Loss of BCAT1 Expression is a Sensitive Marker for IDH-Mutant Diffuse Glioma

Abstract BACKGROUND IDH mutation is an important prognostic factor of diffuse astrocytomas. Although the majority of IDH mutations could be identified by immunohistochemical (IHC) stain for R132H-mutant IDH1, DNA sequencing would be required for IHC negative cases to determine their IDH mutation status. This approach is not cost-effective for tumors with low IDH mutation rates. OBJECTIVE To investigate whether BCAT1 could be used as a surrogate marker for IDH mutations, because BCAT1 is an enzyme related to IDH genes. METHODS A group of 120 anaplastic astrocytomas were immunostained for BCAT1, ATRX, and R132H-mutant IDH1. Staining results correlated with the results of DNA sequencing of IDH1/IDH2. RESULTS DNA sequencing showed IDH1/2 mutations in 50.8% of cases of which 73.8% had IDH1 R132H mutation. Several IDH1 noncodon 132 mutations, ie, G97D, S122N, G123E, I130K, and G131S, which had uncertain prognostic significance, were identified. IHC stain for R132H-mutant IDH1 identified 93.3% of IDH1 R132H mutations and 70.5% of all IDH mutations. BCAT1 loss was seen in 65.8% of cases, its sensitivity to identify IDH mutations was 96.7%. The sensitivity reached 100% for IDH1 codon 132 and IDH2 codon 172 mutations. CONCLUSION Positive BCAT1 stain could be used to exclude diffuse gliomas with IDH1 codon 132 and IDH2 codon 172 mutations. Selecting cases with negative BCAT1 and R132H-mutant IDH1 staining for DNA sequencing of IDH1/2 genes could improve the cost-effectiveness of detecting IDH mutations particularly in tumors with low IDH mutation rates, and confine the need of 1p/19q assay in IDH-mutant tumors.

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Pharmacoresistant seizures and IDH mutation in low grade gliomas

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab146 ◽

2021 ◽

Author(s):

Carlos Eduardo Correia ◽

Yoshie Umemura ◽

Jessica R Flynn ◽

Anne S Reiner ◽

Edward K Avila

Keyword(s):

Tumor Resection ◽

Incidence Rates ◽

P Value ◽

Low Grade ◽

Idh Mutation ◽

Wild Type ◽

Mutation Status ◽

Low Grade Gliomas ◽

Idh1 R132h ◽

Idh Mutations

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.

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Non-IDH1-R132H IDH1/2 mutations are associated with increased DNA methylation and improved survival in astrocytomas, compared to IDH1-R132H mutations

Acta Neuropathologica ◽

10.1007/s00401-021-02291-6 ◽

2021 ◽

Cited By ~ 1

Author(s):

C. Mircea S. Tesileanu ◽

Wies R. Vallentgoed ◽

Marc Sanson ◽

Walter Taal ◽

Paul M. Clement ◽

...

Keyword(s):

Dna Methylation ◽

Phase Iii ◽

Idh Mutation ◽

Independent Dataset ◽

Prognostic Effect ◽

Idh1 R132h ◽

Genome Wide ◽

Idh Mutations ◽

Multiple Tumour ◽

Mutation Type

AbstractSomatic mutations in the isocitrate dehydrogenase genes IDH1 and IDH2 occur at high frequency in several tumour types. Even though these mutations are confined to distinct hotspots, we show that gliomas are the only tumour type with an exceptionally high percentage of IDH1R132H mutations. Patients harbouring IDH1R132H mutated tumours have lower levels of genome-wide DNA-methylation, and an associated increased gene expression, compared to tumours with other IDH1/2 mutations (“non-R132H IDH1/2 mutations”). This reduced methylation is seen in multiple tumour types and thus appears independent of the site of origin. For 1p/19q non-codeleted glioma (astrocytoma) patients, we show that this difference is clinically relevant: in samples of the randomised phase III CATNON trial, patients harbouring tumours with IDH mutations other than IDH1R132H have a better outcome (hazard ratio 0.41, 95% CI [0.24, 0.71], p = 0.0013). Such non-R132H IDH1/2-mutated tumours also had a significantly lower proportion of tumours assigned to prognostically poor DNA-methylation classes (p < 0.001). IDH mutation-type was independent in a multivariable model containing known clinical and molecular prognostic factors. To confirm these observations, we validated the prognostic effect of IDH mutation type on a large independent dataset. The observation that non-R132H IDH1/2-mutated astrocytomas have a more favourable prognosis than their IDH1R132H mutated counterpart indicates that not all IDH-mutations are identical. This difference is clinically relevant and should be taken into account for patient prognostication.

