共查询到20条相似文献,搜索用时 31 毫秒
1.
Sriram Venneti Mariarita Santi Michelle Madden Felicella Dmitry Yarilin Joanna J. Phillips Lisa M. Sullivan Daniel Martinez Arie Perry Peter W. Lewis Craig B. Thompson Alexander R. Judkins 《Acta neuropathologica》2014,128(5):743-753
Pediatric glioblastomas (GBM) are highly aggressive and lethal tumors. Recent sequencing studies have shown that ~30 % of pediatric GBM and ~80 % of diffuse intrinsic pontine gliomas show K27M mutations in the H3F3A gene, a variant encoding histone H3.3. H3F3A K27M mutations lead to global reduction in H3K27me3. Our goal was to develop biomarkers for the histopathologic detection of these tumors. Therefore, we evaluated the utility of measuring H3K27me3 global reduction as a histopathologic and prognostic biomarker and tested an antibody directed specifically against the H3.3 K27M mutation in 290 samples. The study cohort included 203 pediatric (including 38 pediatric high-grade astrocytomas) and 38 adult brain tumors of various subtypes and grades and 49 non-neoplastic reactive brain tissues. Detection of H3.3 K27M by immunohistochemistry showed 100 % sensitivity and specificity and was superior to global reduction in H3K27me3 as a biomarker in diagnosing H3F3A K27M mutations. Moreover, cases that stained positive for H3.3 K27M showed a significantly poor prognosis compared to corresponding negative tumors. These results suggest that immunohistochemical detection of H3.3 K27M is a sensitive and specific surrogate for the H3F3A K27M mutation and defines a prognostically poor subset of pediatric GBM. 相似文献
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Tomohiro Okuda Nobuhiro Hata Satoshi O Suzuki Koji Yoshimoto Koichi Arimura Takeo Amemiya Yojiro Akagi Daisuke Kuga Utako Oba Yuhki Koga Shouichi Ohga Toru Iwaki Koji Iihara 《Neuropathology》2018,38(4):422-427
The 2016 edition of the World Health Organization Classification of Tumors of the Central Nervous System introduced “diffuse midline glioma H3 K27M mutant” as a new diagnostic entity. These tumors predominately affect pediatric patients and arise from midline structures such as the brainstem, thalamus and spinal cord. Here, we report a rare patient with spinal ganglioglioma carrying an H3 K27M mutation. A 10‐year‐old boy presented with an intramedullary tumor in the cervical spinal cord. The lesion was partially removed and histologically diagnosed as ganglioglioma. After the remnant tumor grew within 3 months after surgery, the patient underwent radiotherapy. Genetic analyses revealed an H3F3A K27M mutation but no other genetic alterations such as IDH and BRAF mutations. This case may point to pathological heterogeneity in gliomas with H3 K27M mutations. 相似文献
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A methionine substitution of lysine at residue 27 of histone H3 (H3K27M) mutation has become synonymous with malignant pediatric diffuse midline glioma (DMG), that occurs commonly in the brainstem. Therefore, recent reports that this same mutation occurs in malignant adult glioblastoma (GBM) located in the cerebellum are both unexpected and intriguing. The biological and clinical considerations of this novel finding are discussed. 相似文献
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Yutaka Fujioka Nobuhiro Hata Ryusuke Hatae Satoshi O. Suzuki Yuhei Sangatsuda Yukiko Nakahara Masahiro Mizoguchi Koji Iihara 《Neuropathology》2020,40(1):99-103
Diffuse midline glioma, H3 K27M mutant arises from midline structures of the central nervous system and predominately affects pediatric patients. However, this disease entity was only recently established, and the clinical phenotypic spectrum remains largely unclear. We herein report a rare case of diffuse midline glioma, H3 K27M mutant with an unusual distribution in an elderly woman who presented with a diffuse glioma that invaded both sides of the thalami, and left hippocampus and frontoparietal lobes, thus mimicking a hemispheric malignant glioma. A biopsy of the lobular lesion led to a molecular diagnostic confirmation of diffuse midline glioma, H3 K27M mutant. The patient received concurrent bevacizumab and temozolomide therapy with radiation therapy and survived for 30 months. This case highlights the possibility that a glioma with cerebral hemispheric spread in an elderly patient may harbor the H3 K27M mutation. 相似文献
