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https://www.readbyqxmd.com/read/29016894/diffuse-high-grade-gliomas-with-h3-k27m-mutations-carry-a-dismal-prognosis-independent-of-tumor-location
#1
Michael Karremann, Gerrit H Gielen, Marion Hoffmann, Maria Wiese, Niclas Colditz, Monika Warmuth-Metz, Brigitte Bison, Alexander Claviez, Dannis G van Vuurden, André O von Bueren, Marco Gessi, Ingrid Kühnle, Volkmar H Hans, Martin Benesch, Dominik Sturm, Rolf-Dieter Kortmann, Andreas Waha, Torsten Pietsch, Christof M Kramm
Background: The novel entity of "diffuse midline glioma, H3 K27M-mutant" has been defined in the 2016 revision of the World Health Organization (WHO) classification of tumors of the central nervous system (CNS). Tumors of this entity arise in CNS midline structures of predominantly pediatric patients and are associated with an overall dismal prognosis. They are defined by K27M mutations in H3F3A or HIST1H3B/C, encoding for histone 3 variants H3.3 and H3.1, respectively, which are considered hallmark events driving gliomagenesis...
August 4, 2017: Neuro-oncology
https://www.readbyqxmd.com/read/28986151/braf-v600e-mutation-is-a-significant-prognosticator-of-the-tumour-regrowth-rate-in-brainstem-gangliogliomas
#2
Xin Chen, Changcun Pan, Peng Zhang, Cheng Xu, Yu Sun, Hai Yu, Yuliang Wu, Yibo Geng, Pengcheng Zuo, Zhen Wu, Junting Zhang, Liwei Zhang
BRAF V600E mutations are progression factors in paediatric low-grade gliomas. Furthermore, a high percentage of paediatric brainstem gangliogliomas have BRAF V600E mutations. However, their clinical significance, including possible connections between the biomarkers and ganglioglioma's clinical features, especially a brainstem counterpart, is unclear. To identify potential molecular features predictive of brainstem ganglioglioma's clinical outcomes, a retrospective cohort of 28 World Health Organization (WHO) grade I brainstem gangliogliomas was analysed for BRAF V600E, IDH1 R132H, and IDH2 R172K mutations, TERT C228T/C250T promoter mutation, H3F3A K27M mutation and MGMT methylation...
October 3, 2017: Journal of Clinical Neuroscience: Official Journal of the Neurosurgical Society of Australasia
https://www.readbyqxmd.com/read/28960151/brainstem-pilocytic-astrocytoma-with-h3-k27m-mutation-case-report
#3
Shuhei Morita, Masayuki Nitta, Yoshihiro Muragaki, Takashi Komori, Kenta Masui, Takashi Maruyama, Koichi Ichimura, Yoshiko Nakano, Tatsuo Sawada, Shunichi Koriyama, Shunsuke Tsuzuki, Takayuki Yasuda, Kazutoshi Hashimoto, Akihiro Niwa, Takakazu Kawamata
In this report, the authors present the first case of adult brainstem pilocytic astrocytoma (PA) with the H3 K27M mutation. A 53-year-old man was incidentally found to have a 2.5-cm partially enhanced tumor in the tectum on MRI. The enhancement in the lesion increased over 3 years, and gross-total removal was performed via the occipital transtentorial approach. The resected tissue indicated PA, WHO Grade I, and genetic analysis revealed the H3 K27M mutation. However, although the radiological, surgical, and pathological findings all corresponded to PA, this entity can easily be misdiagnosed as diffuse midline glioma with the H3 K27M mutation, which is classified as a WHO Grade IV tumor according to the updated classification...
September 29, 2017: Journal of Neurosurgery
https://www.readbyqxmd.com/read/28947983/deceptive-morphologic-and-epigenetic-heterogeneity-in-diffuse-intrinsic-pontine-glioma
#4
Marianna Bugiani, Sophie E M Veldhuijzen van Zanten, Viola Caretti, Pepijn Schellen, Eleonora Aronica, David P Noske, William P Vandertop, Gertjan J L Kaspers, Dannis G van Vuurden, Pieter Wesseling, Esther Hulleman
Historically, the diagnosis of diffuse intrinsic pontine glioma (DIPG) was based on typical imaging findings and clinical characteristics instead of pathology. However, the discovery of mutations in histone H3 variants, and the availability of tumor material for molecular analysis, has led to a paradigm shift in DIPG research and clinical practice. Using data from whole-brain autopsies in a series of nine DIPG patients with known histone mutational status, we here aim to review histopathological characteristics with special focus on intratumoral heterogeneity (ITH) and histone 3 K27 trimethylation (H3 K27me3)...