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P04.12 Characteristics of IDH-mutant gliomas with non-canonical IDH mutations

Neuro-Oncology ◽

10.1093/neuonc/noz126.107 ◽

2019 ◽

Vol 21 (Supplement_3) ◽

pp. iii31-iii31

Author(s):

L Poetsch ◽

C Dehais ◽

J Frénel ◽

A Siegfried ◽

S Lacomme ◽

...

Keyword(s):

Idh1 Mutation ◽

Consecutive Series ◽

Idh Mutation ◽

Idh1 R132h ◽

Idh Mutations ◽

History Of ◽

Histological Characteristics ◽

Idh1 And Idh2 Mutations ◽

R132h Mutation ◽

Idh2 Mutation

Abstract BACKGROUND About 10% of IDH-mutant gliomas harbor non-canonical IDH mutations (non-R132H IDH1 and IDH2 mutations). The aim of the present study was to analyze the characteristics of these gliomas in comparison to those of IDH1 R132H mutant gliomas. MATERIAL AND METHODS We retrospectively analyzed the characteristics of a multicentric series of 161 gliomas with non-canonical IDH mutations and compared them to those of consecutive series of 109 IDH1 R132H mutant gliomas. Medical, radiological and pathological were reviewed. RESULTS Median age at diagnosis was 35 years in gliomas with a non-canonical IDH1 mutation, 42 years in those with an IDH2 mutation and 44 years in those with an IDH1R132H mutation. A familial history of cancer was more frequent in gliomas with a non-canonical IDH mutation than in those with an IDH1 R132H mutation (22,3% vs 5,5%, p<0.05). In both IDH1 R132H-mutant and non-canonical IDH-mutant gliomas the most frequent location was the frontal lobe. Yet, compared to IDH1R132H-mutant gliomas those with a non-canonical IDH mutation had more frequently an infratentorial location (5,5% vs 0% p<0,05) and were more frequently multicentric (4,9%, versus 0.9%, p<0.05). Compared to IDH1R132H-mutant gliomas, gliomas with a non-canonical IDH1 mutation were more frequently astrocytomas (65.7% vs 45%, p<0.05) while those with an IDH2 mutation were more frequently oligodendrogliomas (82% vs 55%, p<0.05). The median overall survival in IDH1 R132H-mutant and non-canonical IDH-mutant gliomas was similar (122 versus 120 months). CONCLUSION Gliomas with non-canonical IDH mutations are associated with distinct clinical, radiological and histological characteristics. Their prognosis, however, is similar to that of gliomas with canonical IDH mutations.

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Noninvasive assessment of isocitrate dehydrogenase mutation status in cerebral gliomas by magnetic resonance spectroscopy in a clinical setting

Journal of Neurosurgery ◽

10.3171/2016.10.jns161793 ◽

2018 ◽

Vol 128 (2) ◽

pp. 391-398 ◽

Cited By ~ 31

Author(s):

Anna Tietze ◽

Changho Choi ◽

Bruce Mickey ◽

Elizabeth A. Maher ◽

Benedicte Parm Ulhøi ◽

...

Keyword(s):

