1p Codeletion Research Articles

P19.02.A FUNCTIONAL CONSEQUENCES OF IDH1 AND CIC MUTATIONS ON OLIGODENDROGLIOMA CELLS OF ORIGIN

Abstract BACKGROUND Oligodendrogliomas are primitive tumors of the central nervous system characterized by mutations in isocitrate dehydrogenase 1 (IDH1R132H) gene, codeletion of 1p and 19q chromosomic arms and mutations in Capicua (CIC) gene. Oligodendrocyte precursor cells (OPCs) are potential cells of origin for oligodendrogliomas and OPC-like tumor cells are responsible for tumor amplification at early stages of gliomagenesis. Although genetic alterations are well characterized for these tumors, little is known about the roles of IDH1 and CIC in oligodendroglioma initiation and development. Individually, IDH1 and CIC mutations can induce neoplastic characteristics but are not sufficient for tumoral development. We aim to understand how IDH1 and CIC mutations impact OPC development and whether these alterations are sufficient for tumoral initiation. METHODS We have generated an inducible mouse model allowing endogenous expression of IDH1R132H and inactivation of CIC in postnatal OPCs. We analyzed by immunofluorescence the proliferation and differentiation status of mutated oligodendroglial cells and other brain cells, at postnatal and adult stages. RESULTS We describe distinct effects of these mutations on oligodendroglial cell number and proliferation, at early and late time points. In addition, we found that IDH1R132H increases the proliferation of other brain cell types, suggesting paracrine effects of this mutation in the brain. We find no evidence of tumor in the brain of mice mutated for both IDH1 and CIC at late time points. CONCLUSION Our study describes for the first time the phenotypic impact of the combined expression of IDH1 and CIC mutations on oligodendroglial lineage cells and other brain cells, leading to a better understanding of oligodendroglioma development.

TTFields Prolonged the PFS of Epithelioid Glioblastoma Patient: A Case Report

Epithelioid glioblastoma (EGBM, classified as glioblastoma, IDH wild type, grade 4 according to the fifth edition of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System (CNS) (WHO CNS5)) is a highly aggressive malignancy, with a median progression-free survival (mPFS) of about 6 months in adults. The application of tumor-treating fields (TTFields, possessing anti-cancer capabilities via anti-mitotic effects) in the maintenance of temozolomide (TMZ) chemotherapy showed a benefit for prolonging the mPFS of newly diagnosed glioblastoma (GBM) for patients for up to 6.9 months in the EF-14 clinical trial (NCT00916409). However, studies focusing on the effect of TTFields in EGBM treatment are very limited due to the rarity of EGBM. Here, we have reported a case of a 28-year-old male (recurrent left-sided limb twitching for 1 month and dizziness for 1 week) diagnosed with EGBM. A right frontal lobe occupancy was detected by magnetic resonance imaging (MRI), and a total tumor resection was performed. Meanwhile, a postoperative histopathology test, including immunohistochemistry and molecular characterization, was conducted, and the results revealed a BRAF V600E mutation, no co-deletion of 1p and 19q, and negative O-6-methylguanine DNA methyltransferase (MGMT) promoter methylation. Then, chemoradiotherapy was conducted, and TTFields and TMZ were performed sequentially. Notably, a long-term PFS of 34 months and a Karnofsky Performance Scale (KPS) of 90 were achieved by the patient on TTFields combined with TMZ, whose average daily usage of TTFields was higher than 90%.

Abstract 3224: TTFields-prolonged the PFS of epithelioid glioblastoma patient: a case report

Abstract Epithelioid glioblastoma (EGBM, classified as glioblastoma, wild type, grade IV according to 2021 WHO CNS5 classification of neurological malignancies) is a highly aggressive malignancy, the median progression-free survival (mPFS) of which is about 4.0 months. Although, the introduction of tumor treating fields (TTFields, possessing anti-cancer capability via anti-mitotic effects) in the maintenance of TMZ chemotherapy was demonstrated beneficial for prolonging the mPFS of GBM patients to 6.9 months in the EF-14 clinical trial, studies centering on the significance of TTFields in EGBM treating are very limited due to the rarity of EGBM. Therefore, a 28-year-old patient (male, recurrent left-sided limb twitching for 1 month and dizziness for 1 week) was chosen as a clinical trial participant. A right frontal lobe occupancy was detected based on magnetic resonance imaging (MRI), and total tumor resection was performed on the patient. Meanwhile, postoperative histopathology test, including immunohistochemical and molecular characterization, was conducted and the results revealed a BRAF V600E mutation, no codeletion of 1p and 19q, and negative MGMT promoter methylation, which confirmed EGBM. In this context, chemoradiotherapy was conducted on the patient at first, and then concurrent TTFields and TMZ was performed. Notably, a long-term PFS of 33 months and KPS score of 90 were achieved over the patient upon TTFields combined TMZ, whose average daily usage of TTFields was higher than 90%. This clinical case corroborated the importance of TTFields in EGBM treating, and the higher compliance of TTFields is more beneficial for EGBM patient without additional side effect. YD, QW contributed equally to this work. Citation Format: Yuxuan Ding, Qiang Wang, Feijiang Wang, Nan Wu, Jianrui Li, Xia He, Hao Pan, Lijun Wang. TTFields-prolonged the PFS of epithelioid glioblastoma patient: a case report [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3224.

