NI-10 Reclassification of diffuse gliomas based on molecular diagnosis -evaluation of methionine uptake and treatment outcome-

Abstract Object: The revised 2016 WHO Classification of Tumours of the Central Nervous System incorporates genetic alterations into the classification system, with the goal of creating more homogenous disease categories with greater prognostic value. In this study, we reclassified diffuse gliomas with molecular diagnosis and examined for 11C-methionine uptake and prognosis. Methods. 182 diffuse glioma patients (Grade II in 42 patients, Grade III in 61 patients, Grade IV in 77 patients) treated at Tokyo Medical and Dental University Hospital from 2000 to 2018 were included in this study. The IDH1/2, ATRX and 1p19q status were analyzed using tumor samples. The tumor-to-normal ratio (T/N) of 11 C-methionine uptake was calculated by dividing the mean standardized uptake value (SUV) for the tumor by the mean SUV of the normal brain. Result. By molecular diagnosis, 11 diffuse astrocytomas and 17 anaplastic astrocytomas were diagnosed as “IDH-mutant”, while 14 diffuse astrocytomas and 29 anaplastic astrocytomas were diagnosed as “IDH-wild”. 5 out of 77 grade IV tumors had IDH mutation. 4 tumors were diagnosed as “Diffuse midline glioma, H3 K27M-mutant”. In the 32 oligodendroglial tumors, 12 oligodendrogliomas and 9 anaplastic oligodendrogliomas were diagnosed as “IDH-mutant and 1p/19q-codeleted”. The median T/N ratios in oligodendroglial tumors with “IDH-mutant and 1p/19q-codeleted” were significantly higher than those in astrocytic tumors with “IDH-mutant”. On the other hand, in tumors with the same genetic background, higher grade tumor has significant higher T/N ratio. Kaplan-Meier survival analysis revealed that oligodendroglial tumors with “IDH-mutant and 1p/19q-codeleted” had significantly better outcomes regardless of WHO grade. Overall survival was 90.9% at 5 years and 77.9% at 10 years in oligodendroglial tumors with “IDH-mutant and 1p/19q-codeleted”. IDH wild tumors had significantly worse outcomes.Conclusions. The results indicated that diffuse glioma categories reclassified with molecular classification correlate with the T/N ratio of methionine and the prognosis.

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NI-8 Molecular diagnostic prediction combining T2-FLAIR mismatch sign, calcification, and methionine PET in grade II and III gliomas

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab159.071 ◽

2021 ◽

Vol 3 (Supplement_6) ◽

pp. vi19-vi19

Author(s):

Yusuke Ebiko ◽

Kaoru Tamura ◽

Shoko Hara ◽

Motoki Inaji ◽

Yoji Tanaka ◽

...

Keyword(s):

Molecular Diagnosis ◽

Standardized Uptake Value ◽

Molecular Diagnostic ◽

Normal Brain ◽

Oligodendroglial Tumors ◽

Methionine Uptake ◽

Group A ◽

Grade Ii ◽

The Mean ◽

Met Pet

Abstract Background: The 2016 WHO Classification classified grade II and III gliomas into three molecular subtypes depending on the presence of IDH mutation and 1p/19q codeletion. We combined T2-FLAIR mismatch sign, tumor calcification, and methionine PET uptake to examine whether molecular diagnosis could be predicted. Methods: 53 grade II and III glioma patients with preoperative MRI, CT, and MET-PET who underwent surgical resection or biopsy during 2000–2019 were included in this study. Out of the 53 cases, astrocytic tumors (A group: IDH-mutant, 1p19q non-codeleted) were 17, oligodendroglial tumors (O group: IDH-mutant, 1p19q codeleted) were 15, and IDH wild tumors (W group) were 21. MR and CT scans were evaluated by 3 independent reviewers to assess presence/absence of T2-FLAIR mismatch sign and calcification in the tumor, respectively. The tumor-to-normal (T/N) ratio of methionine uptake was calculated by dividing the maximum standardized uptake value (SUV) for the tumor by the mean SUV of the normal brain. Results: Out of the 53 cases, T2-FLAIR mismatch sign was present in 6 cases in group A and 9 cases in group W (p=0.008). Calcification in tumor was present in 2 cases in group A, 7 cases in group O, and 3 cases in group W (p=0.046). In the T2-FLAIR mismatch-positive cases, assuming MET-PET T/N>1.401 was group W and <1.401 was group A, sensitivity was 100% and specificity was 67%. In the T2-FLAIR mismatch-negative and calcification-positive cases, assuming those group O, the diagnostic predictive value was 70%. In the T2-FLAIR mismatch-negative and calcification-negative cases, assuming MET-PET T/N>2.349 was group W and <2.349 was group A or O, sensitivity was 60% and specificity was 94%. Conclusions: Combined diagnostic prediction of T2-FLAIR mismatch, calcification, and MET-PET T/N may be useful for preoperative molecular diagnosis of grade II and III gliomas.