Magnetic Resonance ◽

Magnetic Resonance Spectroscopy ◽

Isocitrate Dehydrogenase ◽

Prognostic Significance ◽

Resonance Spectroscopy ◽

Idh Mutation ◽

Imaging Protocol ◽

Mutation Status ◽

Idh Mutations ◽

Cerebral Gliomas

OBJECTIVEMutations in the isocitrate dehydrogenase (IDH) genes are of proven diagnostic and prognostic significance for cerebral gliomas. The objective of this study was to evaluate the clinical feasibility of using a recently described method for determining IDH mutation status by using magnetic resonance spectroscopy (MRS) to detect the presence of 2-hydroxyglutarate (2HG), the metabolic product of the mutant IDH enzyme.METHODSBy extending imaging time by 6 minutes, the authors were able to include a point-resolved spectroscopy (PRESS) MRS sequence in their routine glioma imaging protocol. In 30 of 35 patients for whom this revised protocol was used the lesions were subsequently diagnosed histologically as gliomas. Of the remaining 5 patients, 1 had a gangliocytoma, 1 had a primary CNS lymphoma, and 3 had nonneoplastic lesions. Immunohistochemistry and/or polymerase chain reaction were used to detect the presence of IDH mutations in the glioma tissue resected.RESULTSIn vivo MRS for 2HG correctly identified the IDH mutational status in 88.6% of patients. The sensitivity and specificity was 89.5% and 81.3%, respectively, when using 2 mM 2HG as threshold to discriminate IDH-mutated from wildtype tumors. Two glioblastomas that had elevated 2HG levels did not have detectable IDH mutations, and in 2 IDH-mutated gliomas 2HG was not reliably detectable.CONCLUSIONSThe noninvasive determination of the IDH mutation status of a presumed glioma by means of MRS may be incorporated into a routine diagnostic imaging protocol and can be used to obtain additional information for patient care.

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AG-120, an Oral, Selective, First-in-Class, Potent Inhibitor of Mutant IDH1, Reduces Intracellular 2HG and Induces Cellular Differentiation in TF-1 R132H Cells and Primary Human IDH1 Mutant AML Patient Samples Treated Ex Vivo

Blood ◽

10.1182/blood.v124.21.3734.3734 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3734-3734 ◽

Cited By ~ 27

Author(s):

Erica Hansen ◽

Cyril Quivoron ◽

Kim Straley ◽

René M Lemieux ◽

Janeta Popovici-Muller ◽

...

Keyword(s):