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H3K27M and H3.3G34R/V mutations have been identified in pediatric high-grade gliomas (pHGG), though extraneural metastases are rarely reported and poorly characterized. Three pHGG patients from two institutions were identified with extraneural metastasis, harboring histone mutations. Their clinical, imaging and molecular characteristics are reported here. A 17-year old female presented with supratentorial H3.3G34R-mutant glioma with metastatic osseous lesions in the spine, pelvis, bone marrow, pleural effusion and soft tissue of pelvis. Bone marrow biopsy and soft tissue of pelvis biopsy showed neoplastic cells positive for P53. A 20-year old female was diagnosed with H3F3A H3K27M–mutant thalamic glioma. She developed diffuse sclerotic osseous lesions. Biopsy of an osseous lesion was non-diagnostic. A 17-year old female presented with a H3F3A H3K27M-mutant diffuse midline glioma with diffuse spinal cord metastasis. She further developed multifocal chest lymphadenopathy, pleural effusions, and a soft tissue mass in the abdominal wall. The latter was positive for H3K27M mutation. We present the first case series of pHGG with H3F3A mutation and diffuse extraneural dissemination, describing their clinical and molecular profile. 相似文献
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Khuong-Quang DA Buczkowicz P Rakopoulos P Liu XY Fontebasso AM Bouffet E Bartels U Albrecht S Schwartzentruber J Letourneau L Bourgey M Bourque G Montpetit A Bourret G Lepage P Fleming A Lichter P Kool M von Deimling A Sturm D Korshunov A Faury D Jones DT Majewski J Pfister SM Jabado N Hawkins C 《Acta neuropathologica》2012,124(3):439-447
Pediatric glioblastomas (GBM) including diffuse intrinsic pontine gliomas (DIPG) are devastating brain tumors with no effective therapy. Here, we investigated clinical and biological impacts of histone H3.3 mutations. Forty-two DIPGs were tested for H3.3 mutations. Wild-type versus mutated (K27M-H3.3) subgroups were compared for HIST1H3B, IDH, ATRX and TP53 mutations, copy number alterations and clinical outcome. K27M-H3.3 occurred in 71 %, TP53 mutations in 77 % and ATRX mutations in 9 % of DIPGs. ATRX mutations were more frequent in older children (p < 0.0001). No G34V/R-H3.3, IDH1/2 or H3.1 mutations were identified. K27M-H3.3 DIPGs showed specific copy number changes, including all gains/amplifications of PDGFRA and MYC/PVT1 loci. Notably, all long-term survivors were H3.3 wild type and this group of patients had better overall survival. K27M-H3.3 mutation defines clinically and biologically distinct subgroups and is prevalent in DIPG, which will impact future therapeutic trial design. K27M- and G34V-H3.3 have location-based incidence (brainstem/cortex) and potentially play distinct roles in pediatric GBM pathogenesis. K27M-H3.3 is universally associated with short survival in DIPG, while patients wild-type for H3.3 show improved survival. Based on prognostic and therapeutic implications, our findings argue for H3.3-mutation testing at diagnosis, which should be rapidly integrated into the clinical decision-making algorithm, particularly in atypical DIPG. 相似文献
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Adrian M. Dubuc Marc Remke Andrey Korshunov Paul A. Northcott Shing H. Zhan Maria Mendez-Lago Marcel Kool David T. W. Jones Alexander Unterberger A. Sorana Morrissy David Shih John Peacock Vijay Ramaswamy Adi Rolider Xin Wang Hendrik Witt Thomas Hielscher Cynthia Hawkins Rajeev Vibhakar Sidney Croul James T. Rutka William A. Weiss Steven J. M. Jones Charles G. Eberhart Marco A. Marra Stefan M. Pfister Michael D. Taylor 《Acta neuropathologica》2013,125(3):373-384
