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Liangfu Zhou - One of the best experts on this subject based on the ideXlab platform.
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Adult IDH wild-type lower-grade gliomas should be further stratified.
Neuro-oncology, 2017Co-Authors: Abudumijit Aibaidula, Rui Qi Zhang, Zhifeng Shi, Nellie Yuk Fei Chung, Aden Ka-yin Chan, Rui Yang, Yu Yao, Liangfu ZhouAbstract:Background Astrocytoma of the isocitrate dehydrogenase (IDH) wild-type gene is described as a provisional entity within the new World Health Organization (WHO) classification. Some groups believe that IDH wild-type lower-grade gliomas, when interrogated for other biomarkers, will mostly turn out to be glioblastoma. We hypothesize that not all IDH wild-type lower-grade gliomas have very poor outcomes and the group could be substratified prognostically. Methods Seven hundred and eighteen adult WHO grades II and III patients with gliomas from our hospitals were re-reviewed and tested for IDH1/2 mutations. One hundred and sixty-six patients with IDH wild-type cases were identified for further studies, and EGFR and MYB amplifications, mutations of histone H3F3A, TERT promoter (TERTp), and BRAF were examined. Results EGFR amplification, BRAF, and H3F3A mutations were observed in 13.8%, 6.9%, and 9.5% of patients, respectively, in a mutually exclusive pattern in IDH wild-type lower-grade gliomas. TERTp mutations were detected in 26.8% of cases. Favorable outcome was observed in patients with young age, oligodendroglial phenotype, and grade II histology. Independent adverse prognostic values of older age, nontotal resection, grade III histology, EGFR amplification, and H3F3A mutation were confirmed by multivariable analysis. Tumors were further classified into "molecularly" high grade (harboring EGFR, H3F3A, or TERTp) (median overall survival = 1.23 y) and lower grade (lacking all of the 3) (median overall survival = 7.63 y) with independent prognostic relevance. The most favorable survival was noted in molecularly lower-grade gliomas with MYB amplification. Conclusion Adult IDH wild-type lower-grade gliomas are prognostically heterogeneous and do not have uniformly poor prognosis. Clinical information and additional markers, including MYB, EGFR, TERTp, and H3F3A, should be examined to delineate discrete favorable and unfavorable prognostic groups.
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Biomarker-based prognostic stratification of young adult glioblastoma
Oncotarget, 2015Co-Authors: Rui Qi Zhang, Zhifeng Shi, Hong Chen, Nellie Yuk Fei Chung, Zi Yin, Danny T.m. Chan, Wai Sang Poon, Liangfu ZhouAbstract:// Rui-qi Zhang 1, 2, 4, * , Zhifeng Shi 4, * , Hong Chen 5 , Nellie Yuk-Fei Chung 1, 2 , Zi Yin 1, 2 , Kay Ka-Wai Li 1, 2 , Danny Tat-Ming Chan 3 , Wai Sang Poon 3 , Jinsong Wu 4 , Liangfu Zhou 4 , Aden Ka-yin Chan 1, 2 , Ying Mao 4 , Ho-Keung Ng 1, 2 1 Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong, China 2 Shenzhen Research Institute, Chinese University of Hong Kong, Hong Kong, China 3 Neurosurgery Division, Department of Surgery, Chinese University of Hong Kong, Hong Kong, China 4 Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China 5 Department of Neuropathology, Huashan Hospital, Fudan University, Shanghai, China * These authors have contributed equally to this work Correspondence to: Aden Ka-yin Chan, e-mail: adenchan@cuhk.edu. hk Ying Mao, e-mail: yingmao168@hotmail.com Ho-Keung Ng, e-mail: hkng@cuhk.edu.hk Keywords: glioblastoma, IDH1, BRAF, H3F3A, prognostication Received: June 14, 2015 Accepted: September 25, 2015 Published: October 05, 2015 ABSTRACT While the predominant elderly and the pediatric glioblastomas have been extensively investigated, young adult glioblastomas were understudied. In this study, we sought to stratify young adult glioblastomas by BRAF , H3F3A and IDH1 mutations and examine the clinical relevance of the biomarkers. In 107 glioblastomas aged from 17 to 35 years, mutually exclusive BRAF -V600E (15%), H3F3A -K27M (15.9%), H3F3A -G34R/V (2.8%) and IDH1 -R132H (16.8%) mutations were identified in over half of the cases. EGFR amplification and TERT p mutation were only detected in 3.7% and 8.4% in young adult glioblastomas, respectively. BRAF -V600E identified a clinically favorable subset of glioblastomas with younger age, frequent CDKN2A homozygous deletion, and was more amendable to surgical resection. H3F3A -K27M mutated glioblastomas were tightly associated with midline locations and showed dismal prognosis. IDH1 -R132H was associated with older age and favorable outcome. Interestingly, tumors with positive PDGFRA immunohistochemical expression exhibited poorer prognosis and identified an aggressive subset of tumors among K27M mutated glioblastomas. Combining BRAF , H3F3A and IDH1 mutations allowed stratification of young adult glioblastomas into four prognostic subgroups. In summary, our study demonstrates the clinical values of stratifying young adult glioblastomas with BRAF , H3F3A and IDH1 mutations, which has important implications in refining prognostic classification of glioblastomas.
