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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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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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Christian Koelsche Felix Sahm David Capper David Reuss Dominik Sturm David T. W. Jones Marcel Kool Paul A. Northcott Benedikt Wiestler Katja Böhmer Jochen Meyer Christian Mawrin Christian Hartmann Michel Mittelbronn Michael Platten Benjamin Brokinkel Marcel Seiz Christel Herold-Mende Andreas Unterberg Jens Schittenhelm Michael Weller Stefan Pfister Wolfgang Wick Andrey Korshunov Andreas von Deimling 《Acta neuropathologica》2013,126(6):907-915
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Immunohistochemical profiles of IDH1, MGMT and P53: Practical significance for prognostication of patients with diffuse gliomas
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Ryosuke Ogura Yoshihiro Tsukamoto Manabu Natsumeda Mizuho Isogawa Hiroshi Aoki Tsutomu Kobayashi Seiichi Yoshida Kouichiro Okamoto Hitoshi Takahashi Yukihiko Fujii Akiyoshi Kakita 《Neuropathology》2015,35(4):324-335
Genetic and epigenetic status, including mutations of isocitrate dehydrogenase (IDH) and TP53 and methylation of O6‐methylguanine‐DNA methyltransferase (MGMT), are associated with the development of various types of glioma and are useful for prognostication. Here, using routinely available histology sections from 312 patients with diffuse gliomas, we performed immunohistochemistry using antibodies specific for IDH1 mutation, MGMT methylation status, and aberrant p53 expression to evaluate the possible prognostic significance of these features. With regard to overall survival (OS), univariate analysis indicated that an IDH1‐positive profile in patients with glioblastoma (GBM), anaplastic astrocytoma (AA), anaplastic oligoastrocytoma and oligodendroglioma, or a MGMT‐negative profile in patients with GBM and AA were significantly associated with a favorable outcome. Multivariate analysis revealed that both profiles were independent factors influencing prognosis. The OS of patients with IDH1‐positive/MGMT‐negative profiles was significantly longer than that of patients with negative/negative and negative/positive profiles. A p53 profile was not an independent prognostic factor. However, for GBM/AA patients with IDH1‐negative/MGMT‐negative profiles, p53 overexpression was significantly associated with an unfavorable outcome. Thus, the immunohistochemical profiles of IDH1 and MGMT are of considerable significance in gliomas, and a combination of IDH1, MGMT and p53 profiles may be useful for prognostication of GBM/AA. 相似文献
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ObjectiveThis study aimed to assess the prevalence of developmental venous anomaly (DVA) in patients with thalamic glioma. Furthermore, we explored the association between DVA and some important biomarkers, such as IDH1 mutation, and H3K27M mutation.Patients and MethodsPatients who received tumor resection in West China Hospital between August 2009 and October 2017 were enrolled. Propensity score matching was conducted based on a logistic regression model and 1:1 matching for case and control was used to generate a new cohort from patients with meningioma. Chi-square test, t-test, univariate and multivariate analyses were employed to assess the prevalence of DVA in thalamic glioma and meningioma and to identify risk factors associated with DVA.ResultsNinety-nine patients with thalamic glioma were enrolled in the current study (male, n = 54; female, n = 45). The mean age was 42.9 ± 15.3 years old. We identified a higher prevalence of DVA in 99 patients with thalamic glioma when compared with 99 patients with meningioma (18.18% vs. 7.07%), which was slightly lower than the prevalence of DVA in glioma reported in previous studies. Furthermore, the distribution of gender, age, and tumor grade in DVA did not reach statistical significance. Chi-square test, univariate and multivariate analyses showed that IDH1 mutation, ATRX mutation, MGMT promoter methylation, p53 mutation, MMP9, EGFR, and Top II positive expression, TERT mutation, and H3K27M mutation were not associated with the development of DVA in thalamic glioma.ConclusionA higher prevalence of DVA was found in thalamic glioma compared with meningioma. 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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Nobuhiro Hata Ryusuke Hatae Koji Yoshimoto Hideki Murata Daisuke Kuga Yojiro Akagi Yuhei Sangatsuda Satoshi O. Suzuki Toru Iwaki Masahiro Mizoguchi Koji Iihara 《Neuropathology》2017,37(3):200-206
Isocitrate dehydrogenase (IDH) mutation is a good prognostic marker for glioblastoma (GBM). Although it is infrequent in primary tumors, it is found in most lower‐grade gliomas. Thus, it is unclear whether IDH mutation is a marker for a specific phenotype of apparently primary de novo GBMs (pGBMs), or a marker for secondary tumors (sGBMs). We addressed this issue by analyzing clinical, radiographic and molecular findings in our institutional case series. Our cases included 92 pGBMs, with five cases of IDH1 mutations at R132 and no IDH2 mutations. The median overall survival of these five patients was 29 months (range: 4 to >40 months), which is considered good prognoses. Clinical and radiographic characteristics were distinct from IDH‐wildtype (IDH‐wt) pGBMs. IDH‐mutant (IDH‐mut) tumors consistently involved insular lesions and were subdivided into: (i) the two cases of elderly patients with long clinical histories and features implying multistep tumor development; and (ii) the three cases of younger patients with diffusely swelling insular tumors, slight contrast enhancement and no necrosis. Genetic and expression analyses of IDH‐mut pGBMs were similar to those of sGBMs, suggesting that they are indeed distinct from their IDH‐wt counterparts. TERT promoter mutation, a genetic marker of oligodendroglial derivation, was detected in one long‐surviving case, but genetic alterations in the astrocyte‐sGBM pathway were generally prevalent in IDH‐mut pGBMs. Our results present a unique phenotype of IDH‐mut pGBMs arising from insular cortex region, the molecular backgrounds of which are similar to sGBMs. 相似文献
