idh1 r132h
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Author(s):  
Kevin Faust ◽  
Michael K Lee ◽  
Anglin Dent ◽  
Clare Fiala ◽  
Alessia Portante ◽  
...  

Abstract Background Modern molecular pathology workflows in neuro-oncology heavily rely on the integration of morphologic and immunohistochemical patterns for analysis, classification, and prognostication. However, despite the recent emergence of digital pathology platforms and artificial intelligence-driven computational image analysis tools, automating the integration of histomorphologic information found across these multiple studies is challenged by large files sizes of whole slide images (WSIs) and shifts/rotations in tissue sections introduced during slide preparation. Methods To address this, we develop a workflow that couples different computer vision tools including scale-invariant feature transform (SIFT) and deep learning to efficiently align and integrate histopathological information found across multiple independent studies. We highlight the utility and automation potential of this workflow in the molecular subclassification and discovery of previously unappreciated spatial patterns in diffuse gliomas. Results First, we show how a SIFT-driven computer vision workflow was effective at automated WSI alignment in a cohort of 107 randomly selected surgical neuropathology cases (97/107 (91%) showing appropriate matches, AUC = 0.96). This alignment allows our AI-driven diagnostic workflow to not only differentiate different brain tumor types, but also integrate and carry out molecular subclassification of diffuse gliomas using relevant immunohistochemical biomarkers (IDH1-R132H, ATRX). To highlight the discovery potential of this workflow, we also examined spatial distributions of tumors showing heterogenous expression of the proliferation marker MIB1 and Olig2. This analysis helped uncovered an interesting and unappreciated association of Olig2 positive and proliferative areas in some gliomas (r = 0.62). Conclusion This efficient neuropathologist-inspired workflow provides a generalizable approach to help automate a variety of advanced immunohistochemically compatible diagnostic and discovery exercises in surgical neuropathology and neuro-oncology.


Author(s):  
Tomohide Nishikawa ◽  
Reiko Watanabe ◽  
Yotaro Kitano ◽  
Akane Yamamichi ◽  
Kazuya Motomura ◽  
...  

Diagnostics ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. 2129
Author(s):  
Manabu Natsumeda ◽  
Hironaka Igarashi ◽  
Ramil Gabdulkhaev ◽  
Haruhiko Takahashi ◽  
Kunio Motohashi ◽  
...  

We have previously published a study on the reliable detection of 2-hydroxyglutarate (2HG) in lower-grade gliomas by magnetic resonance spectroscopy (MRS). In this short article, we re-evaluated five glioma cases originally assessed as isocitrate dehydrogenase (IDH) wildtype, which showed a high accumulation of 2HG, and were thought to be false-positives. A new primer was used for the detection of IDH2 mutation by Sanger sequencing. Adequate tissue for DNA analysis was available in 4 out of 5 cases. We found rare IDH2 mutations in two cases, with IDH2 R172W mutation in one case and IDH2 R172K mutation in another case. Both cases had very small mutant peaks, suggesting that the tumor volume was low in the tumor samples. Thus, the specificity of MRS for detecting IDH1/2 mutations was higher (81.3%) than that originally reported (72.2%). The detection of 2HG by MRS can aid in the diagnosis of rare, non-IDH1-R132H IDH1 and IDH2 mutations in gliomas.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi78-vi78
Author(s):  
Tyrone Dowdy ◽  
Tomohiro Yamasaki ◽  
Lumin Zhang ◽  
Orieta Celiku ◽  
Adrian Lita ◽  
...  

