1p19q Codeletion Research Articles

PATH-35. SHIFTS IN GLIOMA PROGNOSTIC MOLECULAR FEATURES ACROSS THE LIFESPAN

Abstract INTRODUCTION Epidemiological studies examining glioma prognostic features have consistently identified older age as a negative predictor of survival. Accumulation and co-occurrence of favorable or deleterious molecular alterations across the lifespan likely plays a role in the age-dependent variability seen in glioma patient outcomes. METHODS We assembled 4,297 molecularly and clinically annotated glioma patients from multi-institutional datasets and TCGA, with IDH1/2-mutation, MGMT-methylation, and chromosome 1p19q codeletion status assayed. Patient age was stratified: pediatric (< 20 years), young adult (20-39 years), middle aged (40-64 years), and older adults ( >65 years). Pairwise proportions were tested to study distribution of alterations across age as well as variability in assaying for MGMT-methylation. RESULTS 4,297 patients with glioma were identified with molecular annotation of IDH1/2-mutation status (40.1% IDH1/2-mutant). Of assayed gliomas, 44.3% were MGMT-methylated and 13.9% had chromosome 1p19q codeletion. IDH1/2-mutation incidence decreased with age across all gliomas (85% in young adults, 35% middle aged, and 8% older adults) and in grade 4 gliomas (64% IDH1/2-mutation in young adults, 9% middle aged, and 2% older adults). 1p19q codeletion also decreased in incidence with increasing age (young adult 22%, middle aged 15%, older adults 6%). MGMT-methylation remained consistent across adult patients, between 43-50% across all gliomas. Interestingly, amongst the few patients >65 years old with IDH1/2-mutation or 1p19q codeletion, 87% possessed co-occurring MGMT-methylation, significantly greater than young adults (54%, p< 0.001). Consistent with this, 82% of patients >65yrs with grade 4 IDH1/2-mutant gliomas had co-occurring MGMT-methylation. Despite the treatment response implication of MGMT-methylation, 72.2% of low-grade gliomas were not assayed for MGMT. CONCLUSIONS There is an age-dependent pattern of molecular alterations in gliomas, with the incidence of certain favorable prognostic signatures decreasing over time. Given the stability of MGMT-methylation across the age spectrum and grade, more widespread MGMT profiling may be beneficial to guide treatment decisions.

PATH-04. TRANSFORMATION OF GRADE 2 OLIGODENDROGLIOMA TO GLIOSARCOMA WITH RAPID AND EXTENSIVE PROGRESSION: CASE REPORT.

Abstract Transition of WHO grade 2 oligodendroglioma to gliosarcoma is rare. We report a case of a 40 year-old gentleman with WHO grade 2 oligodendroglioma, isocitrate dehydrogenase enzyme (IDH)-mutant, 1p/19q co-deletion positive, O6-methylguanine-DNA methyltransferase (MGMT) promoter methylated, tumor mutational burden of 5 mutations/megabase, with microsatellite stability. He underwent rapid and extensive transformation to WHO grade 4 glioblastoma with gliosarcomatous features, mesenchymal subclass on DNA methylation, IDH-wild type, 1p/19q co-deletion negative, MGMT promoter methylated. He was diagnosed with bi-hemispheric multifocal partially enhancing, T2-FLAIR hyperintense lesions. Pathology revealed WHO grade 2 oligodendroglioma. He enrolled on a clinical trial to receive proton radiation (45 Gray in 25 fractions) to the involved tumor sites. Three weeks after initiation of radiation, he developed headache, imbalance, and confusion. MRI brain 3 weeks after completion of radiation revealed worsening enhancement, edema, and a new region of non-enhancing T2-FLAIR hyperintensity. Bevacizumab was added for presumed pseudo-progression; followed by chemotherapy with procarbazine and lomustine (PC). Four cycles of PC were completed with observations of gradual clinical and radiographic worsening after each cycle. Re-resection of multifocal tumor for tissue diagnosis and tumor debulking revealed progression to WHO grade 3 oligodendroglioma with high mitotic activity and regions of palisading necrosis. Two weeks postoperatively, malignant cerebral edema developed, requiring left sided decompressive craniectomy. Despite early introduction of 2nd-line chemotherapy with temozolomide, his disease continued to progress and he succumbed 1.5 years after initial diagnosis. Autopsy revealed extensive bi-hemispheric involvement of WHO grade 4 glioblastoma. Our patient demonstrated unusually rapid clinical and radiographic progression within one month after completion of radiation. Other reported cases in the literature have documented progression at 1 to 5 years after initial treatment. Both IDH mutation and 1p19q co-deletion were lost in the gliosarcomatous transformation. This tumor did not respond to alkylating agents despite the MGMT promoter-methylated status.