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NI-06 MOLECULAR DIAGNOSIS, 11C-METHIONINE UPTAKE AND PROGNOSIS IN GRADE 2 AND 3 GLIOMAS

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz039.119 ◽

2019 ◽

Vol 1 (Supplement_2) ◽

pp. ii26-ii26

Author(s):

Kaoru Tamura ◽

Yaeko Furuhashi ◽

Motoki Inaji ◽

Daisuke Kobayashi ◽

Takahiro Ogishima ◽

...

Keyword(s):

Who Classification ◽

Genetic Alterations ◽

Normal Brain ◽

Lower Grade ◽

Who Grade ◽

Oligodendroglial Tumors ◽

Integrated Diagnosis ◽

Lower Grade Glioma ◽

Methionine Uptake ◽

Grade 3

Abstract OBJECT The revised 2016 WHO Classification of Tumours of the Central Nervous System incorporates genetic alterations into the classification system, with the goal of creating more homogenous disease categories with greater prognostic value. In this study, we reclassified 103 consecutive lower grade gliomas using the revised 2016 WHO classification and examined for 11C-methionine uptake and prognosis. METHODS 103 consecutive lower grade glioma patients (Grade 2 in 41 patients, Grade 3 in 62 patients) treated at Tokyo Medical and Dental University Hospital from 2000 to 2018 were included in this study. The IDH1/2, ATRX and 1p19q status were analyzed using tumor samples. The tumor-to-normal ratio (T/N) of 11 C-methionine uptake was calculated by dividing the maximum standardized uptake value (SUV) for the tumor by the mean SUV of the normal brain. RESULT In the integrated diagnosis, 11 astrocytomas and 17 anaplastic astrocytomas were diagnosed as “IDH-mutant”, while 14 astrocytomas and 29 anaplastic astrocytomas were diagnosed as “IDH-wild”. In the 32 oligodendroglial tumors, 12 oligodendrogliomas and 9 anaplastic oligodendrogliomas were diagnosed as “IDH-mutant and 1p/19q-codeleted”. The concordance rate with 1p19q co-deletion and ATRX retention was 94.7%. The median T/N ratios in oligodendroglial tumors with “IDH-mutant and 1p/19q-codeleted” were 1.83 in Grade 2 and 2.83 in grade 3, which were significantly higher than those in astrocytic tumors with “IDH-mutant” (G2: 1.38, G3:1.62). Kaplan-Meier survival analysis revealed that oligodendroglial tumors with “IDH-mutant and 1p/19q-codeleted” had significantly better outcomes regardless of WHO grade. Overall survival was 90.9% at 5 years and 77.9% at 10 years in oligodendroglial tumors with “IDH-mutant and 1p/19q-codeleted”. CONCLUSIONS The results indicated that lower grade glioma categories reclassified with molecular classification correlate with the T/N ratio of methionine and the prognosis.

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Functional outcomes after resection of middle frontal gyrus diffuse gliomas

Journal of Neurosurgery ◽

10.3171/2021.8.jns211624 ◽

2021 ◽

pp. 1-8

Author(s):

Ramin A. Morshed ◽

Anthony T. Lee ◽

Elaina J. Wang ◽

Jacob S. Young ◽

Soonmee Cha ◽

...