Transcriptomic Analysis Identified Two Subtypes of Brain Tumor Characterized by Distinct Immune Infiltration and Prognosis.

BackgroundBrain tumor ranks as the most devastating cancer type. The complex tumor immune microenvironment prevents brain tumor from receiving therapeutic benefits. The purpose of this study was to stratify brain tumors based on their distinct immune infiltration signatures to facilitate better clinical decision making and prognosis prediction.MethodsWe developed a deep learning model to characterize immune infiltration from transcriptome. The developed model was applied to distill expression signatures of transcriptome of brain tumor samples. We performed molecular subtyping with the extracted expression signatures to unveil brain tumor subtypes. Computational methods, including gene set enrichment analysis, Kaplan-Meier survival and multivariate Cox regression analyses, were employed.ResultsWe identified two distinctive subtypes (i.e. C1/2) of brain tumor featured by distinct immune infiltration signatures. The C1 subtype is characterized by protective immune infiltration signatures, including high infiltration of CD8+ T cells and activation of CX3CL1. The C2 subtype has an extensive infiltration of tumor-associated macrophages and microglia, and was enriched with immune suppressive, wound-healing, and angiogenic signatures. The C1 subtype had significantly better prognosis as compared with C2 (Log-rank test, HR: 2.5, 95% CI: 2.2 – 2.7; P = 8.2e-78). This difference remained statistically significant (multivariate Cox model, HR: 2.2, 95% CI: 1.7 – 2.9; P = 3.7e-10) by taking into account age, gender, recurrent/secondary status at sampling time, tumor grade, histology, radio-chemotherapy, IDH mutation, MGMT methylation, and co-deletion of 1p and 19q. This finding was validated in six datasets. The C2 subtype of glioblastoma patients with IDH mutation has poor survival analogous to those without IDH mutation (Log-rank test, adjusted P = 0.8), while C1 has favorable prognosis as compared with glioblastoma of C2 subtype with IDH mutation (Log-rank test, adjusted P = 1.2e-3) or without IDH mutation (Log-rank test, adjusted P = 1.3e-6).ConclusionsWe identified two distinctive subtypes of brain tumor with different immune infiltration signatures, which might be helpful as an independent prognosticator for brain tumor.

Diagnostic and prognostic implications of molecular status in Chinese adults with diffuse glioma: An observational study

Background and Aim: Mutations in isocitrate dehydrogenase (IDH), co-deletion of 1p and 19q, loss or expression of the transcription regulator ATRX, and mutations in telomerase reverse transcriptase (TERT) gene promoters are intimately linked with diffuse gliomas. We further explored the roles of the key molecules in adulthood diffuse gliomas and their prognosis. Materials and Methods: A total of 413 patients who underwent primary surgery between 2009 and 2015 at Xuanwu Hospital, Beijing, China, were included in this observational study. All specimens from the patients were fixed in 10% neutral buffered formalin and embedded in paraffin. The mutational status of IDH1/2 and the TERT promoter was determined using polymerase chain reaction-based direct sequencing. The assay for the 1p and 19q co-deletion was conducted using fluorescence in situ hybridization. Overall- and progression-free survival was calculated using the Kaplan–Meier method and the log-rank test. The study was approved by the Ethics Committee of Xuanwu Hospital, Capital Medical University, China (approval No. [2019]004) on May 22, 2019. Results: We found that tumors characterized by multiple lesions were predominantly free of IDH mutations (P

Combinational analysis of IDH1/IDH2 mutations, 1p/19q deletions and MGMT promoter methylation for molecular testing of glioma.