Ashish Suri - One of the best experts on this subject based on the ideXlab platform.
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genome wide small noncoding rna profiling of pediatric high grade gliomas reveals deregulation of several mirnas identifies downregulation of snorna cluster hbii 52 and delineates H3F3A and tp53 mutant specific mirnas and snornas
International Journal of Cancer, 2015Co-Authors: Prerana Jha, Pankaj Pathak, Suvendu Purkait, Vaishali Suri, Mehar Chand Sharma, Anupam Kumar, Supriyo Mallik, Deepak Gupta, R K Agrawal, Ashish SuriAbstract:Pediatric high-grade gliomas (HGGs) are highly malignant tumors that remain incurable and relatively understudied. The crucial role of noncoding RNAs (ncRNAs) has been reported in various cancers. However, the study on miRNAs in pediatric HGGs is scant and there is no report till date on the status of other small ncRNAs. Genome-wide microarray analysis was performed to investigate small ncRNA expression in pediatric HGG (n = 14) and compared to adult glioblastoma (GBM) signature. The validation of miRNAs and small nucleolar RNAs (snoRNAs) was done by real-time polymerase chain reaction. TP53 and H3F3A mutation-specific miRNA and snoRNA profiles were generated and analyzed. Pediatric HGGs showed upregulation of miR-17/92 and its paralog clusters (miR106b/25 and miR-106a/363), whereas majority of downregulated miRNAs belonged to miR379/656 cluster (14q32). Unsupervised hierarchical clustering identified two distinct groups. Interestingly, Group 2 with downregulated 14q32 cluster showed better overall survival. The miRNAs unique to pediatric HGG as compared to adult GBM were predicted to affect PDGFR and SMAD2/3 pathways. Similarities were seen between pediatric HGG and TP53 mutant miRNA profiles as compared to wild types. Several of H3F3A mutation-regulated genes were found to be the targets of H3F3A mutant-specific miRNAs. Remarkably, a significant downregulation of HBII-52 snoRNA cluster was found in pediatric HGGs, and was specific to H3F3A nonmutants. This is the first genome-wide profiling study on miRNAs and snoRNAs in pediatric HGGs with respect to H3F3A and TP53 mutations. The comparison of miRNA profiles of pediatric HGGs and adult GBM reiterates the overlaps and differences as also seen with their gene expression and methylation signatures.
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Genome‐wide small noncoding RNA profiling of pediatric high‐grade gliomas reveals deregulation of several miRNAs, identifies downregulation of snoRNA cluster HBII‐52 and delineates H3F3A and TP53 mutant‐specific miRNAs and snoRNAs
International journal of cancer, 2015Co-Authors: Prerana Jha, Pankaj Pathak, Suvendu Purkait, Vaishali Suri, Mehar Chand Sharma, Rahul Agrawal, Anupam Kumar, Supriyo Mallik, Deepak Gupta, Ashish SuriAbstract:Pediatric high-grade gliomas (HGGs) are highly malignant tumors that remain incurable and relatively understudied. The crucial role of noncoding RNAs (ncRNAs) has been reported in various cancers. However, the study on miRNAs in pediatric HGGs is scant and there is no report till date on the status of other small ncRNAs. Genome-wide microarray analysis was performed to investigate small ncRNA expression in pediatric HGG (n = 14) and compared to adult glioblastoma (GBM) signature. The validation of miRNAs and small nucleolar RNAs (snoRNAs) was done by real-time polymerase chain reaction. TP53 and H3F3A mutation-specific miRNA and snoRNA profiles were generated and analyzed. Pediatric HGGs showed upregulation of miR-17/92 and its paralog clusters (miR106b/25 and miR-106a/363), whereas majority of downregulated miRNAs belonged to miR379/656 cluster (14q32). Unsupervised hierarchical clustering identified two distinct groups. Interestingly, Group 2 with downregulated 14q32 cluster showed better overall survival. The miRNAs unique to pediatric HGG as compared to adult GBM were predicted to affect PDGFR and SMAD2/3 pathways. Similarities were seen between pediatric HGG and TP53 mutant miRNA profiles as compared to wild types. Several of H3F3A mutation-regulated genes were found to be the targets of H3F3A mutant-specific miRNAs. Remarkably, a significant downregulation of HBII-52 snoRNA cluster was found in pediatric HGGs, and was specific to H3F3A nonmutants. This is the first genome-wide profiling study on miRNAs and snoRNAs in pediatric HGGs with respect to H3F3A and TP53 mutations. The comparison of miRNA profiles of pediatric HGGs and adult GBM reiterates the overlaps and differences as also seen with their gene expression and methylation signatures.
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Altered global histone-trimethylation code and H3F3A-ATRX mutation in pediatric GBM.
