotype. IDH1 mutations are the earliest detectable genetic alteration in precursor low-grade diffuse astrocytomas and in oligodendrogliomas, indicating that these tumors are derived from neural precursor cells that differ from those of primary Glioblastomas. In this review, we summarize epidemiologic, clinical, histopathologic, genetic, and expression features of primary and secondary Glioblastomas and the biologic consequences of IDH1 mutations. We conclude that this genetic alteration is a definitive diagnostic molecular marker of secondary Glioblastomas and more reliable and objective than clinical criteria. Despite a similar histologic appearance, primary and secondary Glioblastomas are distinct tumor entities that originate from different precursor cells and may require different therapeutic approaches.
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idh1 mutations as molecular signature and predictive factor of secondary Glioblastomas
Clinical Cancer Research, 2009Co-Authors: Sumihito Nobusawa, Paul Kleihues, Takuya Watanabe, Hiroko OhgakiAbstract:Purpose: To establish the frequency of IDH1 mutations in Glioblastomas at a population level, and to assess whether they allow reliable discrimination between primary ( de novo ) Glioblastomas and secondary Glioblastomas that progressed from low-grade or anaplastic astrocytoma. Experimental Design: We screened Glioblastomas from a population-based study for IDH1 mutations and correlated them with clinical data and other genetic alterations. Results: IDH1 mutations were detected in 36 of 407 Glioblastomas (8.8%). Glioblastoma patients with IDH1 mutations were younger (mean, 47.9 years) than those with EGFR amplification (60.9 years) and were associated with significantly longer survival (mean, 27.1 versus 11.3 months; P IDH1 mutations were frequent in Glioblastomas diagnosed as secondary (22 of 30; 73%), but rare in primary Glioblastomas (14 of 377; 3.7%: P IDH1 mutations as genetic marker of secondary Glioblastoma corresponded to the respective clinical diagnosis in 95% of cases. Glioblastomas with IDH1 mutation diagnosed as primary had clinical and genetic profiles similar to those of secondary Glioblastomas, suggesting that they may have rapidly progressed from a less malignant precursor lesion that escaped clinical diagnosis and were thus misclassified as primary. Conversely, Glioblastomas without IDH1 mutations clinically diagnosed as secondary typically developed from anaplastic rather than low-grade gliomas, suggesting that at least some were actually primary Glioblastomas, that may have been misclassified, possibly due to histologic sampling error. Conclusion: IDH1 mutations are a strong predictor of a more favorable prognosis and a highly selective molecular marker of secondary Glioblastomas that complements clinical criteria for distinguishing them from primary Glioblastomas. (Clin Cancer Res 2009;15(19):6002–7)
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genetic pathways to primary and secondary Glioblastoma
American Journal of Pathology, 2007Co-Authors: Hiroko Ohgaki, Paul KleihuesAbstract:Glioblastoma is the most frequent and most malignant human brain tumor. The prognosis remains very poor, with most patients dying within 1 year after diagnosis. Primary and secondary Glioblastoma constitute distinct disease subtypes, affecting patients of different age and developing through different genetic pathways. The majority of cases (>90%) are primary Glioblastomas that develop rapidly de novo, without clinical or histological evidence of a less malignant precursor lesion. They affect mainly the elderly and are genetically characterized by loss of heterozygosity 10q (70% of cases), EGFR amplification (36%), p16INK4a deletion (31%), and PTEN mutations (25%). Secondary Glioblastomas develop through progression from low-grade diffuse astrocytoma or anaplastic astrocytoma and manifest in younger patients. In the pathway to secondary Glioblastoma, TP53 mutations are the most frequent and earliest detectable genetic alteration, already present in 60% of precursor low-grade astrocytomas. The mutation pattern is characterized by frequent G:C→A:T mutations at CpG sites. During progression to Glioblastoma, additional mutations accumulate, including loss of heterozygosity 10q25-qter (∼70%), which is the most frequent genetic alteration in both primary and secondary Glioblastomas. Primary and secondary Glioblastomas also differ significantly in their pattern of promoter methylation and in expression profiles at RNA and protein levels. This has significant implications, particularly for the development of novel, targeted therapies, as discussed in this review.
Paul Kleihues - One of the best experts on this subject based on the ideXlab platform.
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Germline MSH6 Mutation in a Patient With Two Independent Primary Glioblastomas.