Abstract BACKGROUND Our study aimed to identify vulnerabilities within sphingolipid metabolism with potential to translate to therapeutics. While the vital role of sphingolipids in maintaining rheostat balance and as secondary messengers for signaling pathways (involving proliferation, invasion, migration, and angiogenesis) has been well-documented, their role has not been widely investigated in gliomas. Therefore, metabolic analysis of sphingolipid pathway for IDH1-R132H (IDH1 mut ) glioma cell lines was conducted in order to elucidate susceptible targets. METHODS Global sphingolipid quantification utilized high-throughput LCMS analysis. Pathway protein expression was measured via Western blots in vitro and derived from patients using The Cancer Genome Atlas analysis. RESULTS We probed the impact of decreasing D-2HG on the sphingolipid metabolism after treating a panel of IDH1 mut glioma cells with IDH1-R132H mut inhibitor, AGI5198. This revealed significant downregulation of N,N-dimethylsphingosine (NDMS), C17-sphingosine, and C18-sphinganine. Coincidentally, sphingosine-1-phosphate (S1P) was significantly upregulated in these gliomas. We conducted rational drug screen which revealed that inhibition of SPHK1 with N,N-dimethylsphingosine in combination with C17-sphingosine triggered biostatic dose-response across IDH1 mut gliomas and low impact on IDH WT glioblastoma (GBM) cells. Western analysis revealed that the IDH1 mut gliomas and IDH WT GBM expressed sphingosine kinase-1 (SPHK1). Data also unveiled a discovery that SPHK2 was highly expressed in the GBM cells while remarkably absent in the glioma cells. CONCLUSION Herein, we provide evidence that certain IDH1 mut gliomas present epigenetic silencing of SPHK2 which creates dependency on SPHK1 for S1P; thus, increasing sensitivity to targeting sphingolipid metabolism, and creating susceptibility to proliferation arrest and subsequent cellular death. S1P production has been reported to be elevated particularly for malignant glioblastomas in prior studies; whereas our research revealed that it is relatively low in IDH mut by comparison with IDH WT tumor cells. These findings suggest targeting the sphingolipid metabolism may present a promising strategy to improve survival for patients diagnosed with IDH1 mut gliomas.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi217-vi217
Author(s):  
Alexander Köpp ◽  
Luzie Gawehn ◽  
Doreen William ◽  
Matthias Preussler ◽  
Susan Richter ◽  
...  

Abstract BACKGROUND Hot-spot mutations in the Isocitrate dehydrogenase 1 (IDH1) cause a new catalytic function resulting in the production of 2-HG, a hallmark in the development of low-grade glioma. The tumorigenic mechanism of this mutation as well as the cell of origin are not known and there is a lack of suitable disease models. Thus, we aim to create a model mimicking glioma development by introducing the IDH1 R132H into human induced pluripotent stem cells (hiPSC) and investigate the influence on stem cell properties and cell differentiation in neuronal progenitor cells. MATERIAL AND METHODS We use CRISPR/Cas9 based genome editing to induce the IDH1 R132H mutation into healthy-control-derived hiPSCs. Successful introduction of the mutation was confirmed on DNA, RNA and protein level. The hiPSCs are then differentiated into cerebral organoids and characterized using transcriptome sequencing and methylation arrays. RESULTS We successfully introduced the IDH1 R132H mutation into hiPSCs and confirmed expression of the mutated protein by Western Blot. Metabolite measurement using liquid chromatography tandem mass spectrometry (LC-MS/MS) showed a forty times increased concentration of 2-HG in IDH-mutated compared to the wildtype hiPSCs, proving that the mutated enzyme is functional. To investigate effects of IDH1 R132H on cell differentiation, we generated cerebral organoids from our iPSC-models. The IDH1 R132H mutation did not inhibit cell differentiation or maturation of cerebral organoids but led to a downregulation of splicosome, proteasome and DNA repair enzymes as well as an upregulation of ECM components. CONCLUSION AND OUTLOOK hiPSCs with R132H mutation pose a promising model for investigations on early glioma development. We are currently step-wise including TP53 and ATRX loss of function mutations in our hiPSC models to recapitulating tumor development in vivo.


2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi219-vi219
Author(s):  
Connor Yanchus ◽  
Kristen Drucker ◽  
Thomas Kollmeyer ◽  
Ricky Tsai ◽  
Lingyan Jiang ◽  
...  