Clinical characteristics and prognostic factors of solitary and multiple adult gliomas: a retrospective study based on propensity score matching.

This study aims to compare the survival and prognostic factors in patients with solitary gliomas to those with multiple to improve the understanding of multiple gliomas and investigate their heterogeneous dissemination pathways. Data on 358 patients diagnosed with adult gliomas confirmed by postoperative pathology were retrospectively collected and analyzed. The clinical characteristics, survival rates and prognosis of patients were analyzed by propensity score matching (PSM). Between the two groups, statistically significant differences were identified in multiple general clinical characteristics, including age, pathological grade, lesion location, 1p19q co-deletion, IDH1 mutation, MGMT promoter methylation expression rate, p53 mutation and NF1 mutation (p<0.05). Before PSM, the mOS for patients with multiple gliomas was shorter than that for those with solitary (p=0.0045). Multivariate Cox regression analysis revealed that age, pathological grade IV, and absence of concurrent chemotherapy were significant risk factors affecting OS. Pathological grade IV, ki-67 expression range of 25-50%, and absence of concurrent chemotherapy were identified as risk factors for PFS. After PSM, the prognostic factors associated with OS were age and concurrent chemotherapy, while those associated with PFS were ki-67 expression range of 50-75% and lesion located in the right frontal lobe (p<0.05). The prognosis for multiple gliomas is extremely poor, which is related to the fact that the most common pathological types are glioblastomas and the surgical procedure is challenging. Concurrent chemotherapy and radiotherapy are the strongest protective prognostic factors, and the differences in their molecular pathology expression compared to solitary gliomas remain for further investigation.

SDPS-17 COMPREHENSIVE ANALYSIS OF CELL DIVISION CYCLE ASSOCIATED GENE FAMILY EXPRESSION PATTERN AND PROGNOSIS VALUE REVEALS CDCA2 AS A NOVEL ONCOGENE FOR GLIOMA

Abstract Glioma is the most common central nervous system tumors. Although many biomarkers have been reported for detecting glioma, the prognosis for the disease remains poor, and therefore, new biomarkers need to be identified. The cell division cycle associated proteins (CDCA) family gene is involved in a wide range of biological functions in human cancers. Nevertheless, the expression characteristics of CDCAs, and prognostic value landscape of glioma are remain unknown. Based on a wide variety of public databases and integrated several bioinformatics analysis methods, we evaluated expression dysregulations, clinical implications, DNA methylation, copy number alterations, prognostic and therapeutic values of CDCA family gene in glioma. Further, we identified crucial biomarker, CDCA2, that influence the progression of malignant glioma and poor prognosis. Thereafter, we disclosed the effect of CDCA2 knockdown on the biological function of glioma cells through various experiments in vitro. We found that the elevated mRNA expression of CDCAs in glioma. The upregulated expression of CDCAs was found to be associated with the tumor grade in glioma. The overexpression of CDCAs mRNA were correlated with the poor prognosis. Moreover, the expression level of CDCA2 was significantly higher in glioma, and the level is correlated with grade, age, IDH1 mutation and 1p19q codeletion states. Further cell experimental results supported that the ability of cell proliferation, migration, invasion and radioresistance of glioma cells was significantly decreased after downregulated CDCA2 expression, and these changes may be achieved through the RAD51 and p21/CDK2/CyclinE1 signaling pathways. These findings provide new insights into CDCAs from a bioinformatics standpoint and highlight the significance of CDCAs in glioma diagnosis and treatment. And knockdown of CDCA2 inhibits glioma cells' proliferation, migration, invasion and radioresistance. Regulation of CDCA2 on malignant progression of glioma cells may be realized through the RAD51 and p21/CDK2/CyclinE1 signaling pathways.

Increased KCNN4 Expression Is Correlated With Poor Survival in Lower Grade Glioma.

Networks of glioma cells are linked to small groups of pacemaker cells in which levels of calcium ions pulse periodically, driving a signal through the network that causes tumor growth. Using inhibitors, one study blocked the activity of the Ca2+activated potassium-channel protein KCa3.1 in in vitro models and mice, preventing the proliferation of glioma cells and tumor expansion. Marked reduction of tumor cell viability occurred within the entire network, as well as reduced tumor growth in mice and extended animal survival. KCa3.1 is encoded by the gene potassium calcium-activated channel subfamily N member 4 (KCNN4) on the chromosomal location 19q13.31. We used the Cancer Genome Atlas (TCGA) to evaluate the effect of KCNN4 on human glioma survival in the TCGA Lower Grade Glioma (LGG) dataset. In humans, KCNN4 is prognostic in glioma; high expression is unfavorable. In addition, KCNN4 copy number variations are prognostic. Increased masked copy number segments are unfavorable in lower grade glioma. KCNN4 is lost in gliomas with the 1p 19q co-deletion, which may explain in part the comparatively favorable prognosis of 1p 19q co-deletion tumors. Our finding of increased KCNN4 expression related to poor survival in human lower grade glioma suggests that developing novel therapies, such as KCa3.1-inhibiting drugs, might be worthwhile.