Bone Marrow ◽

Cellular Differentiation ◽

Ex Vivo ◽

Day Treatment ◽

Relative Proportion ◽

Idh1 R132h ◽

Idh Mutations ◽

Recherche Médicale ◽

Mutant Idh1 ◽

Institut National Du Cancer

Abstract Point mutations in isocitrate dehydrogenase (IDH) define distinct subsets of acute myelogenous leukemia (AML). IDH is a metabolic enzyme that interconverts isocitrate and α-ketoglutarate (α-KG), but cancer-associated point mutations in IDH1 and IDH2 confer a neomorphic activity that allows reduction of α-KG to the oncometabolite R-2-hydroxyglutarate (2-HG). High levels of 2-HG have been shown to inhibit α-KG-dependent dioxygenases including histone and DNA demethylases, which play a key role in regulating the epigenetic state of cells, but the relationship between 2-HG and oncogenesis is not completely understood. Consistent with 2-HG promoting cancer via an effect on chromatin structure, patients harboring IDH mutations display a CpG island methylator phenotype (CIMP) and several studies have shown that overexpression of IDH mutant enzymes can induce histone and DNA hypermethylation as well as block cellular differentiation. In addition, mice engineered to express IDH1-R132H in hematopoietic tissue have increased early hematopoietic progenitors, splenomegaly, anemia, hypermethylated histones and altered DNA methylation patterns similar to those found in AML patients harboring IDH1/2 mutations.[i] Taken together, these data suggest that cancer-associated IDH mutations may induce a block in cellular differentiation to promote tumorigenesis. To investigate whether selective pharmacological inhibition of the mutant IDH1 enzyme could provide an effective way to lower intracellular 2-HG levels and restore normal differentiation, we treated TF-1 cells or primary human AML patient samples expressing mutant IDH1 with AG-120, an oral, selective, first-in-class, potent IDH1 mutant inhibitor currently in phase I clinical trials. Treatment with AG-120 decreased intracellular 2-HG levels, inhibited growth factor independent proliferation and restored erythropoietin (EPO)-induced differentiation in TF-1 IDH1-R132H cells. Similarly, pharmacological inhibition of mutant IDH1 enzyme with AG-120 in primary human blast cells cultured ex vivo provided an effective way to lower intracellular 2-HG levels and induced myeloid differentiation. Taken together, these data demonstrate that AG-120 is effective at lowering 2-HG levels and restoring cellular differentiation, and support further clinical development of this compound. Figure 1: Diagnosis and karyotypes of primary AML patient samples used in ex vivo studies Figure 1:. Diagnosis and karyotypes of primary AML patient samples used in ex vivo studies PB = peripheral blood, BM = bone marrow Figure 2: Percent 2-HG remaining relative to DMSO control after 6-day treatment with AG-120 in IDH1 R132H or IDH1 R132C patient samples Figure 2:. Percent 2-HG remaining relative to DMSO control after 6-day treatment with AG-120 in IDH1 R132H or IDH1 R132C patient samples or following 6 days of treatment with control (DMSO) or AG-120 (0.5, 1.0, and 5.0 μM) Figure 3: Relative proportion of cell types in human AML bone marrow samples untreated Figure 3:. Relative proportion of cell types in human AML bone marrow samples untreated [i] M. Sasaki et al., IDH1(R132H) mutation increases murine haematopoietic progenitors and alters epigenetics. Nature 488(7413):656-9, 2012. Disclosures Hansen: Agios Pharmaceuticals: Employment, Stockholder Other. Quivoron:Institut National de la Santé Et de la Recherche Médicale (INSERM): Grant Other; Association Laurette Fugain: Grant, Grant Other; Institut National du Cancer (INCa): Grant, Grant Other; Association pour la recherche contre le Cancer (ARC): Grant, Grant Other; AGIOS: Grant Other. Straley:Agios Pharmaceuticals: Employment, Stockholder Other. Lemieux:Agios Pharmaceuticals: Employment, Stockholder Other, US20130190249 (pending) Patents & Royalties. Popovici-Muller:Agios Pharmaceuticals: Employment, Stockholder Other. Fathi:Agios Pharmaceuticals: Advisory board participation Other. Gliser:Agios Pharmaceuticals: Employment, Stockholder Other. David:Institut National de la Santé Et de la Recherche Médicale (INSERM): Grant Other; Institut National du Cancer (INCa): Grant, Grant Other; Association pour la Recherche contre le Cancer (ARC): Grant, Grant Other; Association Laurette Fugain: Grant, Grant Other; AGIOS: Grant Other. Bernard:Institut National de la Santé Et de la Recherche Médicale (INSERM): Grant Other; Association Laurette Fugain: Grant, Grant Other; Institut National du Cancer (INCa): Grant, Grant Other; Ligue Nationale contre le cancer (LNCC): Grant, Grant Other; AGIOS: Grant Other. Dorsch:Agios Pharmaceuticals: Employment, Stockholder Other. Yang:Agios Pharmaceuticals: Employment, Stockholder Other. Su:Agios Pharmaceuticals: Employment, Stockholder Other. Agresta:Agios Pharmaceuticals: Employment, Stockholder Other. de Botton:AGIOS: Grant Other. Penard-Lacronique:Institut National de la Santé Et de la Recherche Médicale (INSERM): Grant Other; Association Laurette Fugain: Grant, Grant Other; Institut National du Cancer (INCa): Grant, Grant Other; Association pour la recherche contre le Cancer (ARC): Grant, Grant Other; AGIOS: Grant Other. Yen:Agios Pharmaceuticals: Employment, Stockholder Other.

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Comparison of Three Assays for Identification of IDH Mutations in AML

Blood ◽

10.1182/blood-2019-126494 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5195-5195

Author(s):

Sara Ribeiro ◽

Dorte Wren ◽

Lisa Thompson ◽

Michael Hubank ◽

David Taussig

Keyword(s):