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This study aimed to investigate the impact of TP53 alteration on survival and clinicopathological features of glioma patients with H3K27M mutations. An individual-participant-data (IPD) meta-analysis was performed to investigate the impact of TP53 alteration on survival and clinicopathological features of patients with H3K27M mutations. Three hundred thirty-one individual records from 12 eligible glioma studies involving the H3K27M mutation were finally included in our meta-analysis, and a pooled hazard ratio (HR) of 1.53 (95%CI, 1.10–2.11; P?=?0.01) indicated that TP53 alterations were associated with a shorter overall survival. The pooled odds ratios (ORs) indicated that TP53 alterations were significantly associated with the age at diagnosis ≥?7 years (OR?=?1.97, 95%CI?=?1.15–3.38, P =?0.01), the status of histone H3.3 mutations (OR?=?9.15, 95%CI?=?4.18–20.06, P < 0.00001), and high WHO grade histology (III?+?IV) (OR?=?2.70, 95%CI?=?1.33–5.48, P?=?0.006). However, no association was found between TP53 alterations and gender or tumor location. This IPD meta-analysis suggests that TP53 alteration is a valuable predictor for the prognosis of patients with H3K27M mutated gliomas. TP53 alteration may be used for identifying a subset of patients who potentially benefit from targeted reactivation of TP53 activity. 相似文献
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Chao Liu Shuwen Kuang Lei Wu Quan Cheng Xuan Gong Jun Wu Longbo Zhang 《CNS Neuroscience & Therapeutics》2023,29(7):1721-1737
Background
H3K27M mutated diffuse midline gliomas (DMGs) are extremely aggressive and the leading cause of cancer-related deaths in pediatric brain tumors with 5-year survival <1%. Radiotherapy is the only established adjuvant treatment of H3K27M DMGs; however, the radio-resistance is commonly observed.Methods
We summarized current understandings of the molecular responses of H3K27M DMGs to radiotherapy and provide crucial insights into current advances in radiosensitivity enhancement.Results
Ionizing radiation (IR) can mainly inhibit tumor cell growth by inducing DNA damage regulated by the cell cycle checkpoints and DNA damage repair (DDR) system. In H3K27M DMGs, the aberrant genetic and epigenetic changes, stemness genotype, and epithelial-mesenchymal transition (EMT) disrupt the cell cycle checkpoints and DDR system by altering the associated regulatory signaling pathways, which leads to the development of radio-resistance.Conclusions
The advances in mechanisms of radio-resistance in H3K27M DMGs promote the potential targets to enhance the sensitivity to radiotherapy. 相似文献12.
Adam M. Fontebasso Jeremy Schwartzentruber Dong-Anh Khuong-Quang Xiao-Yang Liu Dominik Sturm Andrey Korshunov David T. W. Jones Hendrik Witt Marcel Kool Steffen Albrecht Adam Fleming Djihad Hadjadj Stephan Busche Pierre Lepage Alexandre Montpetit Alfredo Staffa Noha Gerges Magdalena Zakrzewska Krzystof Zakrzewski Pawel P. Liberski Peter Hauser Miklos Garami Almos Klekner Laszlo Bognar Gelareh Zadeh Damien Faury Stefan M. Pfister Nada Jabado Jacek Majewski 《Acta neuropathologica》2013,125(5):659-669
Recurrent mutations affecting the histone H3.3 residues Lys27 or indirectly Lys36 are frequent drivers of pediatric high-grade gliomas (over 30 % of HGGs). To identify additional driver mutations in HGGs, we investigated a cohort of 60 pediatric HGGs using whole-exome sequencing (WES) and compared them to 543 exomes from non-cancer control samples. We identified mutations in SETD2, a H3K36 trimethyltransferase, in 15 % of pediatric HGGs, a result that was genome-wide significant (FDR = 0.029). Most SETD2 alterations were truncating mutations. Sequencing the gene in this cohort and another validation cohort (123 gliomas from all ages and grades) showed SETD2 