Keyword(s):

Functional Outcomes ◽

Middle Frontal Gyrus ◽

Diffuse Glioma ◽

Minimal Risk ◽

Who Grade ◽

Intraoperative Mapping ◽

Diffuse Gliomas ◽

The Mean ◽

Dti Tractography ◽

Subcortical Mapping

OBJECTIVE The clinical outcomes for patients undergoing resection of diffuse glioma within the middle frontal gyrus (MFG) are understudied. Anatomically, the MFG is richly interconnected to known language areas, and nearby subcortical fibers are at risk during resection. The goal of this study was to determine the functional outcomes and intraoperative mapping results related to resection of MFG gliomas. Additionally, the study aimed to evaluate if subcortical tract disruption on imaging correlated with functional outcomes. METHODS The authors performed a retrospective review of 39 patients with WHO grade II–IV diffuse gliomas restricted to only the MFG and underlying subcortical region that were treated with resection and had no prior treatment. Intraoperative mapping results and postoperative neurological deficits by discharge and 90 days were assessed. Diffusion tensor imaging (DTI) tractography was used to assess subcortical tract integrity on pre- and postoperative imaging. RESULTS The mean age of the cohort was 37.9 years at surgery, and the median follow-up was 5.1 years. The mean extent of resection was 98.9% for the cohort. Of the 39 tumors, 24 were left sided (61.5%). Thirty-six patients (92.3%) underwent intraoperative mapping, with 59% of patients undergoing an awake craniotomy. No patients had positive cortical mapping sites overlying the tumor, and 12 patients (33.3%) had positive subcortical stimulation sites. By discharge, 8 patients had language dysfunction, and 5 patients had mild weakness. By 90 days, 2 patients (5.1%) had persistent mild hand weakness only. There were no persistent language deficits by 90 days. On univariate analysis, preoperative tumor size (p = 0.0001), positive subcortical mapping (p = 0.03), preoperative tumor invasion of neighboring subcortical tracts on DTI tractography (p = 0.0003), and resection cavity interruption of subcortical tracts on DTI tractography (p < 0.0001) were associated with an increased risk of having a postoperative deficit by discharge. There were no instances of complete subcortical tract transections in the cohort. CONCLUSIONS MFG diffuse gliomas may undergo extensive resection with minimal risk for long-term morbidity. Partial subcortical tract interruption may lead to transient but not permanent deficits. Subcortical mapping is essential to reduce permanent morbidity during resection of MFG tumors by avoiding complete transection of critical subcortical tracts.

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P14.95 Is the pathological-grade relevant in “IDH-wild type, TERT-mutant” diffuse-gliomas? An analysis in 147 patients

Neuro-Oncology ◽

10.1093/neuonc/noz126.330 ◽

2019 ◽

Vol 21 (Supplement_3) ◽

pp. iii90-iii90

Author(s):

A E Danyeli ◽

C B Akyerli ◽

A Dinçer ◽

E Coşgun ◽

U Abacıoğlu ◽

...

Keyword(s):