Sanger Sequencing ◽

Leukemic Cell ◽

Cost Effective ◽

Read Depth ◽

Batch Size ◽

Staff Time ◽

Panel Testing ◽

Idh1 R132h ◽

Idh Mutations ◽

Two Samples

Introduction Isocitrate dehydrogenase (IDH) mutations are present in up to 20% of acute myeloid leukemia (AML) patients and lead to production of 2-hydroxyglutarate which promotes impaired differentiation and leukemic cell proliferation. Currently, there are two FDA-approved IDH inhibitors for the treatment of AML: enasidenib and ivosidenib. It is now imperative to establish timely testing so that patients can take advantage of these new therapies. Here we compared three different genotyping strategies to identify the most reliable and cost-effective way of picking up IDH1 and IDH2 mutations in AML. Methodology We have tested 60 AML patient samples across three different methods for detection of IDH1/2 mutations: (i) Capillary Electrophoresis-Single Strand Conformational Analysis (CE-SSCA) with Sanger sequencing, (ii) Next generation sequencing (NGS) myeloid capture panel (SureSeq myPanel, Oxford Gene Technology, OGT; UK) and (iii) multi-cancer NGS amplicon panel (QIAseq Targeted DNA Panel, Qiagen, Germany). The NGS capture assay is a 26 gene panel designed for myeloid-related genes while the NGS amplicon panel includes 33 genes associated with haematological and non-haematological malignancies (Figure 1). We have compared the techniques and assessed the quality of the results by measuring gene coverage, read depth across the panels, sensitivity and specificity per test, and performed a final valuation including some practical considerations: cost analysis, staff timings, ease of assay operation, turnaround times (TATs), ease of analysis and reporting as well as batch size limits. We initially tested 424 AML cases with CE-SSCA and have successfully transferred to amplicon panel testing (to date 200 cases). Results The results from the initial 60 cases were concordant between both NGS technologies and Sanger sequencing. In total across all 3 assays, we have detected IDH mutations in 19% of the 624 samples tested (Figure 2). Two samples showed false positive results by CE-SSCA, but these were identified by Sanger sequencing; therefore CE-SSCA alone is an inadequate test and all positive samples by CE-SSCA have to be confirmed by Sanger sequencing. Two samples showed IDH1 R132H mutation with variant allele frequency less than 10%, which was detected by all methods, however the Sanger sequencing trace was very small and could potentially have been missed. The gene minimum read depth for capture NGS was 682 and 677 for amplicon, and the gene mean depth was 1571 and 934 reads, respectively. We did not identify any new genetic variants in IDH1/2. The cost of reagents was higher for the NGS capture panel at $235 per patient compared to amplicon based at $86 per patient, with CE-SSCA/Sanger sequencing combined costing $50. The amplicon NGS allows processing of up to 96 samples per batch, allowing for high throughput testing, while capture NGS only allows for 16 samples to be processed. The library preparation time (Figure 1) is shorter for NGS amplicon (2 days; 12 hours staff time) compared to capture (3 days; 17 hours staff time), with both techniques taking longer to set-up when compared to CE-SSCA (2 hours) and Sanger sequencing (1 day; 6 hours staff time). Looking at assay operation, CE-SSCA and Sanger are the less complex assays allowing for laboratory accessibility, whereas although NGS amplicon was relatively straight forward, NGS capture was slightly more complex, lending itself to specialist laboratory setup. When looking at analysis, CE-SSCA was straightforward; however certain patterns that are very similar to positive controls can lead to false positives. Both NGS analysis were very straightforward, taking <5min per sample, while CE-SSCA/Sanger can take up to 10min per sample in more difficult cases. Importantly, NGS-based approaches incorporate other clinically-relevant genes whereas CE-SSCA is limited to IDH1/2 evaluation with additional testing being required for other targets. Conclusion: We have established a multi-cancer NGS amplicon assay for the detection of IDH mutations in AML patients. It reduces test costs for patients, improving testing efficiencies, allowing additional clinically-relevant genes to be analysed in parallel It has also helped streamline testing for different cancer types which can now all follow the same workflow and be automated thus improving TAT's contributing to better patient management. Acknowledgements: Celgene provided funding for this study. Disclosures Taussig: Celgene: Research Funding.

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Metachronous oligodendroglial tumours with different IDH mutational profile in a young patient

Neuro-Oncology ◽

10.1093/neuonc/noab195.021 ◽

2021 ◽

Vol 23 (Supplement_4) ◽

pp. iv9-iv10

Author(s):

U Pohl ◽

Santhosh Nagaraju

Keyword(s):

Young Patient ◽

Idh Mutation ◽

Who Grade ◽

1P19q Codeletion ◽

Idh1 R132h ◽

Integrated Diagnosis ◽

Microvascular Proliferation ◽

Idh Mutations ◽

R132h Mutation ◽

Idh2 Mutation

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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Long noncoding RNA MALAT1 may be a prognostic biomarker in IDH1/2 wild-type primary glioblastomas

Bosnian Journal of Basic Medical Sciences ◽

10.17305/bjbms.2019.4297 ◽

2019 ◽

Author(s):

Omer Gokay Argadal ◽

Melis Mutlu ◽

Secil Ak Aksoy ◽

Hasan Kocaeli ◽

Berrin Tunca ◽

...