When to treat: A multicenter retrospective study of timing of radiation therapy in 1p19q co-deleted, IDH mutated oligodendrogliomas.

e14036 Background: Oligodendrogliomas, molecularly defined by IDH mutation and 1p19q codeletion, have a protracted natural history and are more chemoresponsive compared to astrocytomas. While the addition of chemotherapy to radiation improves survival, if chemoradiation should be initiated following diagnosis or at progression remains unknown. Given the potential for early and late radiation-related toxicity, a careful evaluation of timing of treatment is critical to optimize treatment guidelines for oligodendroglioma. We aimed to evaluate the benefit of initial adjuvant radiation therapy (RT) on survival in patients with oligodendrogliomas. Methods: We conducted a multicenter retrospective study of patients treated at the University of Washington and Stanford Medical Center with oligodendrogliomas using both 1p19q codeletion and IDH mutation to define the diagnosis, reflecting the World Health Organization 2021 diagnostic criteria. Survival probability, overall survival (OS) and time to first progression (PFS), were calculated using Kaplan-Meier method with distributions compared using log-rank test in GraphPad Prism. Propensity Score Matching was completed using XLSTAT. Results: 243 patients were identified as oligodendroglioma and 229 had treatment and survival data available with a median follow up of 5.8 years(y). Median OS was 22.5y and median PFS was 5.35y. 110 patients were treated with adjuvant radiation (aRT) within 1y of diagnosis and 119 underwent observation or chemotherapy alone (delayed RT, or dRT). PFS was comparable between aRT (7.7y) and dRT (4.6y) but OS was longer in dRT (27.8y) than aRT (13.7y) (p &lt; 0.001). Given imbalance in baseline characteristics, propensity score matching was used to adjust for high risk factors of age, grade and presence of residual disease resulting in 63 pairs. In this matched cohort, aRT prolonged PFS (aRT = 7.75y v. dRT = 4.33y, p = 0.006) however dRT still demonstrated a survival benefit (p = 0.017). 59 dRT patients were treated with RT at progression and also had longer medan OS of 22.6y compared to 13.7y in the aRT (p = &lt; 0.0001). The time to RT for this cohort ranged be 1.1-19y. Conclusions: To our knowledge this is the largest retrospective study of molecularly defined oligodendrogliomas that includes treatment information. This study confirms the protracted natural history of this disease. In our multi-institution cohort, early adjuvant radiation therapy may increase PFS but was not found to prolong OS. Prospective studies evaluating the timing of treatment in patients with oligodendroglioma are needed. [Table: see text]

Ivosidenib off-label use for IDH mutant gliomas: The MD Anderson Cancer Center real life experience.

e14022 Background: Ivosidenib, a small-molecule IDH inhibitor is FDA approved for relapsed or refractory acute myeloid leukemia and cholangiocarcinoma with IDH1 mutation. Early phase clinical trials have shown promising findings for IDH mutant gliomas and results of larger studies of IDH inhibitors in gliomas are still pending. Meanwhile, neuro-oncologists continue to encounter patients with IDH mutant gliomas with limited treatment options. Here, we describe our experience with off-label use of ivosidenib in IDH mutant gliomas. Methods: This is a retrospective case series study in a single cancer care institute. Data points collected include but not limited to patient demographics, type of IDH mutation, treatment history prior to starting ivosidenib, duration of treatment, and progression-free survival. Descriptive statistics were used to summarize patient’s characteristics. The distribution of median progression-free survival (mPFS) was estimated by the Kaplan-Meier method. Results: From August 2018 to December 2022, we identified 13 patients with IDH-mutant glioma prescribed ivosidenib 500mg daily off-label. Four patients did not receive treatment: two were too sick soon after ivosidenib prescribed, and two were not able to get financial coverage. For the nine patients that were treated, median age was 37 (range 25-44). 8 were males and 1 was female. Five have IDH1 R132H mutations, 1p19q intact and four have IDH mutation and 1p19q co-deletion. The highest grade for the tumor is grade 3. Four have non-enhancing disease only. The median lines of therapy prior to starting ivosidenib was 2 (range 0-5). Three patients did not have radiation by the time they started ivosidenib, including two who received this drug as first-line treatment initiated by providers outside of MD Anderson. All patients are still alive as of January 11th, 2023. Disease control rate (all stable disease) was 78%. After a median follow-up of 17.8 (range 15-29) months, mPFS was 3.81 (95% CI: 1.25, 12.78) months. Patients with non-enhancing disease had better PFS than those with enhancing disease, but this was not statistically significant (median PFS: 8.28 vs 3.81 months, p-value = 0.42). Two patients had adverse events: one with grade 1 lethargy, and another patient had a grade 3 surgical wound infection unrelated to the drug requiring a pause in treatment. Conclusions: Ivosidenib was successfully approved by third party payers for treatment of nine patients with IDH mutant gliomas. Ivosidenib was well-tolerated with a modest PFS. Patients with non-enhancing disease may trend toward better PFS than those with enhancing disease. The updated survival data and potential correlation with clinical, molecular, and radiographic data will be presented at the conference.