Journal of neuro-oncology, 2014Co-Authors: Pankaj Pathak, Prerana Jha, Suvendu Purkait, Vikas Sharma, Vaishali Suri, Mehar Chand Sharma, Mohammed Faruq, Ashish Suri, Chitra SarkarAbstract:Mutations in H3.3-ATRX-DAXX chromatin remodeling pathway have been reported in pediatric GBMs. H3.3 (H3F3A) mutations may affect transcriptional regulation by altered global histone-methylation. Therefore, we analyzed yet partly understood global histone code (H3K-4/9/27/36) trimethylation pattern in H3F3A-ATRX mutants and wild-type. H3F3A, HIST1H3B, IDH1, ATRX, DAXX and Tp53 mutations were identified by sequencing/immunohistochemistry in 27 pediatric GBMs. Global histone-methylation H3K-4/9/27/36me3 and Polycomb-protein EZH2 expression were evaluated by immunohistochemistry. H3F3A-ATRX mutation was observed in 66.7 % (18/27) of pediatric GBMs. K27M and G34R-H3F3A mutations were found in 37 % (10/27) and 14.8 % (4/27) patients respectively. G34V-H3F3A, HIST1H3B and IDH1 mutations were absent. Notably, commonest global histone-methylation mark lost was H3K27me3 (17/25, 68 %) followed by H3K4me3 (45.5 %, 10/22) and H3K9me3 (18.2 %, 4/22). Global H3K36me3 showed no loss. Most significant observation was loss of one or more histone-trimethylation mark in 80 % (20/25) pediatric GBMs. Notably, simultaneous loss of H3K27me3 and H3K4me3 were present in 7/22 (31.8 %) of pediatric GBMs. Low expression of EZH2 was found in 12/24 (50 %) of cases. However no significant correlation of loss of histone-marks or EZH2 expression with H3F3A-ATRX mutants (loss of at least one histone-marks in 87.5 % (14/16) cases) versus wild-types (loss of at least one histone-marks in 75 % (6/8) cases) was seen. The present study highlights for the first time combinatorial loss of one or more histone-trimethylation marks associated with majority of pediatric GBMs and the finding suggests significant role of histone-code in the molecular biology that underlies pediatric GBMs. Hence therapies for patients with particular combinations of histone modifications present opportunity to design innovative patient-tailored treatment protocols.
Prerana Jha - One of the best experts on this subject based on the ideXlab platform.
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Pediatric High Grade Glioma
Advances in Biology and Treatment of Glioblastoma, 2017Co-Authors: Chitra Sarkar, Pankaj Pathak, Suvendu Purkait, Prerana JhaAbstract:Pediatric high grade gliomas (pHGGs) constitute about 20% of childhood gliomas and show poor survival. The underlying molecular pathogenesis of pHGGs is significantly distinct from histologically similar adult GBMs. Frequent driver mutations within chromatin remodeling genes histone H3.1-H3.3 (K27M-G34R/V)-ATRX-DAXX, in addition to alterations in ACVR1, SETD2, FGFR1, BRAF, PDGFRA, NTRK, MYCN, MYC and TP53 genes play a central role in the pHGG pathogenesis. Genome-wide methylation data of pediatric GBM (pGBM) has shown four biologically distinct subgroups, associated with enrichment for mutations (K27 and G34), PDGFRA-amplification, and/or mesenchymal gene expression signatures. pGBMs show rare IDH1-mutation/G-CIMP (Glioma-CpG-Island Methylator Phenotype) and are associated with reactive oxygen species production. Genome-wide miRNA profile of pHGGs has shown a set of uniquely expressed miRNAs distinct from adult GBMs which target PDGFR-b pathway. Functional consequences of histone H3.3 mutation in pHGGs show reprogramming of H3K27 methylation in conjunction with EZH2 over a set of biologically significant genes leading to tumorigenesis. A major loss of expression of global histone trimethylation (H3K-27/−9/−4) code has also been shown in pGBMs. Patients with H3F3A-G34R/V shown better overall survival compared with H3F3A-wild type and -K27M. However H3F3A-K27M show poorest prognosis in pHGGs. Clinical trial designs should now focus on distinct molecular subgrouping in pHGGs and stratify patients applying markers associated with specific subgroup. Targeting chromatin modifiers, central to pHGG pathogenesis offers a rational way to develop highly selective treatment strategies.