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H. G. Vuong T. T. K. Tran H. T. T. Ngo T. Q. Pham T. Nakazawa K.‐M. Fung L. Hassell R. Katoh T. Kondo 《European journal of neurology》2019,26(3):379-387
The clinical outcomes of isocitrate dehydrogenase‐wild‐type (IDH‐wt) lower‐grade glioma (LGG) have been the subject of debate for some time. In this meta‐analysis, we aimed to assess the prognostic values of several known genetic markers (e.g. TERT promoter mutation, H3F3A mutation, CDKN2A loss) in this tumor group. Four electronic databases, including PubMed, Scopus, Web of Science and Virtual Health Library, were searched for relevant articles. Pooled hazard ratio (HR) and corresponding 95% confidence interval (CI) for overall survival were calculated using a random‐effect model weighted by an inverse variance method. A total of 11 studies were finally selected from 2274 articles for meta‐analyses. Several genetic alterations were demonstrated to have a negative impact on prognosis of IDH‐wt LGGs, specifically TERT promoter mutation (HR, 1.96; 95% CI, 1.42–2.70), H3F3A mutation (HR, 3.21; 95% CI, 1.86–5.55) and EGFR amplification (HR, 1.67; 95% CI, 1.02–2.74). However, CDKN loss, ATRX mutation and coexisting gain of chromosome 7/loss of chromosome 10 showed no clinical significance in this glioma entity. Our study results demonstrated that IDH‐wt LGGs are heterogeneous in clinical outcome and not all tumors have a poor prognosis. The presence of TERT promoter mutation, H3F3A mutation and EGFR amplification showed negative prognostic impacts in this tumor entity. These genetic events can be used to better stratify patient outcomes. 相似文献
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P Bady D Sciuscio AC Diserens J Bloch MJ van den Bent C Marosi PY Dietrich M Weller L Mariani FL Heppner DR McDonald D Lacombe R Stupp M Delorenzi ME Hegi 《Acta neuropathologica》2012,124(4):547-560
The methylation status of the O6-methylguanine-DNA methyltransferase (MGMT) gene is an important predictive biomarker for benefit from alkylating agent therapy in glioblastoma. Recent studies in anaplastic
glioma suggest a prognostic value for MGMT methylation. Investigation of pathogenetic and epigenetic features of this intriguingly distinct behavior requires accurate
MGMT classification to assess high throughput molecular databases. Promoter methylation-mediated gene silencing is strongly dependent
on the location of the methylated CpGs, complicating classification. Using the HumanMethylation450 (HM-450K) BeadChip interrogating 176 CpGs annotated for the MGMT gene, with 14 located in the promoter, two distinct regions in the CpG island of the promoter were identified with high importance
for gene silencing and outcome prediction. A logistic regression model (MGMT-STP27) comprising probes cg1243587 and cg12981137
provided good classification properties and prognostic value (kappa = 0.85; log-rank p < 0.001) using a training-set of 63 glioblastomas from homogenously treated patients, for whom MGMT methylation was previously shown to be predictive for outcome based on classification by methylation-specific PCR. MGMT-STP27
was successfully validated in an independent cohort of chemo-radiotherapy-treated glioblastoma patients (n = 50; kappa = 0.88; outcome, log-rank p < 0.001). Lower prevalence of MGMT methylation among CpG island methylator phenotype (CIMP) positive tumors was found in glioblastomas from The Cancer Genome
Atlas than in low grade and anaplastic glioma cohorts, while in CIMP-negative gliomas MGMT was classified as methylated in approximately 50 % regardless of tumor grade. The proposed MGMT-STP27 prediction model allows
mining of datasets derived on the HM-450K or HM-27K BeadChip to explore effects of distinct epigenetic context of MGMT methylation suspected to modulate treatment resistance in different tumor types. 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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Ghazaleh Tabatabai Roger Stupp Martin J. van den Bent Monika E. Hegi Jörg C. Tonn Wolfgang Wick Michael Weller 《Acta neuropathologica》2010,120(5):585-592
Significant progress has been made in the molecular diagnostic subtyping of brain tumors, in particular gliomas. In contrast
to the classical molecular markers in this field, p53 and epidermal growth factor receptor (EGFR) status, the clinical significance of which has remained controversial, at least three important molecular markers with clinical
implications have now been identified: 1p/19q codeletion, O
6-methylguanine methyltransferase (MGMT) promoter methylation and isocitrate dehydrogenase-1 (IDH1) mutations. All three are favorable prognostic markers. 1p/19q codeletion and IDH1 mutations are also useful to support and extend the histological classification of gliomas since they are strongly linked
to oligodendroglial morphology and grade II/III gliomas, as opposed to glioblastoma, respectively. MGMT promoter methylation is the only potentially predictive marker, at least for alkylating agent chemotherapy in glioblastoma.