mutations to be specific to high-grade tumors affecting 15 % of pediatric HGGs (11/73) and 8 % of adult HGGs (5/65) while no SETD2 mutations were identified in low-grade diffuse gliomas (0/45). Furthermore, SETD2 mutations were mutually exclusive with H3F3A mutations in HGGs (P = 0.0492) while they partly overlapped with IDH1 mutations (4/14), and SETD2-mutant tumors were found exclusively in the cerebral hemispheres (P = 0.0055). SETD2 is the only H3K36 trimethyltransferase in humans, and SETD2-mutant tumors showed a substantial decrease in H3K36me3 levels (P < 0.001), indicating that the mutations are loss-of-function. These data suggest that loss-of-function SETD2 mutations occur in older children and young adults and are specific to HGG of the cerebral cortex, similar to the H3.3 G34R/V and IDH mutations. Taken together, our results suggest that mutations disrupting the histone code at H3K36, including H3.3 G34R/V, IDH1 and/or SETD2 mutations, are central to the genesis of hemispheric HGGs in older children and young adults. 相似文献
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目的探讨伴H3 K27M突变的儿童弥漫性中线胶质瘤(DMG)的临床特点、治疗及预后。方法回顾性分析2017年7月至2020年3月首都医科大学附属北京儿童医院神经外科收治的10例DM G伴H3 K27M突变患儿的临床资料。10例患儿中,病变位于丘脑4例,脑干4例,脊髓2例,其中行开颅肿瘤切除术7例,脊髓肿瘤切除术2例,颅内病变活组织检查术1例4例术后行放疗联合化疗,1例行单纯放疗,5例未行放疗或化疗以肿瘤切除率>90%为近全切除,50%~90%为部分切除。术后随访至2020年7月或患儿死亡,随访患儿肿瘤有无进展、生存时间以及死亡原因。结果10例患儿的中位发病年龄为8.9(4.9~9.9)岁,颅内占位临床表现为头痛、恶心、呕吐、肢体无力、癫痫发作、意识障碍及脑神经麻痹;脊髓占位临床表现为进行性肢体无力。肿瘤近全切除4例,部分切除5例,活组织检查术1例。患儿术后症状改善6例,无改变4例;无一例出现中枢神经系统感染;1例在术后放疗期间出现脑积水10例患儿的肿瘤病理学结果均为DMG伴H3 K27M突变(世界卫生组织肿瘤分级Ⅳ级);免疫组织化学检测结果显示,少突胶质细胞转录因子2阳性比例为9/9,胶质纤维酸性蛋白阳性比例为10/10,突变型异柠檬酸脱氢酶1阳性比例为0/9,Ki-67≥40%的比例为8/10。10例患儿术后均得到有效随访;随访时间为1~23个月至末次随访,2例患儿存活,8例患儿因肿瘤进展死亡,生存时间为1~23个月结论初步观察发现,伴H3 K27M突变的儿童DMG临床表现多样,可选择手术、术后放疗和(或)化疗治疗,患儿的生存预后差。 相似文献
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IntroductionThe differential diagnoses for multifocal lesions with pineal and suprasellar involvement in a young adult include germ cell tumour and intracranial metastasis. Other differentials include atypical teratoid/rhabdoid tumour and pineoblastoma. We present the first known case of multicentric H3K27M mutant diffuse midline glioma, which is typically defined by its diffuse nature, midline location, and H3K27M mutation.Case reportA young Chinese female presented subacutely with giddiness, right abducens nerve palsy and unsteady gait. Magnetic resonance imaging (MRI) of the brain with contrast revealed a moderately sized pineal region tumour, extending into the third ventricle, associated with hydrocephalus. There were two other synchronous lesions noted in the suprasellar and left occipital region. Serum and cerebrospinal fluid tumour markers, along with a computed tomography scan of her thorax and abdomen and were unremarkable. She underwent an endoscopic third ventriculostomy and biopsy of pineal and suprasellar lesions. Histology demonstrated a poor prognosis variant multifocal glioblastoma multiforme that was IDH wildtype, H3K27M positive, and MGMT unmethylated. MRI of the whole spine did not reveal any drop metastasis. The patient subsequently underwent adjuvant chemotherapy and radiotherapy after she was deemed to be unsuitable for surgical resection.ConclusionAlthough rare, multicentric H3K27M mutant diffuse midline glioma should be included in the list of differential diagnoses for multifocal enhancing lesions with involvement of the pineal and suprasellar regions, especially if the lesions demonstrate imaging features atypical for more common diagnosis such as germ cell tumours. 相似文献
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Prerana Jha Niveditha Manjunath Jyotsna Singh Kalaivani Mani Ajay Garg Kavneet Kaur Mehar C. Sharma Amol Raheja Ashish Suri Chitra Sarkar Vaishali Suri 《Neuropathology》2019,39(6):413-424