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genome wide small noncoding rna profiling of pediatric high grade gliomas reveals deregulation of several mirnas identifies downregulation of snorna cluster hbii 52 and delineates H3F3A and tp53 mutant specific mirnas and snornas
International Journal of Cancer, 2015Co-Authors: Prerana Jha, Pankaj Pathak, Suvendu Purkait, Vaishali Suri, Mehar Chand Sharma, Anupam Kumar, Supriyo Mallik, Deepak Gupta, R K Agrawal, Ashish SuriAbstract:Pediatric high-grade gliomas (HGGs) are highly malignant tumors that remain incurable and relatively understudied. The crucial role of noncoding RNAs (ncRNAs) has been reported in various cancers. However, the study on miRNAs in pediatric HGGs is scant and there is no report till date on the status of other small ncRNAs. Genome-wide microarray analysis was performed to investigate small ncRNA expression in pediatric HGG (n = 14) and compared to adult glioblastoma (GBM) signature. The validation of miRNAs and small nucleolar RNAs (snoRNAs) was done by real-time polymerase chain reaction. TP53 and H3F3A mutation-specific miRNA and snoRNA profiles were generated and analyzed. Pediatric HGGs showed upregulation of miR-17/92 and its paralog clusters (miR106b/25 and miR-106a/363), whereas majority of downregulated miRNAs belonged to miR379/656 cluster (14q32). Unsupervised hierarchical clustering identified two distinct groups. Interestingly, Group 2 with downregulated 14q32 cluster showed better overall survival. The miRNAs unique to pediatric HGG as compared to adult GBM were predicted to affect PDGFR and SMAD2/3 pathways. Similarities were seen between pediatric HGG and TP53 mutant miRNA profiles as compared to wild types. Several of H3F3A mutation-regulated genes were found to be the targets of H3F3A mutant-specific miRNAs. Remarkably, a significant downregulation of HBII-52 snoRNA cluster was found in pediatric HGGs, and was specific to H3F3A nonmutants. This is the first genome-wide profiling study on miRNAs and snoRNAs in pediatric HGGs with respect to H3F3A and TP53 mutations. The comparison of miRNA profiles of pediatric HGGs and adult GBM reiterates the overlaps and differences as also seen with their gene expression and methylation signatures.
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Genome‐wide small noncoding RNA profiling of pediatric high‐grade gliomas reveals deregulation of several miRNAs, identifies downregulation of snoRNA cluster HBII‐52 and delineates H3F3A and TP53 mutant‐specific miRNAs and snoRNAs
International journal of cancer, 2015Co-Authors: Prerana Jha, Pankaj Pathak, Suvendu Purkait, Vaishali Suri, Mehar Chand Sharma, Rahul Agrawal, Anupam Kumar, Supriyo Mallik, Deepak Gupta, Ashish SuriAbstract:Pediatric high-grade gliomas (HGGs) are highly malignant tumors that remain incurable and relatively understudied. The crucial role of noncoding RNAs (ncRNAs) has been reported in various cancers. However, the study on miRNAs in pediatric HGGs is scant and there is no report till date on the status of other small ncRNAs. Genome-wide microarray analysis was performed to investigate small ncRNA expression in pediatric HGG (n = 14) and compared to adult glioblastoma (GBM) signature. The validation of miRNAs and small nucleolar RNAs (snoRNAs) was done by real-time polymerase chain reaction. TP53 and H3F3A mutation-specific miRNA and snoRNA profiles were generated and analyzed. Pediatric HGGs showed upregulation of miR-17/92 and its paralog clusters (miR106b/25 and miR-106a/363), whereas majority of downregulated miRNAs belonged to miR379/656 cluster (14q32). Unsupervised hierarchical clustering identified two distinct groups. Interestingly, Group 2 with downregulated 14q32 cluster showed better overall survival. The miRNAs unique to pediatric HGG as compared to adult GBM were predicted to affect PDGFR and SMAD2/3 pathways. Similarities were seen between pediatric HGG and TP53 mutant miRNA profiles as compared to wild types. Several of H3F3A mutation-regulated genes were found to be the targets of H3F3A mutant-specific miRNAs. Remarkably, a significant downregulation of HBII-52 snoRNA cluster was found in pediatric HGGs, and was specific to H3F3A nonmutants. This is the first genome-wide profiling study on miRNAs and snoRNAs in pediatric HGGs with respect to H3F3A and TP53 mutations. The comparison of miRNA profiles of pediatric HGGs and adult GBM reiterates the overlaps and differences as also seen with their gene expression and methylation signatures.
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Altered global histone-trimethylation code and H3F3A-ATRX mutation in pediatric GBM.