The role of DSC MR perfusion in predicting IDH mutation and 1p19q codeletion status in gliomas: meta-analysis and technical considerations

PurposeIsocitrate dehydrogenase (IDH) mutation and 1p19q codeletion status are important for managing glioma patients. However, current practice dictates invasive tissue sampling for histomolecular classification. We investigated the current value of dynamic susceptibility contrast (DSC) MR perfusion imaging as a tool for the non-invasive identification of these biomarkers.MethodsA systematic search of PubMed, Medline, and Embase up to 2023 was performed, and meta-analyses were conducted. We removed studies employing machine learning models or using multiparametric imaging. We used random-effects standardized mean difference (SMD) and bivariate sensitivity-specificity meta-analyses, calculated the area under the hierarchical summary receiver operating characteristic curve (AUC) and performed meta-regressions using technical acquisition parameters (e.g., time to echo [TE], repetition time [TR]) as moderators to explore sources of heterogeneity. For all estimates, 95% confidence intervals (CIs) are provided.ResultsSixteen eligible manuscripts comprising 1819 patients were included in the quantitative analyses. IDH mutant (IDHm) gliomas had lower rCBV values compared to their wild-type (IDHwt) counterparts. The highest SMD was observed for rCBVmean, rCBVmax, and rCBV 75th percentile (SMD≈ − 0.8, 95% CI ≈ [− 1.2, − 0.5]). In meta-regression, shorter TEs, shorter TRs, and smaller slice thicknesses were linked to higher absolute SMDs. When discriminating IDHm from IDHwt, the highest pooled specificity was observed for rCBVmean (82% [72, 89]), and the highest pooled sensitivity (i.e., 92% [86, 93]) and AUC (i.e., 0.91) for rCBV 10th percentile. In the bivariate meta-regression, shorter TEs and smaller slice gaps were linked to higher pooled sensitivities. In IDHm, 1p19q codeletion was associated with higher rCBVmean (SMD = 0.9 [0.2, 1.5]) and rCBV 90th percentile (SMD = 0.9 [0.1, 1.7]) values.ConclusionsIdentification of vascular signatures predictive of IDH and 1p19q status is a novel promising application of DSC perfusion. Standardization of acquisition protocols and post-processing of DSC perfusion maps are warranted before widespread use in clinical practice.

Stalled oligodendrocyte differentiation in IDH-mutant gliomas

BackgroundRoughly 50% of adult gliomas harbor isocitrate dehydrogenase (IDH) mutations. According to the 2021 WHO classification guideline, these gliomas are diagnosed as astrocytomas, harboring no 1p19q co-deletion, or oligodendrogliomas, harboring 1p19q co-deletion. Recent studies report that IDH-mutant gliomas share a common developmental hierarchy. However, the neural lineages and differentiation stages in IDH-mutant gliomas remain inadequately characterized.MethodsUsing bulk transcriptomes and single-cell transcriptomes, we identified genes enriched in IDH-mutant gliomas with or without 1p19q co-deletion, we also assessed the expression pattern of stage-specific signatures and key regulators of oligodendrocyte lineage differentiation. We compared the expression of oligodendrocyte lineage stage-specific markers between quiescent and proliferating malignant single cells. The gene expression profiles were validated using RNAscope analysis and myelin staining and were further substantiated using data of DNA methylation and single-cell ATAC-seq. As a control, we assessed the expression pattern of astrocyte lineage markers.ResultsGenes concordantly enriched in both subtypes of IDH-mutant gliomas are upregulated in oligodendrocyte progenitor cells (OPC). Signatures of early stages of oligodendrocyte lineage and key regulators of OPC specification and maintenance are enriched in all IDH-mutant gliomas. In contrast, signature of myelin-forming oligodendrocytes, myelination regulators, and myelin components are significantly down-regulated or absent in IDH-mutant gliomas. Further, single-cell transcriptomes of IDH-mutant gliomas are similar to OPC and differentiation-committed oligodendrocyte progenitors, but not to myelinating oligodendrocyte. Most IDH-mutant glioma cells are quiescent; quiescent cells and proliferating cells resemble the same differentiation stage of oligodendrocyte lineage. Mirroring the gene expression profiles along the oligodendrocyte lineage, analyses of DNA methylation and single-cell ATAC-seq data demonstrate that genes of myelination regulators and myelin components are hypermethylated and show inaccessible chromatin status, whereas regulators of OPC specification and maintenance are hypomethylated and show open chromatin status. Markers of astrocyte precursors are not enriched in IDH-mutant gliomas.ConclusionsOur studies show that despite differences in clinical manifestation and genomic alterations, all IDH-mutant gliomas resemble early stages of oligodendrocyte lineage and are stalled in oligodendrocyte differentiation due to blocked myelination program. These findings provide a framework to accommodate biological features and therapy development for IDH-mutant gliomas.