Overall Survival ◽

Progression Free Survival ◽

Genetic Alterations ◽

Lower Grade ◽

Wild Type ◽

Ki 67 ◽

Who Grade ◽

Free Survival ◽

Tert Promoter ◽

Diffuse Gliomas

Abstract BACKGROUND Although the word “glioblastoma” still denotes a grade-IV pathology, basic molecular studies have clearly indicated that a significant proportion of lower-grade gliomas harbor genetic alterations typical of glioblastomas. Based on these findings cIMPACT-NOW update 3 has defined an entity called the “diffuse astrocytic glioma, IDH-wildtype, with molecular features of glioblastoma, WHO grade IV”. A TERT-promoter mutation is one of these typical molecular markers of glioblastomas. In this study we analyzed IDH-wild type, TERT-mutant diffuse gliomas of different pathological grades to look for differences in demographic, clinical and survival characteristics. MATERIAL AND METHODS 147 adult hemispheric diffuse-gliomas with wild-type IDH1/2 and mutant TERT-promoter (C228T or C250T) were retrospectively analyzed. Primary thalamic, cerebellar brainstem or spinal cases were excluded. 126 (86%), 16(11%) and 5(3%) patients were WHO grade IV, III and II respectively. After surgical treatment or stereotactic biopsy all patients underwent chemoradiation. Median follow-up was 16mo (1–110). Tumors of different grades were compared for age, gender, multifocality, gliomatosis pattern, Ki-67 index, progression-free survival and overall-survival. RESULTS Mean age at presentation for grade II, III and IV were comparable (58.1, 58 and 58.1; ANOVA, p=0.72). There was a slight male predominance in both lower-grades and WHO-grade IV (M:F ratios 1.625 and 1.74). Mean Ki-67 index was significantly higher in higher grades (0.06, 0.14 and 0.25 for grades II, III and IV; ANOVA, p=0.001). Multifocality was comparable (chi-sq, p=1) in lower-grades (3/21; 14.3%) vs. WHO-grade IV (18/126; 14.3%). Gliomatosis pattern was comparable (chi-sq, p=0.095) in lower-grades (2/21; 9.5%) vs. (3/126; 2.3%). Median recurrence free survival (RFS) was 16 months (0–63) in lower-grades and 8months (1–50) in WHO-grade IV. PFS was significantly different between 3 WHO-grades (Log rank, p=0.007) and also between lower-grades and WHO-grade IV (Log rank, p=0.002). Median overall survival was 26 months(2–110) in lower-grades and 15mo(1–91) in WHO-grade IV. OS was significantly different between 3 WHO-grades (Log rank, p=0.014) and also between lower-grades and WHO-grade IV (Log rank, p=0.007). CONCLUSION Increasing pathological grades of hemispheric “IDH-wild type, TERT-mutant diffuse gliomas” have similar demographic and clinical characteristics but incrasing proliferation indices, decrasing progression free survival and shorter overall survival. The findings may be suggesitve of different grades of one common tumor entity.

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NCOG-25. REVISITING THE PIGNATTI RISK SCORE IN LOW-GRADE GLIOMA PATIENTS IN THE MOLECULAR ERA

Neuro-Oncology ◽

10.1093/neuonc/noab196.616 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi157-vi157

Author(s):

Christine Jungk ◽

Mara Gluszak ◽

Philip Dao Trong ◽

Andreas von Deimling ◽

Christel Herold-Mende ◽

...

Keyword(s):

Prognostic Factors ◽

Risk Score ◽

Low Grade ◽

Tumor Diameter ◽

Diffuse Glioma ◽

Who Grade ◽

Cox Regression Analysis ◽

Diffuse Gliomas ◽

The Individual

Abstract Until now, the Pignatti risk score has been used to guide treatment decisions after histological diagnosis of diffuse glioma WHO grade 2. However, its prognostic value was derived from a historic cohort that has been diagnosed by morphologic rather than molecular criteria. We re-challenged the Pignatti score in a contemporary, molecularly characterized cohort. From our institutional cohort of 422 diffuse gliomas WHO grade 2, 202 patients were identified for whom IDH mutation status was known and 1p/19q co-deletion or loss of ATRX expression unambiguously classified tumors into astrocytoma or oligodendroglioma. Patients with IDH wildtype astrocytoma (n=9), multifocal lesions or brainstem involvement were excluded. Potential prognostic factors including the individual items of the Pignatti score (astrocytoma; age ≥40 years; neurologic deficit; maximum tumor diameter ≥6cm; tumor crossing midline) were correlated with progression-free survival (PFS) by univariate log-rank und multivariate Cox regression analysis. 165 patients with astrocytoma or oligodendroglioma were analysed of whom 109 (66%) did not receive adjuvant radio- or chemotherapy. 94 untreated patients with a minimum follow-up of 24 months entered survival analysis. These patients were classified as “high-risk” (Pignatti 3-5) and “low-risk” (Pignatti 0-2) in 15% and 85% and did not differ with regard to potential prognostic factors (gender; resection vs. biopsy; tumor recurrence) other than the individual Pignatti score items. Diameter ≥6 cm (p=0.006; HR=2.18) and midline crossing (p=0.003; HR=3.54) were identified as independent prognostic factors of PFS. Noteworthy, prognostic factors coincided when all patients (n=144) with a minimum follow-up of 24 months, regardless of adjuvant treatment, were analysed. In IDH mutant, molecularly characterized diffuse gliomas WHO grade 2, the Pignatti risk score as a whole no longer seems to be of prognostic relevance. Instead, outcome seems to be determined by tumor burden.