Journal of neuro-oncology, 2014Co-Authors: Pankaj Pathak, Prerana Jha, Suvendu Purkait, Vikas Sharma, Vaishali Suri, Mehar Chand Sharma, Mohammed Faruq, Ashish Suri, Chitra SarkarAbstract:Mutations in H3.3-ATRX-DAXX chromatin remodeling pathway have been reported in pediatric GBMs. H3.3 (H3F3A) mutations may affect transcriptional regulation by altered global histone-methylation. Therefore, we analyzed yet partly understood global histone code (H3K-4/9/27/36) trimethylation pattern in H3F3A-ATRX mutants and wild-type. H3F3A, HIST1H3B, IDH1, ATRX, DAXX and Tp53 mutations were identified by sequencing/immunohistochemistry in 27 pediatric GBMs. Global histone-methylation H3K-4/9/27/36me3 and Polycomb-protein EZH2 expression were evaluated by immunohistochemistry. H3F3A-ATRX mutation was observed in 66.7 % (18/27) of pediatric GBMs. K27M and G34R-H3F3A mutations were found in 37 % (10/27) and 14.8 % (4/27) patients respectively. G34V-H3F3A, HIST1H3B and IDH1 mutations were absent. Notably, commonest global histone-methylation mark lost was H3K27me3 (17/25, 68 %) followed by H3K4me3 (45.5 %, 10/22) and H3K9me3 (18.2 %, 4/22). Global H3K36me3 showed no loss. Most significant observation was loss of one or more histone-trimethylation mark in 80 % (20/25) pediatric GBMs. Notably, simultaneous loss of H3K27me3 and H3K4me3 were present in 7/22 (31.8 %) of pediatric GBMs. Low expression of EZH2 was found in 12/24 (50 %) of cases. However no significant correlation of loss of histone-marks or EZH2 expression with H3F3A-ATRX mutants (loss of at least one histone-marks in 87.5 % (14/16) cases) versus wild-types (loss of at least one histone-marks in 75 % (6/8) cases) was seen. The present study highlights for the first time combinatorial loss of one or more histone-trimethylation marks associated with majority of pediatric GBMs and the finding suggests significant role of histone-code in the molecular biology that underlies pediatric GBMs. Hence therapies for patients with particular combinations of histone modifications present opportunity to design innovative patient-tailored treatment protocols.
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Genome-wide methylation profiling identifies an essential role of reactive oxygen species in pediatric glioblastoma multiforme and validates a methylome specific for H3 histone family 3A with absence of G-CIMP/isocitrate dehydrogenase 1 mutation
Neuro-oncology, 2014Co-Authors: Prerana Jha, Pankaj Pathak, Vikas Sharma, Vaishali Suri, Irene Rosita Pia Patric, Sudhanshu Shukla, Jagriti Pal, Sivaarumugam Thinagararanjan, Vani Santosh, Mehar Chand SharmaAbstract:Background. Pediatric glioblastoma multiforme (GBM) is rare, and there is a single study, a seminal discovery showing association of histone H3.3 and isocitrate dehydrogenase (IDH) 1 mutation with a DNA methylation signature. The present study aims to validate these findings in an independent cohort of pediatric GBM, compare it with adult GBM, and evaluate the involvement of important functionally altered pathways. Methods. Genome-wide methylation profiling of 21 pediatric GBM cases was done and compared with adult GBM data (GSE22867). We performed gene mutation analysis of IDH1 and H3 histone family 3A (H3F3A), status evaluation of glioma cytosine-phosphate-guanine island methylator phenotype (G-CIMP), and Gene Ontology analysis. Experimental evaluation of reactive oxygen species (ROS) association was also done. Results. Distinct differences were noted between methylomes of pediatric and adult GBM. Pediatric GBM was characterized by 94 hypermethylated and 1206 hypomethylated cytosine-phosphate-guanine (CpG) islands, with 3 distinct clusters, having a trend to prognostic correlation. Interestingly, none of the pediatric GBM cases showed G-CIMP/IDH1 mutation. Gene Ontology analysis identified ROS association in pediatric GBM, which was experimentally validated. H3F3A mutants (36.4%; all K27M) harbored distinct methylomes and showed enrichment of processes related to neuronal development, differentiation, and cell-fate commitment. Conclusions. Our study confirms that pediatric GBM has a distinct methylome compared with that of adults. Presence of distinct clusters and an H3F3A mutation-specific methylome indicate existence of epigenetic subgroups within pediatric GBM. Absence of IDH1/G-CIMP status further indicates that findings in adult GBM cannot be simply extrapolated to pediatric GBM and that there is a strong need for identification of separate prognostic markers. A possible role of ROS in pediatric GBM pathogenesis is demonstrated for the first time and needs further evaluation.
Zhifeng Shi - One of the best experts on this subject based on the ideXlab platform.
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Pediatric low-grade gliomas can be molecularly stratified for risk.
Acta neuropathologica, 2018Co-Authors: Rui Ryan Yang, Zhifeng Shi, Danny T.m. Chan, Wai Sang Poon, Aden Ka-yin Chan, Abudumijiti Aibaidula, Wei Wei Wang, Zhen-yu Zhang, Xian Zhi LiuAbstract:Pediatric low-grade gliomas (PLGGs) consist of a number of entities with overlapping histological features. PLGGs have much better prognosis than the adult counterparts, but a significant proportion of PLGGs suffers from tumor progression and recurrence. It has been shown that pediatric and adult low-grade gliomas are molecularly distinct. Yet the clinical significance of some of newer biomarkers discovered by genomic studies has not been fully investigated. In this study, we evaluated in a large cohort of 289 PLGGs a list of biomarkers and examined their clinical relevance. TERT promoter (TERTp), H3F3A and BRAF V600E mutations were detected by direct sequencing. ATRX nuclear loss was examined by immunohistochemistry. CDKN2A deletion, KIAA1549-BRAF fusion, and MYB amplification were determined by fluorescence in situ hybridization (FISH). TERTp, H3F3A, and BRAF V600E mutations were identified in 2.5, 6.4, and 7.4% of PLGGs, respectively. ATRX loss was found in 4.9% of PLGGs. CDKN2A deletion, KIAA1549-BRAF fusion and MYB amplification were detected in 8.8, 32.0 and 10.6% of PLGGs, respectively. Survival analysis revealed that TERTp mutation, H3F3A mutation, and ATRX loss were significantly associated with poor PFS (p
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Adult IDH wild-type lower-grade gliomas should be further stratified.