Abstract Low-grade glioma (LGG) are generally slowly growing brain cancers, that frequently undergo malignant progression to aggressive, secondary glioblastoma with a dismal prognosis. By combining genetically engineered Idh1-mutant mice with in vivo CRISPR gene editing we generated a mouse model faithfully recapitulating the founder mutations of LGG. Clonal activation of the neomorphic Idh1 R132H mutation cooperates with Trp53 and Atrx mutations to trigger development of brain tumors but only with ~30% penetrance and very long latency. To elucidate the molecular mechanisms underlying the malignant progression of IDH1-mutant LGG, we devised and deployed a direct in vivo CRISPR screen targeting genes commonly mutated in human IDH-mutant secondary glioblastoma. Stereotaxic delivery of a lentiviral sgRNA library targeting the mouse orthologs of these genes into the brain of Idh1 R132H ;Trp53;Atrx;Cas9 and control Idh1 wt ;Trp53;Atrx;Cas9 compound mutant mice resulted in rapid formation of tumors that recapitulate human Idh1-mutant glioblastoma. Deconvoluting the screen showed that PI3K pathway members Pten and Pik3ca as well as Notch1, Smarca4 and Fat1 are preferentially enriched in Idh1 R132H-tumors, while Rb1 and NF2 were enriched in Idh1 wt tumors. Co-mutation analysis further identified additional co-occurring driver combinations such as Bcor-Met, Olig2-Met, Olig2-Med12 or Bcor-Olig2. We validated the tumor suppressive function of Notch1 and Pten using conventional floxed knock-out alleles and found that Notch1 functions in a haploinsufficient manner. Interestingly, Idh1 R132H did not alter tumor latency or pathology in a high grade p53;Pten;Rb1 mutant background, indicating that the neomorphic IDH-mutations can drive low but not high grade glioma development. Our study provides a functional landscape of gliomagenesis suppressors in vivo.


2021 ◽  
Author(s):  
Shruti Patrick ◽  
Pruthvi Gowda ◽  
Kirti Lathoria ◽  
Vaishali Suri ◽  
Ellora Sen

Mutation in isocitrate dehydrogenase 1 (IDH1) gene, leading to the production of oncometabolite D-2-hydroxyglutarate (2-HG) from α-ketoglutarate, is associated with better prognosis in glioma. As Yes-associated protein 1 (YAP1) is an important regulator of tumor progression, its role in glioma expressing IDH1 R132H mutation was investigated. Diminished nuclear YAP1 in IDH1 mutant patient gliomas and cell lines was accompanied by decreased TFAM levels. Luciferase reporter assays and chromatin immunoprecipitation indicated the functionality of TEAD2 site on TFAM promoter in mediating its YAP1-dependent expression. YAP1-dependent mitochondrial fragmentation and ROS generation was accompanied by decreased TERT levels and increased mitochondrial TERT localization in IDH1 R132H cells. Treatment with Bosutinib that prevents extranuclear TERT shuttle, further elevated ROS in IDH1 R132H cells and triggered apoptosis. Importantly, Bosutinib elevated ROS levels and induced apoptosis in IDH1 WT cells upon concurrent depletion of YAP1. These findings highlight the involvement of YAP1 in coupling mitochondrial dysfunction with TERT mitochondrial shuttle to constitute an essential non-canonical function of YAP1 in regulating redox homeostasis.


Author(s):  
Carlos Eduardo Correia ◽  
Yoshie Umemura ◽  
Jessica R Flynn ◽  
Anne S Reiner ◽  
Edward K Avila

Abstract Purpose Many low-grade gliomas (LGG) harbor isocitrate dehydrogenase (IDH) mutations. Although IDH mutation is known to be epileptogenic, the rate of refractory seizures in LGG with IDH mutation vs wild-type had not been previously compared. We therefore compared seizure pharmacoresistance in IDH-mutated and wild-type LGGs. Methods Single-institution retrospective study of patients with histologic proven LGG, known IDH mutation status, seizures, and ≥ 2 neurology clinic encounters. Seizure history was followed until histological high-grade transformation or death. Seizures requiring ≥ 2 changes in anti-epileptic drugs were considered pharmacoresistant. Incidence rates of pharmacoresistant seizures were estimated using competing risks methodology. Results Of 135 patients, 25 patients (19%) had LGGs classified as IDH wild-type. Of those with IDH mutation, 104 (94.5%) were IDH1 R132H; only six were IDH2 R172K. 120 patients (89%) had tumor resection and 14 (10%) had biopsy. Initial post-surgical management included observation (64%), concurrent chemoradiation (23%), chemotherapy alone (9%), and radiotherapy alone (4%). Seizures became pharmacoresistant in 24 IDH-mutated patients (22%) and in 3 IDH wild-type patients (12%). The 4-year cumulative incidence of intractable seizures was 17.6% (95% CI: 10.6%-25.9%) in IDH-mutated and 11% (95% CI: 1.3%-32.6%) in IDH wild-type LGG (Gray’s P-value= 0.26). Conclusions 22% of the IDH-mutated patients developed pharmacoresistant seizures, compared to 12% of the IDH wild-type tumors.The likelihood of developing pharmacoresistant seizures in patients with LGG-related epilepsy is independent to IDH mutation status, however, IDH-mutated tumors were approximately twice as likely to experience LGG-related pharmacoresistant seizures.