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Molecular diagnosis of diffuse glioma using a chip-based digital PCR system to analyze IDH, TERT, and H3 mutations in the cerebrospinal fluid

Journal of Neuro-Oncology ◽

10.1007/s11060-020-03682-7 ◽

2021 ◽

Author(s):

Yutaka Fujioka ◽

Nobuhiro Hata ◽

Yojiro Akagi ◽

Daisuke Kuga ◽

Ryusuke Hatae ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Molecular Diagnosis ◽

Point Mutations ◽

High Sensitivity ◽

Digital Pcr ◽

World Health ◽

Molecular Diagnostic ◽

Diffuse Glioma ◽

Who Grade ◽

Tumor Dna

Abstract Purpose Conventional genetic analyzers require surgically obtained tumor tissues to confirm the molecular diagnosis of diffuse glioma. Recent technical breakthroughs have enabled increased utilization of cell-free tumor DNA (ctDNA) in body fluids as a reliable resource for molecular diagnosis in various cancers. Here, we tested the application of a chip-based digital PCR system for the less invasive diagnosis (i.e., liquid biopsy) of diffuse glioma using the cerebrospinal fluid (CSF). Methods CSF samples from 34 patients with diffuse glioma were collected from the surgical field during craniotomy. Preoperative lumbar CSF collection was also performed in 11 patients. Extracted ctDNA was used to analyze diagnostic point mutations in IDH1 R132H, TERT promoter (C228T and C250T), and H3F3A (K27M) on the QuantStudio® 3D Digital PCR System. These results were compared with their corresponding tumor DNA samples. Results We detected either of the diagnostic mutations in tumor DNA samples from 28 of 34 patients. Among them, we achieved precise molecular diagnoses using intracranial CSF in 20 (71%). Univariate analyses revealed that the World Health Organization (WHO) grade (p = 0.0034), radiographic enhancement (p = 0.0006), and Mib1 index (p = 0.01) were significant predictors of precise CSF-based molecular diagnosis. We precisely diagnosed WHO grade III or IV diffuse gliomas using lumbar CSF obtained from 6 (87%) of 7 patients with tumors harboring any mutation. Conclusion We established a novel, non-invasive molecular diagnostic method using a chip-based digital PCR system targeting ctDNA derived from CSF with high sensitivity and specificity, especially for high-grade gliomas.

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NIMG-32. THE PREDICTIVE CAPACITY OF PRE-OPERATIVE IMAGING ANALYSIS IN DIFFUSE GLIOMA: A COMPARISON OF CONNECTOMICS, RADIOMICS, AND CLINICAL PREDICTIVE MODELS

Neuro-Oncology ◽

10.1093/neuonc/noaa215.645 ◽

2020 ◽

Vol 22 (Supplement_2) ◽

pp. ii154-ii155

Author(s):

Rebecca Harrison ◽

Bryce Wei Quan Tan ◽

Hong Qi Tan ◽

Lloyd Tan ◽

Mei Chin Lim ◽

...

Keyword(s):