Predictive significance of PRR11 in prognosis and immune infiltration of glioma patients.

Glioma, characterized by invasive growth and high recurrence, is the main cause of brain-tumor-related deaths. Currently, proline rich 11 (PRR11) has served as a reliable predictor in diagnosis, prognosis, and immunotherapeutic response of several human cancers. However, the predictive significance of PRR11 in prognosis and immune infiltration of glioma patients is still uncertain. Therefore, glioma-related information from multiple data sets and single-cell sequencing (scRNA-seq), including CGGA, TCGA_GTEx, GEO, 10x Genomics, and Smart-seq, was included in this study. Then, clinical correlation analysis, univariate and multivariate Cox analysis, Kaplan-Meier survival analysis, and receiver operating characteristic curve analysis were utilized to explore diagnostic and prognostic value of PRR11 in glioma. Besides, functional mechanisms of PRR11 in glioma were also carried out via Spearman's correlation, immune infiltration, scRNA-seq, gene ontology enrichment, and Kyoto encyclopedia of genes and genomes analysis. Finally, we selected two glioma cell lines, U251 and LN229, for validation of oncogenic role of PRR11 in glioma. As a result, PRR11 is a promising and reliable predictor in diagnosis and prognosis of glioma patients, positively correlates with clinical malignancy, World Health Organization grades, IDH mutation status, 1p19q codeletion status, histology, and poor survival time. Mechanically, PRR11 is specifically overexpressed in Mano/Macro_C21 and CD8Tex cells and interferes with cell-cycle, transcription factors, immune infiltration, MYC targets, and PI3K/AKT/mTOR signaling. Further exploration of biological mechanisms of PRR11 in glioma patients reveals that PRR11 might exert its oncogenic effects via involvement with chromosome segregation, coenzyme binding, cell cycle, and pyruvate metabolism. Moreover, PRR11 knockdown suppressed cell viability, migration, cell-cycle progression, and induced apoptosis and autophagy in glioma cells. In summary, our results suggest that PRR11 might be a novel and reliable diagnostic and prognostic predictor in glioma patients, providing a promising clinical therapeutic target for glioma.

Molecular subtypes based on centrosome-related genes can predict prognosis and therapeutic responsiveness in patients with low-grade gliomas.

Abnormalities in centrosome regulatory genes can induce chromosome instability, cell differentiation errors, and tumorigenesis. However, a limited number of comprehensive analyses of centrosome-related genes have been performed in low-grade gliomas (LGG). LGG data were extracted from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA) databases. The ConsensusClusterPlus" R package was used for unsupervised clustering. We constructed a centrosome-related genes (CRGs) signature using a random forest model, lasso Cox model, and multivariate Cox model, and quantified the centrosome-related risk score (centS). The prognostic prediction efficacy of centS was evaluated using a Receiver Operating Characteristic (ROC) curve. Immune cell infiltration and genomic mutational landscapes were evaluated using the ESTIMATE algorithm, single-sample Gene Set Enrichment Analysis (ssGSEA) algorithm, and "maftools" R package, respectively. Differences in clinical features, isocitrate dehydrogenase (IDH) mutation, 1p19q codeletion, O6-methylguanine-DNA methyltransferase promoter (MGMTp) methylation, and response to antitumor therapy between the high- and low-centS groups were explored. "pRRophetic" R packages were used for temozolomide (TMZ) sensitivity analysis. qRT-PCR verified the differential expression of the centrosomal gene team, the core of which is CEP135, between LGG cells and normal cells. Two distinct CRG-based clusters were identified using consensus unsupervised clustering analysis. The prognosis, biological characteristics, and immune cell infiltration of the two clusters differed significantly. A well-performing centS signature was developed to predict the prognosis of patients with LGG based on 12 potential CRGs. We found that patients in the high-centS group showed poorer prognosis and lower proportion of IDH mutation and 1p19q codeletion compared to those in the low-centS group. Furthermore, patients in the high-centS group showed higher sensitivity to TMZ, higher tumor mutation burden, and immune cell infiltration. Finally, we identified a centrosomal gene team whose core was CEP135, and verified their differential expression between LGG cells and normal glial cells. Our findings reveal a novel centrosome-related signature for predicting the prognosis and therapeutic responsiveness of patients with LGG. This may be helpful for the accurate clinical treatment of LGG.