September 1, 2017: Oncotarget
https://www.readbyqxmd.com/read/28880421/diffuse-midline-gliomas-with-histone-h3-k27m-mutation-a-rare-case-with-pnet-like-appearance-and-neuropil-like-islands
#5
Yue Gao, Yang-Yang Feng, Juan-Han Yu, Qing-Chang Li, Xue-Shan Qiu, En-Hua Wang
Diffuse midline glioma with histone H3-K27M mutation is a new tumor entity defined by the 2016 WHO Classification of Tumors of the Central Nervous System. A 51-year-old Chinese woman presented with neck pain for a month. Subsequent MRI revealed an intramedullary neoplasm extending from C5 to C7. Histologically, the cellular area of the tumor was composed of primitive, poorly differentiated, small cells with scant cytoplasm, nuclear molding, and brisk mitotic activity, exhibiting PNET-like appearance, while in the hypocellular area, oligodendroglioma-like cells were observed...
September 6, 2017: Neuropathology: Official Journal of the Japanese Society of Neuropathology
https://www.readbyqxmd.com/read/28855157/h3-k27m-i-mutations-promote-context-dependent-transformation-in-acute-myeloid-leukemia-with-runx1-alterations
#6
Bernhard Lehnertz, Yu Wei Zhang, Isabel Boivin, Nadine Mayotte, Elisa Tomellini, Jalila Chagraoui, Vincent-Philippe Lavallée, Josée Hébert, Guy Sauvageau
Neomorphic missense mutations affecting crucial lysine residues in histone H3 genes significantly contribute to a variety of solid cancers. Despite the high prevalence of H3(K27M) mutations in pediatric glioblastoma and their well-established impact on global histone H3 lysine 27 di and trimethylation (H3K27me2/3), the relevance of these mutations has not been studied in acute myeloid leukemia (AML). Here, we report the first identification of H3(K27M) and H3(K27I) mutations in AML patients. We find that these lesions are major determinants of reduced H3K27me2/3 in these patients and that they associate with common aberrations in the RUNX1 gene...
August 30, 2017: Blood
https://www.readbyqxmd.com/read/28852847/distinct-molecular-profile-of-diffuse-cerebellar-gliomas
#7
Masashi Nomura, Akitake Mukasa, Genta Nagae, Shogo Yamamoto, Kenji Tatsuno, Hiroki Ueda, Shiro Fukuda, Takayoshi Umeda, Tomonari Suzuki, Ryohei Otani, Keiichi Kobayashi, Takashi Maruyama, Shota Tanaka, Shunsaku Takayanagi, Takahide Nejo, Satoshi Takahashi, Koichi Ichimura, Taishi Nakamura, Yoshihiro Muragaki, Yoshitaka Narita, Motoo Nagane, Keisuke Ueki, Ryo Nishikawa, Junji Shibahara, Hiroyuki Aburatani, Nobuhito Saito
Recent studies have demonstrated that tumor-driving alterations are often different among gliomas that originated from different brain regions and have underscored the importance of analyzing molecular characteristics of gliomas stratified by brain region. Therefore, to elucidate molecular characteristics of diffuse cerebellar gliomas (DCGs), 27 adult, mostly glioblastoma cases were analyzed. Comprehensive analysis using whole-exome sequencing, RNA sequencing, and Infinium methylation array (n = 17) demonstrated their distinct molecular profile compared to gliomas in other brain regions...