Model Building ◽

Gray Matter Volume ◽

Brain Mri ◽

Cox Proportional Hazards ◽

Interaction Matrix ◽

Diffuse Glioma ◽

Who Grade ◽

Clinical Model ◽

Clinical Variables ◽

The Mean

Abstract BACKGROUND Radiomics and connectome analysis are distinct and non-invasive methods of deriving biologic information from MRI. Radiomics analyzes features intrinsic to the tumor, and connectomics incorporates data regarding the tumor and surrounding neural circuitry. In this study we used both techniques to predict glioma survival. METHODS We retrospectively identified 305 adult patients with histopathologically confirmed WHO grade II–IV gliomas who had presurgical, 3D, T1-weighted brain MRI. Available clinical variables included tumor lobe, hemisphere, multifocal nature grade, histology extent of surgical resection, patient age gender. For connectomics, we calculated nodal efficiencies, network size and degree for all pairs of 33 voxel cubes spanning the entire gray matter volume using similarity-based extraction and graph theory. Radiomic features were extracted using Pyradiomics and subjected to patient-level and population-level clustering (N=172). These clusters were then used to construct a multi-regional spatial interaction matrix for model building. Cox proportional hazards models were fit for clinical variables alone, connectomics alone, radiomics alone, connectomics+clinical and radiomics+clinical. We implemented 10-folds cross-validation and examined the mean area under the curve (AUC) across validation loops. RESULTS Median survival time was 134.2 months. The mean AUC for the clinical model was 0.79 +/- 0.01, the connectome model was 0.88 +/- 0.01, the combined connectome + clinical model was 0.93 +/- 0.01, the radiomic model was 0.64 +/- 0.05 and the radiomics+clinical model was 0.89+/-0.03. Radiomic analysis of the entire dataset as well as comparisons of radiomic+connectomics +/- clinical models are pending. CONCLUSIONS The combination of clinical variables and connectome analysis provided a more robust predictive model than other models. This suggests that connectome analysis incorporates valuable clinically-predictive information which can augment our capacity for prognostication of patients with diffuse glioma. These methods warrant further evaluation in larger prospective study of patients with diffuse glioma.

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NGMA-1. Quantification of IDH mutant alleles predicts outcome in diffuse gliomas

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab070.016 ◽

2021 ◽

Vol 3 (Supplement_2) ◽

pp. ii4-ii4

Author(s):

Mathew Voisin ◽

Gelareh Zadeh

Keyword(s):

Overall Survival ◽

Progression Free Survival ◽

Absolute Quantification ◽

Specific Method ◽

Diffuse Glioma ◽

Who Grade ◽

Initial Surgery ◽

Highly Sensitive ◽

Idh Mutations ◽

Diffuse Gliomas

Abstract Background IDH mutation is the main factor used in the prognostication of diffuse gliomas, however within IDH mutated gliomas there still remains a high variability in both tumor progression and overall survival.1 Digital droplet polymerase chain reaction (ddPCR) is one of the latest molecular amplification techniques that offers high precision in addition to the ability of absolute quantification of mutant allele copies.2 Methods A total of 102 IDH mutant diffuse glioma tumor samples ranging from WHO grade 2 to 4 were collected. This cohort includes a total of 45 paired samples collected at two distinct surgical timepoints: initial and recurrent. All samples underwent DNA extraction. A total of 5 ng of tumor DNA from each sample was analyzed using ddPCR for the detection and quantification of IDH1 R132H mutant alleles. Sanger sequencing was performed on all samples as a gold standard. Results ddPCR was highly sensitive (100%) and specific (99%) for the detection of IDH mutations. Initial tumor samples with a high number of IDH mutant copies split by median demonstrated decreased overall survival (p = 0.04) and shorter progression free survival (p = 0.024). The number of IDH mutant copies was independent of WHO grade (p = 0.6) and 1p19q codeletion status (p = 0.86). Tumor pairs that had IDH mutant copies increase at recurrence were trending but not significantly related to a decrease in remaining survival (p = 0.1). Conclusions ddPCR is a highly sensitive and specific method of detecting IDH mutations in diffuse gliomas. The number of IDH mutant copies in tumors at initial surgery can serve as an independent prognostic factor to help guide future treatment and follow-up.

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ECOA-6. Genomic and transcriptomic analyses reveal diverse mechanisms responsible for deregulation of epigenetic enzyme/modifier expression in glioblastoma

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab070.006 ◽

2021 ◽

Vol 3 (Supplement_2) ◽

pp. ii2-ii2

Author(s):

Marta Maleszewska ◽

Bartosz Wojtas ◽

Bartlomiej Gielniewski ◽

Shamba Mondal ◽

Jakub Mieczkowski ◽

...