Artificial-intelligence-based molecular classification of diffuse gliomas using rapid, label-free optical imaging.

Molecular classification has transformed the management of brain tumors by enabling more accurate prognostication and personalized treatment. However, timely molecular diagnostic testing for patients with brain tumors is limited, complicating surgical and adjuvant treatment and obstructing clinical trial enrollment. In this study, we developed DeepGlioma, a rapid (<90 seconds), artificial-intelligence-based diagnostic screening system to streamline the molecular diagnosis of diffuse gliomas. DeepGlioma is trained using a multimodal dataset that includes stimulated Raman histology (SRH); a rapid, label-free, non-consumptive, optical imaging method; and large-scale, public genomic data. In a prospective, multicenter, international testing cohort of patients with diffuse glioma (n = 153) who underwent real-time SRH imaging, we demonstrate that DeepGlioma can predict the molecular alterations used by the World Health Organization to define the adult-type diffuse glioma taxonomy (IDH mutation, 1p19q co-deletion and ATRX mutation), achieving a mean molecular classification accuracy of 93.3 ± 1.6%. Our results represent how artificial intelligence and optical histology can be used to provide a rapid and scalable adjunct to wet lab methods for the molecular screening of patients with diffuse glioma.

Urinary 8-hydroxy-2′-deoxyguanosine levels are elevated in patients with IDH1-wildtype glioblastoma and are associated with tumor recurrence in gliomas

2021 World Health Organization (WHO) Central Nervous System (CNS) Tumor Classification includes molecular diagnostic parameters such as isocitrate dehydrogenase (IDH) mutation or 1p19q codeletion status, in addition to the classical histological classification. Several studies have revealed that patients with IDH1 mutation have a longer survival rate compared to wildtype individuals. In glioma cells, increased oxidative stress has been identified. However, till now, the relation between oxidative stress levels and IDH1 mutation status in those patients was not examined. Therefore, the aim of this study was to investigate the urinary levels of oxidatively induced DNA damage products, 8-hydroxy-2′- deoxyguanosine (8-OH-dG), (5′R) and (5′S)-8,5′-cyclo-2′-deoxyadenosines (R-cdA and S-cdA) as reliable oxidative stress markers in patients with IDH1-wildtype (n = 20) and IDH1-mutant (n = 22) glioma. Absolute quantification of 8-OH-dG, R-cdA and S-cdA was achieved by liquid chromatography-tandem mass spectrometry with isotope dilution. The levels of 8-OH-dG were significantly greater in IDH1-wildtype glioma patients than those in IDH1-mutant ones (p = 0.017). No statistically significant difference was observed for R-cdA and S-cdA levels. 8-OH-dG levels were positively correlated with patients’ tumor recurrence in all patients (r = 0.382, p = 0.014). The mutation status of glioma is well correlated with oxidative stress. Examination of noninvasively measured oxidative DNA damage products along with IDH1 mutation status in glioma patients, might be particularly important in terms of evaluating and monitoring the effectiveness of treatment.

A prognostic NAD+ metabolism-related gene signature for predicting response to immune checkpoint inhibitor in glioma.

Nicotinamide adenine dinucleotide (NAD+) metabolism is involved in a series of cancer pathogenesis processes, and is considered a promising therapeutic target for cancer treatment. However, a comprehensive analysis of NAD+ metabolism events on immune regulation and cancer survival has not yet been conducted. Here, we constructed a prognostic NAD+ metabolism-related gene signature (NMRGS) associated with immune checkpoint inhibitor (ICI) efficacy in glioma. 40 NAD+ metabolism-related genes (NMRGs) were obtained from the Reactome database and the Kyoto Encyclopedia of Genes and Genomes (KEGG) database. Glioma cases with transcriptome data and clinical information were obtained from Chinese Glioma Genome Atlas (CGGA) and The Cancer Genome Atlas (TCGA). NMRGS was constructed based on the calculated risk score using univariate analysis, Kaplan-Meier analysis, multivariate Cox regression, and nomogram. This NMRGS was verified in training (CGGA693) and validation (TCGA and CGGA325) cohorts. The immune characteristics, mutation profile, and response to ICI therapy were subsequently analyzed for different NMRGS subgroups. Six NAD+ metabolism-related genes, including CD38, nicotinamide adenine dinucleotide kinase (NADK), nicotinate phosphoribosyltransferase (NAPRT), nicotinamide/nicotinic acid mononucleotide adenylyltransferase 3 (NMNAT3), poly(ADP-Ribose) polymerase family member 6 (PARP6), and poly(ADP-Ribose) polymerase family member 9 (PARP9), were ultimately used to construct a comprehensive risk model for glioma patients. Patients in the NMRGS-high group showed a poorer survival outcome than those in the NMRGS-low group. The area under curve (AUC) indicated that NMRGS has good potential in glioma prognostic prediction. A nomogram with improved accuracy was established based on independent prognostic factors (NMRGS score, 1p19q codeletion status, and WHO grade). Furthermore, patients in the NMRGS-high group showed a more immunosuppressive microenvironment, higher tumor mutation burden (TMB), higher human leucocyte antigen (HLA) expression and a more therapeutic response to ICI therapy. This study constructed a prognostic NAD+ metabolism-related signature associated with the immune landscape in glioma, which can be used for guiding individualized ICI therapy.