e13152 Background: Mutations in IDH1 and IDH2, co-deletion of 1p and 19q, and the hyper methylation of the MGMT promoter are the most reported genetic alterations in glioma tumors. Therefore, we designed a study to analyze the prevalence of these biomarkers in glioma, and the correlation of these biomarkers with diagnosis and prognosis. Methods: From September 2018 to January 2019, eighteen patients with primary glioma were prospectively enrolled. For each patient, freshly frozen tissue or FFPE samples were collected. DNA was extracted from these samples and sequenced to at least 5,000× coverage. IDH1/IDH2 mutations and 1p/19q deletions were detected from the sequencing data, whereas MGMT promoter methylation was evaluated by real-time fluorescence qPCR. Results: Of the eighteen patients, 44.4%(8/18) and 33.3%(6/18) harbored IDH1 /IDH2 mutations and 1p/19q deletions, respectively, and 72.2%(13/18) contained MGMT promoter hyper methylation. Within these patients, we found a correlation between IDH1/IDH2 mutation and 1p/19q deletion. Namely, among the 8 patients with a IDH1/IDH2 mutation, 75%(6/8) also contained a 1p/19q deletion, whereas none of the 10 patients with wide-type IDH1/IDH2 displayed the 1p/19q deletion. There was also a correlation between mutations at the loci and MGMT promoter hyper-methylation, specifically, 87.5%(7/8) of the patients with IDH1/IDH2 mutations also exhibited hyper-methylation in MGMT, whereas only hyper-methylation was observed in only 40% (4/10) of IDH1/IDH2 negative patients. Conclusions: From our preliminary result, IDH1/IDH2 mutations may be associated with 1p/19q deletion. To further verify this result, a larger, longitudinal study is ongoing at our institution.

Multigene signature for predicting prognosis of patients with 1p19q co-deletion diffuse glioma.

Co-deletion of 1p and 19q marks a diffuse glioma subtype associated with relatively favorable overall survival; however, heterogeneous clinical outcomes are observed within this category. We assembled gene expression profiles and sample annotation of 374 glioma patients carrying the 1p/19q co-deletion. We predicted 1p/19q status using gene expression when annotation was missing. A first cohort was randomly split into training (n = 170) and a validation dataset (n = 163). A second validation set consisted of 41 expression profiles. An elastic-net penalized Cox proportional hazards model was applied to build a classifier model through cross-validation within the training dataset. The selected 35-gene signature was used to identify high-risk and low-risk groups in the validation set, which showed significantly different overall survival (P = .00058, log-rank test). For time-to-death events, the high-risk group predicted by the gene signature yielded a hazard ratio of 1.78 (95% confidence interval, 1.02-3.11). The signature was also significantly associated with clinical outcome in the The Cancer Genome Atlas (CGA) IDH-mutant 1p/19q wild-type and IDH-wild-type glioma cohorts. Pathway analysis suggested that high risk was associated with increased acetylation activity and inflammatory response. Tumor purity was found to be significantly decreased in high-risk IDH-mutant with 1p/19q co-deletion gliomas and IDH-wild-type glioblastomas but not in IDH-wild-type lower grade or IDH-mutant, non-co-deleted gliomas. We identified a 35-gene signature that identifies high-risk and low-risk categories of 1p/19q positive glioma patients. We have demonstrated heterogeneity amongst a relatively new glioma subtype and provided a stepping stone towards risk stratification.

Immune infiltration, glioma stratification, and therapeutic implications

By definition, gliomas are brain tumors emanating from glial precursor cells. Gliomas include glioblastoma (GBM), astrocytoma, oligodendroglioma, and ependymoma. The World Health Organization (WHO) traditionally classifies brain tumors according to their pathological features, with GBM having the highest grade (IV), while lower grades (mostly II, III) are typically assigned to various types of astrocytic, oligodendroglial, and ependymal tumors (1), which collectively are referred to as lower grade gliomas (LGG). In the latest NCI SEER (Surveillance, Epidemiology, and End Results) report and projection, the estimated 2016 incidence and deaths for brain and other CNS tumors is 23,770 and 16,050, respectively (2). According to CBTRUS (Central Brain Tumor Registry of the United States), glioma represents about 27% of all, and 80% of malignant brain and CNS tumors (3). The majority (55.1%) of gliomas are classified as GBMs. For GBMs, the current standard of care consists of surgical resection, radiotherapy with chemotherapy (temozolomide or TMZ). The median survival rate, which ranges from 14.5 to 16.6 months [see (4,5) for review], remains dismally poor despite decades of research and discoveries, leading up to the current era of genomics, targeted therapeutics, and immunotherapeutics. LGGs on the other hand have more favorable clinical outcome, especially cases possessing IDH mutation and co-deletion of 1p and 19q chromosomal arms.