Journal of Neuropathology and Experimental Neurology, 2017Co-Authors: Linda M. Forsström, Paul Kleihues, Hiroko Ohgaki, Koichiro Sumi, Markus J. Mäkinen, Ji Eun Oh, Riitta Herva, Lauri A. AaltonenAbstract:We previously reported a patient who had developed 2 Glioblastomas at the age of 54 and 64 years, respectively. The first Glioblastoma in the right frontal lobe was treated with surgery and radiotherapy. Ten years later, the patient developed a second, left frontal Glioblastoma. Discordant patterns of TP53 and PTEN mutations suggested that the second tumor was not a recurrence but an independently developed Glioblastoma. To determine the molecular mechanism underlying this enigmatic case with 10-year survival, we performed whole-exome sequencing. We found that both tumors were IDH-wildtype, excluding the possibility of secondary Glioblastomas that developed from a less malignant astrocytic precursor lesion. We here report that the patient carried a heterozygous germline mutation [c.3305_3306insT; p.1102-fs-insT(Gly1105/TrpfsX3)] in the MSH6 mismatch repair gene. Further sequencing revealed that in addition to the germline MSH6 mutation, the first Glioblastoma showed loss of the MSH6 wild-type allele, and the second Glioblastoma carried a somatic MSH6 mutation [c.1403G>A; p.Arg468His]. Our results indicate that both Glioblastomas had 2 hits in the MSH6 gene, and that loss of MSH6 function was the key event in the pathogenesis of these 2 independent primary Glioblastomas.
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The Definition of Primary and Secondary Glioblastoma
Clinical Cancer Research, 2012Co-Authors: Hiroko Ohgaki, Paul KleihuesAbstract:Glioblastoma is the most frequent and malignant brain tumor. The vast majority of Glioblastomas (∼90%) develop rapidly de novo in elderly patients, without clinical or histologic evidence of a less malignant precursor lesion (primary Glioblastomas). Secondary Glioblastomas progress from low-grade diffuse astrocytoma or anaplastic astrocytoma. They manifest in younger patients, have a lesser degree of necrosis, are preferentially located in the frontal lobe, and carry a significantly better prognosis. Histologically, primary and secondary Glioblastomas are largely indistinguishable, but they differ in their genetic and epigenetic profiles. Decisive genetic signposts of secondary Glioblastoma are IDH1 mutations, which are absent in primary Glioblastomas and which are associated with a hypermethylation phenotype. IDH1 mutations are the earliest detectable genetic alteration in precursor low-grade diffuse astrocytomas and in oligodendrogliomas, indicating that these tumors are derived from neural precursor cells that differ from those of primary Glioblastomas. In this review, we summarize epidemiologic, clinical, histopathologic, genetic, and expression features of primary and secondary Glioblastomas and the biologic consequences of IDH1 mutations. We conclude that this genetic alteration is a definitive diagnostic molecular marker of secondary Glioblastomas and more reliable and objective than clinical criteria. Despite a similar histologic appearance, primary and secondary Glioblastomas are distinct tumor entities that originate from different precursor cells and may require different therapeutic approaches. Clin Cancer Res; 19(4); 764–72. ©2012 AACR .
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The Definition of Primary and Secondary Glioblastoma
Clinical cancer research : an official journal of the American Association for Cancer Research, 2012Co-Authors: Hiroko Ohgaki, Paul KleihuesAbstract:Glioblastoma is the most frequent and malignant brain tumor. The vast majority of Glioblastomas (~90%) develop rapidly de novo in elderly patients, without clinical or histologic evidence of a less malignant precursor lesion (primary Glioblastomas). Secondary Glioblastomas progress from low-grade diffuse astrocytoma or anaplastic astrocytoma. They manifest in younger patients, have a lesser degree of necrosis, are preferentially located in the frontal lobe, and carry a significantly better prognosis. Histologically, primary and secondary Glioblastomas are largely indistinguishable, but they differ in their genetic and epigenetic profiles. Decisive genetic signposts of secondary Glioblastoma are IDH1 mutations, which are absent in primary Glioblastomas and which are associated with a hypermethylation phenotype. IDH1 mutations are the earliest detectable genetic alteration in precursor low-grade diffuse astrocytomas and in oligodendrogliomas, indicating that these tumors are derived from neural precursor cells that differ from those of primary Glioblastomas. In this review, we summarize epidemiologic, clinical, histopathologic, genetic, and expression features of primary and secondary Glioblastomas and the biologic consequences of IDH1 mutations. We conclude that this genetic alteration is a definitive diagnostic molecular marker of secondary Glioblastomas and more reliable and objective than clinical criteria. Despite a similar histologic appearance, primary and secondary Glioblastomas are distinct tumor entities that originate from different precursor cells and may require different therapeutic approaches.