Keyword(s):

Epigenetic Modification ◽

Malignant Gliomas ◽

Genetic Alterations ◽

Common Denominator ◽

Normal Brain ◽

Lower Grade ◽

Down Regulation ◽

Regulation Of Expression ◽

Aberrant Expression ◽

Who Grade

Abstract Malignant gliomas represent over 70% of primary brain tumors and the most deadly is glioblastoma (GBM, WHO grade IV), due to frequent dysfunctions of tumor suppressors or/and oncogenes. Recent whole genome studies of gliomas demonstrated that besides genetic alterations, epigenetic dysfunctions contribute to tumor development and progression. Alterations in genes encoding epigenetic enzyme/protein or aberrations in epigenetic modification pattern have been found in gliomas of lower grade, yet no epigenetic driver was identified in GBM. We sought to identify different mechanisms driving aberrant expression of epigenetic genes in GBM. We analyzed gene expression and coding/non-coding regions of 96 major epigenetic enzymes and chromatin modifiers in 28 GBMs, 23 benign gliomas (juvenile pilocytic astrocytomas, JPAs, WHO grade I) and 7 normal brain samples. We found a profound and global down-regulation of expression of most tested epigenetic enzymes and modifiers in GBMs when compared to normal brains and JPAs. For some genes changes in mRNA level correlated with newly identified single nucleotide variants within non-coding regulatory regions. To find a common denominator responsible for the coordinated down-regulation of expression of epigenetic enzymes/modifiers, we employed PWMEnrich tool for DNA motif scanning and enrichment analysis. Among others, we discovered the presence of high affinity motifs for the E2F1/E2F4 transcription factors, within the promoters of the epigenetic enzyme/modifier encoding genes. Knockdown of the E2F1/E2F4 expression affected the expression of a set of epigenetic enzymes/modifiers. Altogether, our results reveal a novel epigenetic-related pathway by which E2F1/E2F4 factors contribute to glioma pathogenesis and indicate novel targets for glioma therapy. Supported by a National Science Centre grant 2013/09/B/NZ3/01402 (MM).

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MPC-18 CATEGORIZATION OF LOWER GRADE GLIOMA USING ONCOPANEL

Neuro-Oncology Advances ◽

10.1093/noajnl/vdz039.113 ◽

2019 ◽

Vol 1 (Supplement_2) ◽

pp. ii25-ii25

Author(s):

Hiroyuki Uchida ◽

Toshiaki Akahane ◽

Nayuta Higa ◽

Mari Kirishima ◽

Tsubasa Hiraki ◽

...

Keyword(s):

Genetic Alterations ◽

Lower Grade ◽

Diffuse Glioma ◽

Diffuse Astrocytoma ◽

Idh Mutation ◽

Who Grade ◽

Egfr Amplification ◽

Integrated Diagnosis ◽

Lower Grade Glioma ◽

Tert Mutation

Abstract PURPOSE We are developing a 48-gene OncoPanel (Kagoshima Brain Tumor 48 OncoPanel) specializing in glioma diagnosis. Clinical application of genetic diagnosis derived from genetic alterations detected by OncoPanel, including IDH mutation, 1p/19q-codeletion, and other gene mutations in lower-grade glioma was verified. METHODS The 48 genes consist of 24 genes related to glioma and 24 genes on chromosomes 1 and 19. DNA was extracted from tumor FFPE samples and blood samples, and then single nucleotide variants and copy number variants were detected using next-generation sequencer. RESULTS Among the 99 diffuse glioma cases that had undergone OncoPanel analysis by July 2019, 40 cases diagnosed histologically as WHO grade 2 or 3 diffuse glioma were included. The integrated diagnosis by conventional gene analysis were Diffuse astrocytoma 10 cases, anaplastic astrocytoma 11 cases, oligodendroglioma 10 cases, anaplastic oligodendroglioma 9 cases. IDH1 mutation was detected in 30 cases, of which in 19 cases 1p/19q-codeletion was detected, all with TERT mutation. Among 11 cases with 1p/19q-non-codeletion, ATRX mutation was detected in 10 cases and was almost mutually exclusive with TERT mutation. In 10 cases without IDH mutation, EGFR amplification or mutation was detected in 6 cases, of which 4 cases were accompanied by TERT mutation. DISCUSSION KBT48 can detect TERT and ATRX mutations in a mutually exclusive manner and can improve the classification accuracy of oligodendroglioma and astrocytoma. Groups with gene profiles similar to glioblastoma with EGFR amplification/mutation and TERT mutation can also be classified. CONCLUSIONS In the diagnostic classification of lower-grade glioma, KBT48 can well classify into oligodendroglioma group, astrocytoma group and glioblastoma-like group, and is considered to be applicable in clinical practice.

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