Diffuse midline gliomas (DMGs) are rare and devastating tumors with limited therapeutic options. Programmed death‐ligand 1 (PD‐L1) expression represents a potential predictive biomarker for immunotherapy. One hundred and twenty‐six DMGs (89 adult and 37 pediatric) were assessed for immune profile (PD‐L1, cluster of differentiation (CD3, CD8) and genetic markers (mutation in 27th amino acid of histone H3 (H3K27M), alpha thalassemia/mental retardation syndrome X‐linked (ATRX), isocitrate dehydrogenase 1 (IDH1), p53) by immunohistochemistry. Sanger sequencing was done for IDH1 and H3K27M. The thalamus was the commonest site. Four molecular subgroups of DMGs were identified. H3K27M mutation was more frequent in children (P = 0.0001). The difference in median overall survival (OS) was not significant in any of the four molecular subgroups (P > 0.05). PD‐L1 expression was significantly higher in H3K27M/IDH1 double‐negative adult glioblastomas (GBMs) (P = 0.002). Strong PD‐L1 expression was more frequent in grade IV tumors and thalamic location, although the difference was not significant (P = 0.14 and P = 0.19 respectively). Positive PD‐L1 expression was significantly associated with high tumor‐infiltrating lymphocytes count (P < 0.05). There was no significant difference in median OS in PD‐L1‐positive versus negative cases among four genetic subgroups (P > 0.05). On univariate analysis, there was no direct correlation of PD‐L1 with any genetic alteration, except H3K27M mutation (P = 0.01). CD3 infiltration was similar in both adults and pediatric ages (84.3% and 78.4%, respectively) while CD8 expression was significantly greater in adults compared to children (74.1% vs 37.8%, P = 0.0001). This is the first comprehensive analysis highlighting molecular and immune profiles of DMGs. Despite molecular and clinicopathological diversity, overall survival in DMGs remains dismal. Multicentric studies with larger numbers of cases should be undertaken for stratifying DMGs according to their age, immune and molecular profiles, to develop effective immunotherapies. 相似文献
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Kyu-Won Shim Guifa Xi Barbara-Mania Farnell Dong-Seok Kim Takao Tsurubuchi Tadanori Tomita C. Shekhar Mayanil 《Child's nervous system》2013,29(8):1245-1251
Objective
This study investigated epigenetic modifications in human central nervous system atypical teratoid rhabdoid tumors (AT/RTs), in response to inhibition of insulin-like growth factor receptor 1 (IGF-1R).Materials and methods
Tumor tissue was obtained from two pediatric patients, tissue was dissociated, and primary cultures were established. Cultured cells were treated with picropodophyllin (PPP; 0, 1, and 2 μM for 48 h), a selective IGF-1R inhibitor. Histone acetylation and methylation patterns (H3K9ac, H3K18ac, H3K4me3, H3K27me3) and levels of histone deacetylases (HDACs; HDAC1, HDAC3, and SirT1) and histone acetyl transferases (GCN5 and p300) were examined. H3K9ac and H3K18ac decreased in response to treatment with PPP. HDAC levels showed a biphasic response, increasing with 1 μM PPP, but then decreasing with 2 μM PPP.Conclusion
Inhibition of IGF-1R modified epigenetic status in AT/RT. Determining the mechanisms behind these modifications will guide the development of novel therapeutic targets for this malignant embryonal cancer. 相似文献19.
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《Neurocirugía (Asturias, Spain)》2022,33(6):356-360
The WHO classification of tumors of the CNS in 2016 defined “diffuse midline glioma, H3 K27M-mutant” as a new tumor entity locating in the CNS midline. However, the H3 K27M-mutation in “non-midline” glioblastoma are rare and their characteristics have been rarely reported. A 16-year-old girl presented a hyper-intense lesion at her left temporal stem on T2WI, FLAIR and DWI. Biopsy was performed and molecular pathological diagnosis was glioblastoma with H3 K27M-mutant. Accordingly, the possibility of H3 K27M-mutant should be examined not only for diffuse glioma without IDH mutation that develops at a midline location, but also in non-midline locations. 相似文献