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idh1 mutations as molecular signature and predictive factor of secondary Glioblastomas
Clinical Cancer Research, 2009Co-Authors: Sumihito Nobusawa, Paul Kleihues, Takuya Watanabe, Hiroko OhgakiAbstract:Purpose: To establish the frequency of IDH1 mutations in Glioblastomas at a population level, and to assess whether they allow reliable discrimination between primary ( de novo ) Glioblastomas and secondary Glioblastomas that progressed from low-grade or anaplastic astrocytoma. Experimental Design: We screened Glioblastomas from a population-based study for IDH1 mutations and correlated them with clinical data and other genetic alterations. Results: IDH1 mutations were detected in 36 of 407 Glioblastomas (8.8%). Glioblastoma patients with IDH1 mutations were younger (mean, 47.9 years) than those with EGFR amplification (60.9 years) and were associated with significantly longer survival (mean, 27.1 versus 11.3 months; P IDH1 mutations were frequent in Glioblastomas diagnosed as secondary (22 of 30; 73%), but rare in primary Glioblastomas (14 of 377; 3.7%: P IDH1 mutations as genetic marker of secondary Glioblastoma corresponded to the respective clinical diagnosis in 95% of cases. Glioblastomas with IDH1 mutation diagnosed as primary had clinical and genetic profiles similar to those of secondary Glioblastomas, suggesting that they may have rapidly progressed from a less malignant precursor lesion that escaped clinical diagnosis and were thus misclassified as primary. Conversely, Glioblastomas without IDH1 mutations clinically diagnosed as secondary typically developed from anaplastic rather than low-grade gliomas, suggesting that at least some were actually primary Glioblastomas, that may have been misclassified, possibly due to histologic sampling error. Conclusion: IDH1 mutations are a strong predictor of a more favorable prognosis and a highly selective molecular marker of secondary Glioblastomas that complements clinical criteria for distinguishing them from primary Glioblastomas. (Clin Cancer Res 2009;15(19):6002–7)
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genetic pathways to primary and secondary Glioblastoma
American Journal of Pathology, 2007Co-Authors: Hiroko Ohgaki, Paul KleihuesAbstract:Glioblastoma is the most frequent and most malignant human brain tumor. The prognosis remains very poor, with most patients dying within 1 year after diagnosis. Primary and secondary Glioblastoma constitute distinct disease subtypes, affecting patients of different age and developing through different genetic pathways. The majority of cases (>90%) are primary Glioblastomas that develop rapidly de novo, without clinical or histological evidence of a less malignant precursor lesion. They affect mainly the elderly and are genetically characterized by loss of heterozygosity 10q (70% of cases), EGFR amplification (36%), p16INK4a deletion (31%), and PTEN mutations (25%). Secondary Glioblastomas develop through progression from low-grade diffuse astrocytoma or anaplastic astrocytoma and manifest in younger patients. In the pathway to secondary Glioblastoma, TP53 mutations are the most frequent and earliest detectable genetic alteration, already present in 60% of precursor low-grade astrocytomas. The mutation pattern is characterized by frequent G:C→A:T mutations at CpG sites. During progression to Glioblastoma, additional mutations accumulate, including loss of heterozygosity 10q25-qter (∼70%), which is the most frequent genetic alteration in both primary and secondary Glioblastomas. Primary and secondary Glioblastomas also differ significantly in their pattern of promoter methylation and in expression profiles at RNA and protein levels. This has significant implications, particularly for the development of novel, targeted therapies, as discussed in this review.
Kosuke Funato - One of the best experts on this subject based on the ideXlab platform.
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sirt2 mediated inactivation of p73 is required for Glioblastoma tumorigenicity
EMBO Reports, 2018Co-Authors: Kosuke Funato, Tomoatsu Hayashi, Kanae Echizen, Lumi Negishi, Naomi Shimizu, Yasuyuki Morishita, Ryo Koyamanasu, Yukiko Nasunishimura, Viviane TabarAbstract:Abstract Glioblastoma is one of the most aggressive forms of cancers and has a poor prognosis. Genomewide analyses have revealed that a set of core signaling pathways, the p53, RB, and RTK pathways, are commonly deregulated in Glioblastomas. However, the molecular mechanisms underlying the tumorigenicity of Glioblastoma are not fully understood. Here, we show that the lysine deacetylase SIRT2 is required for the proliferation and tumorigenicity of Glioblastoma cells, including Glioblastoma stem cells. Furthermore, we demonstrate that SIRT2 regulates p73 transcriptional activity by deacetylation of its C‐terminal lysine residues. Our results suggest that SIRT2‐mediated inactivation of p73 is critical for the proliferation and tumorigenicity of Glioblastoma cells and that SIRT2 may be a promising molecular target for the therapy of Glioblastoma.
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SIRT2‐mediated inactivation of p73 is required for Glioblastoma tumorigenicity
EMBO reports, 2018Co-Authors: Kosuke Funato, Tomoatsu Hayashi, Kanae Echizen, Lumi Negishi, Naomi Shimizu, Ryo Koyama-nasu, Yukiko Nasu-nishimura, Yasuyuki Morishita, Viviane Tabar, Tomoki TodoAbstract:Abstract Glioblastoma is one of the most aggressive forms of cancers and has a poor prognosis. Genomewide analyses have revealed that a set of core signaling pathways, the p53, RB, and RTK pathways, are commonly deregulated in Glioblastomas. However, the molecular mechanisms underlying the tumorigenicity of Glioblastoma are not fully understood. Here, we show that the lysine deacetylase SIRT2 is required for the proliferation and tumorigenicity of Glioblastoma cells, including Glioblastoma stem cells. Furthermore, we demonstrate that SIRT2 regulates p73 transcriptional activity by deacetylation of its C‐terminal lysine residues. Our results suggest that SIRT2‐mediated inactivation of p73 is critical for the proliferation and tumorigenicity of Glioblastoma cells and that SIRT2 may be a promising molecular target for the therapy of Glioblastoma.