Neuro-oncology, 2017Co-Authors: Abudumijit Aibaidula, Rui Qi Zhang, Zhifeng Shi, Nellie Yuk Fei Chung, Aden Ka-yin Chan, Rui Yang, Yu Yao, Liangfu ZhouAbstract:Background Astrocytoma of the isocitrate dehydrogenase (IDH) wild-type gene is described as a provisional entity within the new World Health Organization (WHO) classification. Some groups believe that IDH wild-type lower-grade gliomas, when interrogated for other biomarkers, will mostly turn out to be glioblastoma. We hypothesize that not all IDH wild-type lower-grade gliomas have very poor outcomes and the group could be substratified prognostically. Methods Seven hundred and eighteen adult WHO grades II and III patients with gliomas from our hospitals were re-reviewed and tested for IDH1/2 mutations. One hundred and sixty-six patients with IDH wild-type cases were identified for further studies, and EGFR and MYB amplifications, mutations of histone H3F3A, TERT promoter (TERTp), and BRAF were examined. Results EGFR amplification, BRAF, and H3F3A mutations were observed in 13.8%, 6.9%, and 9.5% of patients, respectively, in a mutually exclusive pattern in IDH wild-type lower-grade gliomas. TERTp mutations were detected in 26.8% of cases. Favorable outcome was observed in patients with young age, oligodendroglial phenotype, and grade II histology. Independent adverse prognostic values of older age, nontotal resection, grade III histology, EGFR amplification, and H3F3A mutation were confirmed by multivariable analysis. Tumors were further classified into "molecularly" high grade (harboring EGFR, H3F3A, or TERTp) (median overall survival = 1.23 y) and lower grade (lacking all of the 3) (median overall survival = 7.63 y) with independent prognostic relevance. The most favorable survival was noted in molecularly lower-grade gliomas with MYB amplification. Conclusion Adult IDH wild-type lower-grade gliomas are prognostically heterogeneous and do not have uniformly poor prognosis. Clinical information and additional markers, including MYB, EGFR, TERTp, and H3F3A, should be examined to delineate discrete favorable and unfavorable prognostic groups.
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Biomarker-based prognostic stratification of young adult glioblastoma
Oncotarget, 2015Co-Authors: Rui Qi Zhang, Zhifeng Shi, Hong Chen, Nellie Yuk Fei Chung, Zi Yin, Danny T.m. Chan, Wai Sang Poon, Liangfu ZhouAbstract:// Rui-qi Zhang 1, 2, 4, * , Zhifeng Shi 4, * , Hong Chen 5 , Nellie Yuk-Fei Chung 1, 2 , Zi Yin 1, 2 , Kay Ka-Wai Li 1, 2 , Danny Tat-Ming Chan 3 , Wai Sang Poon 3 , Jinsong Wu 4 , Liangfu Zhou 4 , Aden Ka-yin Chan 1, 2 , Ying Mao 4 , Ho-Keung Ng 1, 2 1 Department of Anatomical and Cellular Pathology, Chinese University of Hong Kong, Hong Kong, China 2 Shenzhen Research Institute, Chinese University of Hong Kong, Hong Kong, China 3 Neurosurgery Division, Department of Surgery, Chinese University of Hong Kong, Hong Kong, China 4 Department of Neurosurgery, Huashan Hospital, Fudan University, Shanghai, China 5 Department of Neuropathology, Huashan Hospital, Fudan University, Shanghai, China * These authors have contributed equally to this work Correspondence to: Aden Ka-yin Chan, e-mail: adenchan@cuhk.edu. hk Ying Mao, e-mail: yingmao168@hotmail.com Ho-Keung Ng, e-mail: hkng@cuhk.edu.hk Keywords: glioblastoma, IDH1, BRAF, H3F3A, prognostication Received: June 14, 2015 Accepted: September 25, 2015 Published: October 05, 2015 ABSTRACT While the predominant elderly and the pediatric glioblastomas have been extensively investigated, young adult glioblastomas were understudied. In this study, we sought to stratify young adult glioblastomas by BRAF , H3F3A and IDH1 mutations and examine the clinical relevance of the biomarkers. In 107 glioblastomas aged from 17 to 35 years, mutually exclusive BRAF -V600E (15%), H3F3A -K27M (15.9%), H3F3A -G34R/V (2.8%) and IDH1 -R132H (16.8%) mutations were identified in over half of the cases. EGFR amplification and TERT p mutation were only detected in 3.7% and 8.4% in young adult glioblastomas, respectively. BRAF -V600E identified a clinically favorable subset of glioblastomas with younger age, frequent CDKN2A homozygous deletion, and was more amendable to surgical resection. H3F3A -K27M mutated glioblastomas were tightly associated with midline locations and showed dismal prognosis. IDH1 -R132H was associated with older age and favorable outcome. Interestingly, tumors with positive PDGFRA immunohistochemical expression exhibited poorer prognosis and identified an aggressive subset of tumors among K27M mutated glioblastomas. Combining BRAF , H3F3A and IDH1 mutations allowed stratification of young adult glioblastomas into four prognostic subgroups. In summary, our study demonstrates the clinical values of stratifying young adult glioblastomas with BRAF , H3F3A and IDH1 mutations, which has important implications in refining prognostic classification of glioblastomas.