August 29, 2017: Acta Neuropathologica
https://www.readbyqxmd.com/read/28811969/k27m-mutant-histone-3-as-a-novel-target-for-glioma-immunotherapy
#8
Katharina Ochs, Martina Ott, Theresa Bunse, Felix Sahm, Lukas Bunse, Katrin Deumelandt, Jana K Sonner, Melanie Keil, Andreas von Deimling, Wolfgang Wick, Michael Platten
Mutation-specific vaccines have become increasingly important in glioma immunotherapy; however, shared neoepitopes are rare. For diffuse gliomas, a driver mutation in the gene for isocitrate dehydrogenase type-1 has been shown to produce an immunogenic epitope currently targeted in clinical trials. For highly aggressive midline gliomas, a recurrent point mutation in the histone-3 gene (H3F3A) causes an amino acid change from lysine to methionine at position 27 (K27M). Here, we demonstrate that a peptide vaccine against K27M-mutant histone-3 is capable of inducing effective, mutation-specific, cytotoxic T-cell- and T-helper-1-cell-mediated immune responses in a major histocompatibility complex (MHC)-humanized mouse model...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28718400/histone-h3g34r-mutation-causes-replication-stress-homologous-recombination-defects-and-genomic-instability-in-s-pombe
#9
Rajesh K Yadav, Carolyn M Jablonowski, Alfonso G Fernandez, Brandon R Lowe, Ryan A Henry, David Finkelstein, Kevin J Barnum, Alison L Pidoux, Yin-Ming Kuo, Jie Huang, Matthew J O'Connell, Andrew J Andrews, Arzu Onar-Thomas, Robin C Allshire, Janet F Partridge
Recurrent somatic mutations of H3F3A in aggressive pediatric high-grade gliomas generate K27M or G34R/V mutant histone H3.3. H3.3-G34R/V mutants are common in tumors with mutations in p53 and ATRX, an H3.3-specific chromatin remodeler. To gain insight into the role of H3-G34R, we generated fission yeast that express only the mutant histone H3. H3-G34R specifically reduces H3K36 tri-methylation and H3K36 acetylation, and mutants show partial transcriptional overlap with set2 deletions. H3-G34R mutants exhibit genomic instability and increased replication stress, including slowed replication fork restart, although DNA replication checkpoints are functional...
July 18, 2017: ELife
https://www.readbyqxmd.com/read/28681244/survival-rates-and-prognostic-predictors-of-high-grade-brain-stem-gliomas-in-childhood-a-systematic-review-and-meta-analysis
#10
REVIEW
Hadeel Hassan, Anne Pinches, Susan V Picton, Robert S Phillips
Diagnosis of a pediatric high grade brain stem glioma is devastating with dismal outcomes. This systematic review and meta-analysis was undertaken to determine the survival rates and assess potential prognostic factors including selected interventions. Studies included involved pediatric participants with high grade brain stem gliomas diagnosed by magnetic resonance imaging or biopsy reporting overall survival rates. Meta-analysis was undertaken using a binomial random effects model. Sixty-five studies (2336 participants) were included...
July 5, 2017: Journal of Neuro-oncology
https://www.readbyqxmd.com/read/28674742/characterization-of-gliomas-from-morphology-to-molecules
#11
Sean P Ferris, Jeffrey W Hofmann, David A Solomon, Arie Perry
This article reviews the histologic and molecular characterization of gliomas, including the new "integrated diagnoses" of the World Health Organization Classification, 2016 edition. The entities reviewed within include diffuse gliomas (astrocytoma, oligodendroglioma, glioblastoma), as well as circumscribed and low-grade gliomas (angiocentric glioma, pilocytic astrocytoma, subependymal giant cell astrocytoma, pleomorphic xanthoastrocytoma, pilomyxoid astrocytoma, ependymoma, myxopapillary ependymoma, and subependymoma)...
July 4, 2017: Virchows Archiv: An International Journal of Pathology
https://www.readbyqxmd.com/read/28623522/h3-k27m-mutations-are-extremely-rare-in-posterior-fossa-group-a-ependymoma
#12
Scott Ryall, Miguel Guzman, Samer K Elbabaa, Betty Luu, Stephen C Mack, Michal Zapotocky, Michael D Taylor, Cynthia Hawkins, Vijay Ramaswamy
BACKGROUND: Mutations in the tail of histone H3 (K27M) are frequently found in pediatric midline high-grade glioma's but have rarely been reported in other malignancies. Recently, recurrent somatic nucleotide variants in histone H3 (H3 K27M) have been reported in group A posterior fossa ependymoma (EPN_PFA), an entity previously described to have no recurrent mutations. However, the true incidence of H3 K27M mutations in EPN_PFA is unknown. METHODS: In order to discern the frequency of K27M mutations in histone H3 in EPN_PFA, we analyzed 151 EPN_PFA previously profiled with genome-wide methylation arrays using a validated droplet digital PCR assay...