Keyword(s):

Long Noncoding Rna ◽

Noncoding Rna ◽

Prognostic Significance ◽

Normal Brain ◽

Wild Type ◽

Mutation Status ◽

Primary Glioblastoma ◽

Idh1 R132h ◽

Idh Mutations ◽

Brain Tissues

Primary glioblastoma (GB) is the most aggressive type of brain tumors. While mutations in isocitrate dehydrogenase (IDH) genes are frequent in secondary GBs and correlate with a better prognosis, most primary GBs are IDH wild-type. Recent studies have shown that the long noncoding RNA metastasis associated lung adenocarcinoma transcript-1 (MALAT1) is associated with aggressive tumor phenotypes in different cancers. Our aim was to clarify the prognostic significance of MALAT1 in IDH1/2 wild-type primary GB tumors. We analyzed IDH1/2 mutation status in 75 patients with primary GB by DNA sequencing. The expression of MALAT1 was detected in the 75 primary GB tissues and 5 normal brain tissues using reverse transcription quantitative PCR (RT-qPCR). The associations between MALAT1 expression, IDH1/2 mutation status, and clinicopathological variables of patients were determined. IDH1 (R132H) mutation was observed in 5/75 primary GBs. IDH2 (R172H) mutation was not detected in any of our cases. MALAT1 expression was significantly upregulated in primary GB vs. normal brain tissues (p = 0.025). Increased MALAT1 expression in IDH1/2 wild-type primary GBs correlated with patient age and tumor localization (p = 0.032 and p = 0.025, respectively). A multivariate analysis showed that high MALAT1 expression was an unfavorable prognostic factor for overall survival (p = 0.034) in IDH1/2 wild-type primary GBs. High MALAT1 expression may have a prognostic role in primary GBs independent of IDH mutations.

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Prognostic Significance of Preoperative Neutrophil-to-Lymphocyte Ratio in Patients With Meningiomas

Frontiers in Oncology ◽

10.3389/fonc.2020.592470 ◽

2020 ◽

Vol 10 ◽

Author(s):

Yuki Kuranari ◽

Ryota Tamura ◽

Noboru Tsuda ◽

Kenzo Kosugi ◽

Yukina Morimoto ◽

...

Keyword(s):

Prognostic Significance ◽

Laboratory Data ◽

Progression Free Survival ◽

Cost Effective ◽

Tumor Location ◽

Neutrophil To Lymphocyte Ratio ◽

Ki 67 ◽

Who Grade ◽

Lymphocyte Ratio ◽

Subtotal Removal

BackgroundMeningiomas are the most common benign intracranial tumors. However, even WHO grade I meningiomas occasionally show local tumor recurrence. Prognostic factors for meningiomas have not been fully established. Neutrophil-to-lymphocyte ratio (NLR) has been reported as a prognostic factor for several solid tumors. The prognostic value of NLR in meningiomas has been analyzed in few studies.Materials and MethodsThis retrospective study included 160 patients who underwent surgery for meningiomas between October 2010 and September 2017. We analyzed the associations between patients’ clinical data (sex, age, primary/recurrent, WHO grade, extent of removal, tumor location, peritumoral brain edema, and preoperative laboratory data) and clinical outcomes, including recurrence and progression-free survival (PFS).ResultsForty-four meningiomas recurred within the follow-up period of 3.8 years. WHO grade II, III, subtotal removal, history of recurrence, Ki-67 labeling index ≥3.0, and preoperative NLR value ≥2.6 were significantly associated with shorter PFS (P < 0.001, < 0.001, 0.002, < 0.001, and 0.015, respectively). Furthermore, NLR ≥ 2.6 was also significantly associated with shorter PFS in a subgroup analysis of WHO grade I meningiomas (P = 0.003). In univariate and multivariate analyses, NLR ≥2.6 remained as a significant predictive factor for shorter PFS in patients with meningioma (P = 0.014).ConclusionsNLR may be a cost-effective and novel preoperatively usable biomarker in patients with meningiomas.

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