Mehar Chand Sharma - One of the best experts on this subject based on the ideXlab platform.
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genome wide small noncoding rna profiling of pediatric high grade gliomas reveals deregulation of several mirnas identifies downregulation of snorna cluster hbii 52 and delineates H3F3A and tp53 mutant specific mirnas and snornas
International Journal of Cancer, 2015Co-Authors: Prerana Jha, Pankaj Pathak, Suvendu Purkait, Vaishali Suri, Mehar Chand Sharma, Anupam Kumar, Supriyo Mallik, Deepak Gupta, R K Agrawal, Ashish SuriAbstract:Pediatric high-grade gliomas (HGGs) are highly malignant tumors that remain incurable and relatively understudied. The crucial role of noncoding RNAs (ncRNAs) has been reported in various cancers. However, the study on miRNAs in pediatric HGGs is scant and there is no report till date on the status of other small ncRNAs. Genome-wide microarray analysis was performed to investigate small ncRNA expression in pediatric HGG (n = 14) and compared to adult glioblastoma (GBM) signature. The validation of miRNAs and small nucleolar RNAs (snoRNAs) was done by real-time polymerase chain reaction. TP53 and H3F3A mutation-specific miRNA and snoRNA profiles were generated and analyzed. Pediatric HGGs showed upregulation of miR-17/92 and its paralog clusters (miR106b/25 and miR-106a/363), whereas majority of downregulated miRNAs belonged to miR379/656 cluster (14q32). Unsupervised hierarchical clustering identified two distinct groups. Interestingly, Group 2 with downregulated 14q32 cluster showed better overall survival. The miRNAs unique to pediatric HGG as compared to adult GBM were predicted to affect PDGFR and SMAD2/3 pathways. Similarities were seen between pediatric HGG and TP53 mutant miRNA profiles as compared to wild types. Several of H3F3A mutation-regulated genes were found to be the targets of H3F3A mutant-specific miRNAs. Remarkably, a significant downregulation of HBII-52 snoRNA cluster was found in pediatric HGGs, and was specific to H3F3A nonmutants. This is the first genome-wide profiling study on miRNAs and snoRNAs in pediatric HGGs with respect to H3F3A and TP53 mutations. The comparison of miRNA profiles of pediatric HGGs and adult GBM reiterates the overlaps and differences as also seen with their gene expression and methylation signatures.
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Genome‐wide small noncoding RNA profiling of pediatric high‐grade gliomas reveals deregulation of several miRNAs, identifies downregulation of snoRNA cluster HBII‐52 and delineates H3F3A and TP53 mutant‐specific miRNAs and snoRNAs
International journal of cancer, 2015Co-Authors: Prerana Jha, Pankaj Pathak, Suvendu Purkait, Vaishali Suri, Mehar Chand Sharma, Rahul Agrawal, Anupam Kumar, Supriyo Mallik, Deepak Gupta, Ashish SuriAbstract:Pediatric high-grade gliomas (HGGs) are highly malignant tumors that remain incurable and relatively understudied. The crucial role of noncoding RNAs (ncRNAs) has been reported in various cancers. However, the study on miRNAs in pediatric HGGs is scant and there is no report till date on the status of other small ncRNAs. Genome-wide microarray analysis was performed to investigate small ncRNA expression in pediatric HGG (n = 14) and compared to adult glioblastoma (GBM) signature. The validation of miRNAs and small nucleolar RNAs (snoRNAs) was done by real-time polymerase chain reaction. TP53 and H3F3A mutation-specific miRNA and snoRNA profiles were generated and analyzed. Pediatric HGGs showed upregulation of miR-17/92 and its paralog clusters (miR106b/25 and miR-106a/363), whereas majority of downregulated miRNAs belonged to miR379/656 cluster (14q32). Unsupervised hierarchical clustering identified two distinct groups. Interestingly, Group 2 with downregulated 14q32 cluster showed better overall survival. The miRNAs unique to pediatric HGG as compared to adult GBM were predicted to affect PDGFR and SMAD2/3 pathways. Similarities were seen between pediatric HGG and TP53 mutant miRNA profiles as compared to wild types. Several of H3F3A mutation-regulated genes were found to be the targets of H3F3A mutant-specific miRNAs. Remarkably, a significant downregulation of HBII-52 snoRNA cluster was found in pediatric HGGs, and was specific to H3F3A nonmutants. This is the first genome-wide profiling study on miRNAs and snoRNAs in pediatric HGGs with respect to H3F3A and TP53 mutations. The comparison of miRNA profiles of pediatric HGGs and adult GBM reiterates the overlaps and differences as also seen with their gene expression and methylation signatures.