2021 ◽  
Vol 23 (Supplement_4) ◽  
pp. iv9-iv10
Author(s):  
U Pohl ◽  
Santhosh Nagaraju

Abstract Aims Oligodendroglioma is molecularly defined by mutation of isocitrate dehydrogenase (IDH) and 1p19q codeletion. IDH mutation is an early driver of tumorigenesis, via its oncometabolite 2-hydroxyglutarate, regardless of the exact mutational subtype in homologues IDH1 or IDH2. IDH mutant cells then acquire 1p19q codeletion, with haploinsufficiency likely to contribute to oncogenesis by reduced expression of genes on 1p and 19q, as well as mutations in TERT, FUBP1 (on 1p31.1) in ~30% and CIC (on 19q13.2) in ~>60% of 1p19q-codeleted gliomas. We present a case of a young patient with metachronous oligodendroglial tumours, initially thought to represent contralateral recurrence of the same disease. However, IDH mutation analysis in each tumour revealed distinct types of mutations, involving both IDH1 and IDH2, indicating different cellular lineages of tumorigenesis. We aim to present this unusual combination by illustrating the histology and molecular profile, and review the literature with regards to multifocal but molecularly distinct glioma. Method Case: The patient is a 33 year old man initially presenting with seizures, who was found to have a frontal lobe lesion (hence called tumour 1) with focal radiological enhancement, followed by a contralateral lesion in the parietal lobe 6 months later (hence designated as tumour 2). He underwent separate surgical debulking, and each time, tumour tissue was histologically and genetically examined. Testing included targeted mutation screening by immunohistochemistry and PCR based methods, pyrosequencing for MGMT methylation analysis, FISH for chromosomal LOH analysis of 1p and 19q, immunohistochemistry for mismatch repair enzymes and next generation sequencing. Results Histology of tumour 1 revealed a neoplasm with uniform cells, round nuclei and oligodendroglioma-like clear cell change, without mitoses, microvascular proliferation or necrosis. Immunohistochemistry showed absence of IDH1 R132H mutation, retained expression of ATRX and no altered p53 staining. The ki-67 index reached 6%. Sequencing of IDH1/2 mutations revealed a rare IDH2 mutation (non-/R172K). FISH confirmed codeletion of 1p19q, and the integrated diagnosis was oligodendroglioma, IDH mutant and 1p19q codeleted, WHO grade II. Histology of tumour 2 demonstrated oligodendroglioma morphology in areas, but more cellular and nuclear pleomorphism and focally brisk mitotic activity (7 mitoses in 10 hpf; ki67 index 20%), while both microvascular proliferation and necrosis were absent. Immunohistochemistry showed IDH1 R132H mutation and retained ATRX, while p53 was not expressed. FISH studies confirmed codeletion of 1p19q, and the integrated diagnosis was anaplastic oligodendroglioma, IDH mutant and 1p19q codeleted, WHO-2016 grade III. NGS data and MMR results are compared. Conclusion We present a patient with two histologically similar, but molecularly distinct oligodendroglial tumours affecting both cerebral hemispheres. Apart from the grade, the important difference is the presence of different IDH mutations, 1) a rare IDH2 mutation (non-R172K) and 2) the common IDH1 (R132H) mutation. While both types of IDH mutations identified are known to occur in oligodendroglioma, the difference clearly indicates two distinct lineages of tumorigenesis, especially as IDH mutation is considered an early event in gliomagenesis. IDH2 mutations are often associated with oligodendrogliomas, while IDH1 R132H is recognised to be frequent in both diffuse oligodendroglial and astroglial neoplasms. Multifocal divergent gliomas have been described previously but oligodendrogliomas with differing IDH mutations in the same patient have not knowingly been reported yet. Importantly, though therapeutically irrelevant here, multicentric gliomas do not automatically imply relatedness. However, a common origin or predisposition (here, even predating IDH mutation) may not be ruled out.


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