Cancer Registration, Molecular Marker Status, and Adherence to the WHO 2016 Classification of Pathology Reports for Glioma Diagnosed during 2017–2019 in Belgium

Introduction: The objective of this study was to cross-check and, if necessary, adjust registered ICD-O-3 topography and morphology codes with the findings in pathology reports available at the Belgian Cancer Registry (BCR) for glioma patients. Additionally, integration of molecular markers in the pathological diagnosis and concordance with WHO 2016 classification is investigated. Methods: Since information regarding molecular tests and corresponding conclusions are not available as structured data at population level, a manual screening of all pseudonymized pathology reports available at the BCR for registered glioma patients (2017–2019) was conducted. ICD-O-3 morphology and topography codes from the BCR database (based on information as provided by hospital oncological care programmes and pathology laboratories), were, at tumour level, cross-checked with the data from the pathology reports and, if needed, specified or corrected. Relevant molecular markers (IDH1/2, 1p19q codeletion, promoter region of the MGMT gene [MGMTp]) were manually extracted from the pathology reports. Results: In 95.3% of gliomas, the ICD-O-3 morphology code was correct. Non-specific topography codes were specified in 9.3%, while 3.3% of specific codes were corrected. The IDH status was known in 75.2% of astrocytic tumours. The rate of correct integrated diagnoses varied from 47.6% to 56.4% among different gliomas. MGMTp methylation status was available in 32.2% of glioblastomas. Conclusion: Both the integration of molecular markers in the conclusion of the pathology reports and the delivery of those reports to the BCR can be improved. The availability of distinct ICD-O-3 codes for each molecularly defined tumour entity within the WHO classification would increase the consistency of cancer registration, facilitate population level research and international benchmarking.

Apparent Diffusion Coefficient as Imaging Biomarker for Identifying IDH Mutation, 1p19q Codeletion, and MGMT Promoter Methylation Status in Patients With Glioma.

Glioma genotypes are of importance for clinical decision-making. This data can only be acquired through histopathological analysis based on resection or biopsy. Consequently, there is a need for alternative biomarkers that noninvasively provide reliable information for preoperatively identifying molecular characteristics. To investigate apparent diffusion coefficient (ADC) as imaging biomarker for preoperatively identifying glioma genotypes based on the 2021 World Health Organization (WHO) classification of central nervous system (CNS) tumors. Retrospective. One hundred and fifty-nine patients (47.6 ± 14.4 years) diagnosed with WHO grade 2-4 glioma including 93 males and 66 females. A 3 T/spin echo echo planner imaging. The ADC measurements were assessed by two neuroradiologists (both with 6 years of experience). Three different lowest portions inside the tumors without overlap were manually drawn on the ADC maps as regions of interest (ROIs). The mean ADC value of the three ROIs was defined as the minimum ADC value (ADCmin ). An ROI was placed in the contralateral normal appearing white matter (NAWM) to obtain the ADC value (ADCNAWM ). The ADCmin to ADCNAWM ratio (ADCratio ) was calculated. Genetics results were retrospectively recorded from pathologic and genetic test reports. Two-sample independent t-tests, receiver operating characteristic curve analysis, and intraclass correlation coefficient analysis were used. Statistical significance was set at P < 0.05. Isocitrate dehydrogenase (IDH)-mutated glioma showed higher ADCmin and ADCratio than IDH wild-type glioma. Among IDH-mutated glioma, higher ADCmin and ADCratio were found in 1p19q intact glioma than in 1p19q codeletion glioma. ADC parameters enabled differentiation of IDH mutation status with area under the curve (AUC) of 0.84 and 0.86. ADC has potential discriminative value for IDH mutation and 1p19q codeletion status. 3. Stage 2.

Direct image to subtype prediction for brain tumors using deep learning.