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Altered global histone-trimethylation code and H3F3A-ATRX mutation in pediatric GBM.
Journal of neuro-oncology, 2014Co-Authors: Pankaj Pathak, Prerana Jha, Suvendu Purkait, Vikas Sharma, Vaishali Suri, Mehar Chand Sharma, Mohammed Faruq, Ashish Suri, Chitra SarkarAbstract:Mutations in H3.3-ATRX-DAXX chromatin remodeling pathway have been reported in pediatric GBMs. H3.3 (H3F3A) mutations may affect transcriptional regulation by altered global histone-methylation. Therefore, we analyzed yet partly understood global histone code (H3K-4/9/27/36) trimethylation pattern in H3F3A-ATRX mutants and wild-type. H3F3A, HIST1H3B, IDH1, ATRX, DAXX and Tp53 mutations were identified by sequencing/immunohistochemistry in 27 pediatric GBMs. Global histone-methylation H3K-4/9/27/36me3 and Polycomb-protein EZH2 expression were evaluated by immunohistochemistry. H3F3A-ATRX mutation was observed in 66.7 % (18/27) of pediatric GBMs. K27M and G34R-H3F3A mutations were found in 37 % (10/27) and 14.8 % (4/27) patients respectively. G34V-H3F3A, HIST1H3B and IDH1 mutations were absent. Notably, commonest global histone-methylation mark lost was H3K27me3 (17/25, 68 %) followed by H3K4me3 (45.5 %, 10/22) and H3K9me3 (18.2 %, 4/22). Global H3K36me3 showed no loss. Most significant observation was loss of one or more histone-trimethylation mark in 80 % (20/25) pediatric GBMs. Notably, simultaneous loss of H3K27me3 and H3K4me3 were present in 7/22 (31.8 %) of pediatric GBMs. Low expression of EZH2 was found in 12/24 (50 %) of cases. However no significant correlation of loss of histone-marks or EZH2 expression with H3F3A-ATRX mutants (loss of at least one histone-marks in 87.5 % (14/16) cases) versus wild-types (loss of at least one histone-marks in 75 % (6/8) cases) was seen. The present study highlights for the first time combinatorial loss of one or more histone-trimethylation marks associated with majority of pediatric GBMs and the finding suggests significant role of histone-code in the molecular biology that underlies pediatric GBMs. Hence therapies for patients with particular combinations of histone modifications present opportunity to design innovative patient-tailored treatment protocols.
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Genome-wide methylation profiling identifies an essential role of reactive oxygen species in pediatric glioblastoma multiforme and validates a methylome specific for H3 histone family 3A with absence of G-CIMP/isocitrate dehydrogenase 1 mutation
Neuro-oncology, 2014Co-Authors: Prerana Jha, Pankaj Pathak, Vikas Sharma, Vaishali Suri, Irene Rosita Pia Patric, Sudhanshu Shukla, Jagriti Pal, Sivaarumugam Thinagararanjan, Vani Santosh, Mehar Chand SharmaAbstract:Background. Pediatric glioblastoma multiforme (GBM) is rare, and there is a single study, a seminal discovery showing association of histone H3.3 and isocitrate dehydrogenase (IDH) 1 mutation with a DNA methylation signature. The present study aims to validate these findings in an independent cohort of pediatric GBM, compare it with adult GBM, and evaluate the involvement of important functionally altered pathways. Methods. Genome-wide methylation profiling of 21 pediatric GBM cases was done and compared with adult GBM data (GSE22867). We performed gene mutation analysis of IDH1 and H3 histone family 3A (H3F3A), status evaluation of glioma cytosine-phosphate-guanine island methylator phenotype (G-CIMP), and Gene Ontology analysis. Experimental evaluation of reactive oxygen species (ROS) association was also done. Results. Distinct differences were noted between methylomes of pediatric and adult GBM. Pediatric GBM was characterized by 94 hypermethylated and 1206 hypomethylated cytosine-phosphate-guanine (CpG) islands, with 3 distinct clusters, having a trend to prognostic correlation. Interestingly, none of the pediatric GBM cases showed G-CIMP/IDH1 mutation. Gene Ontology analysis identified ROS association in pediatric GBM, which was experimentally validated. H3F3A mutants (36.4%; all K27M) harbored distinct methylomes and showed enrichment of processes related to neuronal development, differentiation, and cell-fate commitment. Conclusions. Our study confirms that pediatric GBM has a distinct methylome compared with that of adults. Presence of distinct clusters and an H3F3A mutation-specific methylome indicate existence of epigenetic subgroups within pediatric GBM. Absence of IDH1/G-CIMP status further indicates that findings in adult GBM cannot be simply extrapolated to pediatric GBM and that there is a strong need for identification of separate prognostic markers. A possible role of ROS in pediatric GBM pathogenesis is demonstrated for the first time and needs further evaluation.