Beyond these classical markers, the increasing repertoire of anti-angiogenic agents that are currently explored within registration
trials for gliomas urgently calls for efforts to identify molecular markers that predict the benefit derived from these novel
treatments, too. 相似文献
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Jaemoon Koh Hwajin Cho Hannah Kim Seong Ik Kim Sumi Yun Chul‐Kee Park Se‐Hoon Lee Seung Hong Choi Sung‐Hye Park 《Neuropathology》2015,35(3):236-244
Glioblastomas (GBMs) are the most aggressive type of primary brain tumors and provide a dismal prognosis. Thus far, several key genes have been identified in GBMs as prognostic and therapeutic targets. Mutations in two isocitrate dehydrogenase (IDH) genes, IDH1 and IDH2, commonly occur in low‐grade gliomas and secondary high‐grade gliomas, but are rare in primary GBMs. These mutations alter the catalytic activity of IDH proteins, promoting gliomagenesis. Gliomas with IDH1 or IDH2 mutation have better outcomes than do gliomas with wild‐type IDH. The hot spots of IDH1 mutations (R132) and IDH2 mutations (R140 and R172) are well known and are considered as a possible biochemical explanation for the differing clinical characteristics of primary and secondary GBMs. We sought to find the incidence of IDH2 mutation and the characteristics of the gliomas with IDH2 mutation. Among 134 gliomas, which were operated in our hospital consecutively, we studied IDH1 and IDH2 mutations by Sanger sequencing and IDH2 mutation was identified in seven cases (5.2%, four oligodendrogliomas and three GBMs). IDH2 mutation was found in 3.3% of GBMs (3/90 cases) and 9.0% (4/44) of grades II to III gliomas. Here, we report the clinicopathological characteristics of the gliomas with IDH2 mutations including two cases of primary GBM carrying a novel missense IDH2 mutation (c. 484C>T, p. P162S). 相似文献
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Xiao-Yang Liu Noha Gerges Andrey Korshunov Nesrin Sabha Dong-Anh Khuong-Quang Adam M. Fontebasso Adam Fleming Djihad Hadjadj Jeremy Schwartzentruber Jacek Majewski Zhifeng Dong Peter Siegel Steffen Albrecht Sidney Croul David TW Jones Marcel Kool Martje Tonjes Guido Reifenberger Damien Faury Gelareh Zadeh Stefan Pfister Nada Jabado 《Acta neuropathologica》2012,124(5):615-625
Gliomas are the most common primary brain tumors in children and adults. We recently identified frequent alterations in chromatin remodelling pathways including recurrent mutations in H3F3A and mutations in ATRX (α-thalassemia/mental-retardation-syndrome-X-linked) in pediatric and young adult glioblastoma (GBM, WHO grade IV astrocytoma). H3F3A mutations were specific to pediatric high-grade gliomas and identified in only 3.4?% of adult GBM. Using sequencing and/or immunohistochemical analyses, we investigated ATRX alterations (mutation/loss of expression) and their association with TP53 and IDH1 or IDH2 mutations in 140 adult WHO grade II, III and IV gliomas, 17 pediatric WHO grade II and III astrocytomas and 34 pilocytic astrocytomas. In adults, ATRX aberrations were detected in 33?% of grade II and 46?% of grade III gliomas, as well as in 80?% of secondary and 7?% of primary GBMs. They were absent in the 17 grade II and III astrocytomas in children, and the 34 pilocytic astrocytomas. ATRX alterations closely overlapped with mutations in IDH1/2 (p?<?0.0001) and TP53 (p?<?0.0001) in samples across all WHO grades. They were prevalent in astrocytomas and oligoastrocytomas, but were absent in oligodendrogliomas (p?<?0.0001). No significant association of ATRX mutation/loss of expression and alternative lengthening of telomeres was identified in our cohort. In summary, our data show that ATRX alterations are frequent in adult diffuse gliomas and are specific to astrocytic tumors carrying IDH1/2 and TP53 mutations. Combined alteration of these genes may contribute to drive the neoplastic growth in a major subset of diffuse astrocytomas in adults. 相似文献