Deep Learning (DL) can predict molecular alterations of solid tumors directly from routine histopathology slides. Since the 2021 update of the World Health Organization (WHO) diagnostic criteria, the classification of brain tumors integrates both histopathological and molecular information. We hypothesize that DL can predict molecular alterations as well as WHO subtyping of brain tumors from hematoxylin and eosin-stained histopathology slides. We used weakly supervised DL and applied it to three large cohorts of brain tumor samples, comprising N = 2845 patients. We found that the key molecular alterations for subtyping, IDH and ATRX, as well as 1p19q codeletion, were predictable from histology with an area under the receiver operating characteristic curve (AUROC) of 0.95, 0.90, and 0.80 in the training cohort, respectively. These findings were upheld in external validation cohorts with AUROCs of 0.90, 0.79, and 0.87 for prediction of IDH, ATRX, and 1p19q codeletion, respectively. In the future, such DL-based implementations could ease diagnostic workflows, particularly for situations in which advanced molecular testing is not readily available.

Astrocytoma with 1p19q codeletion

Using the example of a recurrent tumor with a 10-year follow-up, the authors show that mutation of the IDH1/2 genes in astrocytomas is not always an early event in the pathogenesis of glioma, that in rare cases a 1p19q codeletion can be found in astrocytomas, and that IDH-mutant tumors can occur in childhood.

Mitotic count is prognostic in IDH mutant astrocytoma without homozygous deletion of CDKN2A/B. Results of consensus panel review of EORTC trial 26053 (CATNON) and EORTC trial 22033-26033.

Gliomas with IDH1/2 mutations without 1p19q codeletion have been identified as the distinct diagnostic entity of IDH mutant astrocytoma (IDHmut astrocytoma). Homozygous deletion of Cyclin-dependent kinase 4 inhibitor A/B (CDKN2A/B) has recently been incorporated in the grading of these tumors. The question of whether histologic parameters still contribute to prognostic information on top of the molecular classification, remains unanswered. Here we evaluated consensus histologic parameters for providing additional prognostic value in IDHmut astrocytomas. An international panel of seven neuropathologists scored 13 well-defined histologic features in virtual microscopy images of 192 IDHmut astrocytomas from EORTC trial 22033-26033 (low-grade gliomas) and 263 from EORTC 26053 (CATNON) (1p19q non-codeleted anaplastic glioma). For 192 gliomas the CDKN2A/B status was known. Consensus (agreement ≥ 4/7 panelists) histologic features were tested together with homozygous deletion (HD) of CDKN2A/B for independent prognostic power. Among consensus histologic parameters, the mitotic count (cut-off of 2 mitoses per 10 high power fields standardized to a field diameter of 0.55 mm and an area of 0.24 mm2) significantly influences PFS (P = .0098) and marginally the OS (P = .07). Mitotic count also significantly affects the PFS of tumors with HD CDKN2A/B, but not the OS, possibly due to limited follow-up data. The mitotic index (cut-off 2 per 10 40× HPF) is of prognostic significance in IDHmut astrocytomas without HD CDKN2A/B. Therefore, the mitotic index may direct the therapeutic approach for patients with IDHmut astrocytomas with native CDKN2A/B status.

Activation of embryonic/germ cell-like axis links poor outcomes of gliomas

BackgroundIt is unclear which core events drive the malignant progression of gliomas. Earlier studies have revealed that the embryonic stem (ES) cell/early PGC state is associated with tumourigenicity. This study was designed to investigate the role of ES/PGC state in poor outcomes of gliomas.MethodsCrispr-Cas9 technology, RT–PCR and animal experiments were used to investigate whether PGC-like cell formation play crucial roles in the tumorigenicity of human glioma cells. Bioinformatic analysis was used to address the link between ES/PGC developmental axis and glioma overall outcomes.ResultsHere, our findings showed that germ cell-like cells were present in human gliomas and cultured glioma cells and that the formation of germ cell-like cells was essential for glioma tumours. Bioinformatic analysis showed that the mRNA levels of genes related to embryonic/germ cell development could be detected in most gliomas. Our findings showed that the activation of genes related to reprogramming or the germ cell-like state alone seemed to be insufficient to lead to a malignant prognosis, whereas increased mRNA levels of genes related to the activation of the embryonic/germ cell-like cycle (somatic PGC-EGC-like cycle and somatic parthenogenetic embryo-like cycle) were positively correlated with malignant prognoses and poor clinical outcomes of gliomas. Genes related to the embryonic/germ cell cycle alone or in combination with the WHO grade or 1p19q codeletion status could be used to subdivide gliomas with distinct clinical behaviours.ConclusionTogether, our findings indicated that a crucial role of germ cell-like cell formation in glioma initiation as well as activation of genes related with the parthenogenetic embryo-like cycle and PGC-EGC-like cycle link to the malignant prognosis and poor outcomes of gliomas, which might provide a novel way to better understand the nature of and develop targeted therapies for gliomas as well as important markers for predicting clinical outcomes in gliomas.