July 2017: Child's Nervous System: ChNS: Official Journal of the International Society for Pediatric Neurosurgery
https://www.readbyqxmd.com/read/28592714/the-2016-who-classification-of-tumours-of-the-central-nervous-system-the-major-points-of-revision
#13
Takashi Komori
The updated 2016 edition of the World Health Organization (WHO) Classification of Tumours of the Central Nervous System (CNS) uses molecular parameters and the histology to define the main tumor categories for the first time. This represents a shift from the traditional principle of using neuropathological diagnoses, which are primarily based on the microscopic features, to using molecularly-oriented diagnoses. Major restructuring was made with regard to diffuse gliomas, medulloblastomas and other embryonal tumors...
July 15, 2017: Neurologia Medico-chirurgica
https://www.readbyqxmd.com/read/28587626/evaluation-of-a-novel-antibody-to-define-histone-3-3-g34r-mutant-brain-tumours
#14
Farhana Haque, Pascale Varlet, Julien Puntonet, Lisa Storer, Aikaterini Bountali, Ruman Rahman, Jacques Grill, Angel M Carcaboso, Chris Jones, Robert Layfield, Richard G Grundy
Missense somatic mutations affecting histone H3.1 and H3.3 proteins are now accepted as the hallmark of paediatric diffuse intrinsic pontine gliomas (DIPG), non-brain stem paediatric high grade gliomas (pHGG) as well as a subset of adult glioblastoma multiforme (GBM). Different mutations give rise to one of three amino acid substitutions at two critical positions within the histone tails, K27M, G34R/V. Several studies have highlighted gene expression and epigenetic changes associated with histone H3 mutations; however their precise roles in tumourigenesis remain incompletely understood...
June 6, 2017: Acta Neuropathologica Communications
https://www.readbyqxmd.com/read/28562358/a-phase-2-study-of-the-first-imipridone-onc201-a-selective-drd2-antagonist-for-oncology-administered-every-three-weeks-in-recurrent-glioblastoma
#15
Isabel Arrillaga-Romany, Andrew S Chi, Joshua E Allen, Wolfgang Oster, Patrick Y Wen, Tracy T Batchelor
ONC201 is an oral, small molecule selective antagonist of the G protein-coupled receptor DRD2 that causes p53-independent apoptosis in tumor cells via integrated stress response activation and Akt/ERK inactivation. We performed a Phase II study that enrolled 17 patients with recurrent, bevacizumab-naïve, IDH1/2 WT glioblastoma who received 625mg ONC201 every three weeks. Median OS was 41.6 weeks with OS6 of 71% and OS9 of 53%. Seven of 17 patients are alive. PFS6 was 11.8% with two patients remaining on study who continue to receive ONC201 for >12 months...
May 12, 2017: Oncotarget
https://www.readbyqxmd.com/read/28547652/histone-h3-k27m-mutations-in-adult-cerebellar-high-grade-gliomas
#16
Satoshi Nakata, Sumihito Nobusawa, Tatsuya Yamazaki, Tadashi Osawa, Keishi Horiguchi, Yasuhiro Hashiba, Hiroyuki Yaoita, Nozomi Matsumura, Hayato Ikota, Junko Hirato, Yuhei Yoshimoto, Hideaki Yokoo
Adult cerebellar high-grade gliomas (HGG) are rare and their molecular basis has not been fully elucidated. Although a diffuse midline glioma H3 K27M-mutant, a recently characterized variant of HGG, was reported to occasionally occur in the cerebellum, adult cases were rarely tested for this mutation; only five mutant cases have been reported to date. It currently remains unknown whether H3 K27M-mutant cerebellar gliomas share common histological features or have a uniformly dismal prognosis. In the present study, we assessed the prevalence of histone H3 K27M mutations in ten adult cerebellar HGG, identifying two H3F3A-mutant cases...
July 2017: Brain Tumor Pathology
https://www.readbyqxmd.com/read/28522693/histone-h3-3k27m-represses-p16-to-accelerate-gliomagenesis-in-a-murine-model-of-dipg
#17
Francisco J Cordero, Zhiqing Huang, Carole Grenier, Xingyao He, Guo Hu, Roger E McLendon, Susan K Murphy, Rintaro Hashizume, Oren J Becher
Diffuse intrinsic pontine glioma (DIPG) is a highly aggressive pediatric brainstem tumor genetically distinguished from adult GBM by the high prevalence of the K27M mutation in the histone H3 variant H3.3 (H3F3A). This mutation reprograms the H3K27me3 epigenetic landscape of DIPG by inhibiting the H3K27-specific histone methyltransferase EZH2. This globally reduces H3K27me2/3, critical repressive marks responsible for cell fate decisions, and also causes focal gain of H3K27me3 throughout the epigenome. To date, the tumor-driving effects of H3...
September 2017: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/28484590/histone-3-3-hotspot-mutations-in-conventional-osteosarcomas-a-comprehensive-clinical-and-molecular-characterization-of-six-h3f3a-mutated-cases
#18
Christian Koelsche, Daniel Schrimpf, Lars Tharun, Eva Roth, Dominik Sturm, David T W Jones, Eva-Kristin Renker, Martin Sill, Annika Baude, Felix Sahm, David Capper, Melanie Bewerunge-Hudler, Wolfgang Hartmann, Andreas E Kulozik, Iver Petersen, Uta Flucke, Hendrik W B Schreuder, Reinhard Büttner, Marc-André Weber, Peter Schirmacher, Christoph Plass, Stefan M Pfister, Andreas von Deimling, Gunhild Mechtersheimer
BACKGROUND: Histone 3.3 (H3.3) hotspot mutations in bone tumors occur in the vast majority of giant cell tumors of bone (GCTBs; 96%), chondroblastomas (95%) and in a few cases of osteosarcomas. However, clinical presentation, histopathological features, and additional molecular characteristics of H3.3 mutant osteosarcomas are largely unknown. METHODS: In this multicentre, retrospective study, a total of 106 conventional high-grade osteosarcomas, across all age groups were re-examined for hotspot mutations in the H3...
2017: Clinical Sarcoma Research
https://www.readbyqxmd.com/read/28447171/prevalence-and-clinicopathological-features-of-h3-3-g34-mutant-high-grade-gliomas-a-retrospective-study-of-411-consecutive-glioma-cases-in-a-single-institution
#19
Koji Yoshimoto, Ryusuke Hatae, Yuhei Sangatsuda, Satoshi O Suzuki, Nobuhiro Hata, Yojiro Akagi, Daisuke Kuga, Murata Hideki, Koji Yamashita, Osamu Togao, Akio Hiwatashi, Toru Iwaki, Masahiro Mizoguchi, Koji Iihara
A recurrent glycine-to-arginine/valine alteration at codon 34 (G34R/V) within H3F3A, a gene that encodes the replication-independent histone variant H3.3, reportedly occurs exclusively in pediatric glioblastomas. However, the clinicopathological and biological significances of this mutation have not been completely elucidated; especially, no such data exist for tumor samples from Japanese patients. We analyzed 411 consecutive glioma cases representing patients of all ages. Our results demonstrated that 14 patients (3...
July 2017: Brain Tumor Pathology
https://www.readbyqxmd.com/read/28416018/detection-of-histone-h3-mutations-in-cerebrospinal-fluid-derived-tumor-dna-from-children-with-diffuse-midline-glioma
#20
Tina Y Huang, Andrea Piunti, Rishi R Lulla, Jin Qi, Craig M Horbinski, Tadanori Tomita, C David James, Ali Shilatifard, Amanda M Saratsis
Diffuse midline gliomas (including diffuse intrinsic pontine glioma, DIPG) are highly morbid glial neoplasms of the thalamus or brainstem that typically arise in young children and are not surgically resectable. These tumors are characterized by a high rate of histone H3 mutation, resulting in replacement of lysine 27 with methionine (K27M) in genes encoding H3 variants H3.3 (H3F3A) and H3.1 (HIST1H3B). Detection of these gain-of-function mutations has clinical utility, as they are associated with distinct tumor biology and clinical outcomes...
April 17, 2017: Acta Neuropathologica Communications
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