Loss of heterozygosity 1p/19q and survival in glioma: a meta-analysis

Glioma is rarely curable, and factors that influence the prognosis of glioma patients are not fully understood. Loss of heterozygosity (LOH) of 1p/19q has long been known to be a typical molecular signature of oligodendroglial neoplasms. However, whether LOH of 1p/19q is associated with survival in gliomas remains controversial. Here our goal was to evaluate the association between LOH of 1p/19q and progression-free survival (PFS) and overall survival (OS) by conducting a meta-analysis among glioma cases. The PubMed and Embase databases were searched from the earliest records to May 2013 to identify studies that met prestated inclusion criteria. Reference lists of retrieved articles were also reviewed. Three authors independently extracted information needed for further analysis. Either a fixed- or a random-effects model was used to calculate the overall combined hazard ratio (HR) estimates. Twenty-eight eligible studies involving 3 408 cases were included in the meta-analysis. Compared with the chromosomal intact group, codeletion of 1p and 19q was associated with a better PFS (HR = 0.63; 95% CI, 0.52-0.76) and OS (HR = 0.43; 95% CI, 0.35-0.53). Subgroup analyses showed this association to be independent of detection methods and the grades and subtypes of gliomas. Furthermore, isodeletion of chromosome 1p predicted a similar favorable disease outcome (PFS: HR = 0.68; 95% CI, 0.47-0.97) (OS: HR = 0.51; 95% CI, 0.35-0.75), especially in low-grade gliomas, whereas isodeletion of 19q only indicated longer PFS (HR = 0.70; 95% CI, 0.56-0.87). Codeletion of 1p and 19q is associated with better survival rates in glioma. Isodeletion of 1p predicts similar outcomes but to a lesser extent, whereas the effects of isodeletion of 19q remained only marginal.

Codeletion of 1p and 19q determines distinct gene methylation and expression profiles in IDH-mutated oligodendroglial tumors

Oligodendroglial tumors (OTs) are primary brain tumors that show variable clinical and biological behavior. The 1p/19q codeletion is frequent in these tumors, indicating a better prognosis and/or treatment response. Recently, the prognostically favorable CpG island methylator phenotype (CIMP) in gliomas (G-CIMP+) was associated with mutations in the isocitrate dehydrogenase 1 and isocitrate dehydrogenase 2 (IDH) genes, as opposed to G-CIMP- tumors, highlighting the relevance of epigenetic mechanisms. We performed a whole-genome methylation study in 46 OTs, and a gene expression study of 25 tumors, correlating the methylation and transcriptomic profiles with molecular and clinical variables. Here, we identified two different epigenetic patterns within the previously described main G-CIMP+ profile. Both IDH mutation-associated methylation profiles featured one group of OTs with 1p/19q loss (CD-CIMP+), most of which were pure oligodendrogliomas, and a second group with intact 1p/19q and frequent TP53 mutation (CIMP+), most of which exhibited a mixed histopathology. A third group of OTs lacking the CIMP profile (CIMP-), and with a wild-type IDH and an intact 1p/19q, similar to the G-CIMP- subgroup, was also observed. The three CIMP groups presented a significantly better (CD-CIMP+), intermediate (CIMP+) or worse (CIMP-) prognosis. Furthermore, transcriptomic analyses revealed CIMP-specific gene expression signatures, indicating the impact of genetic status (IDH mutation, 1p/19q codeletion, TP53 mutation) on gene expression, and pointing to candidate biomarkers. Therefore, the CIMP profiles contributed to the identification of subgroups of OTs characterized by different prognoses, histopathologies, molecular features and gene expression signatures, which may help in the classification of OTs.

Glioblastoma with oligodendroglial component represents a subgroup of glioblastoma with high prevalence of IDH1 mutation and association with younger age

Glioblastoma with an oligodendroglial component (GBMO) is recognized as a subgroup of glioblastoma (GBM); however, the molecular and clinicopathological characteristics of GBMO are obscure. We evaluated the methylation status of MGMT, IDH1/2 mutation, deletions of 1p and 19q and expression of IDH1, p53, p16, CD151, and galectin3 proteins in 42 GBMOs (32 primary and 10 secondary tumors). Our aims were to correlate our molecular findings with clinicopathologic features, and to compare molecular-to-clinical correlations in the 42 GBMOs with the corresponding correlations in 45 GBMs. GBMO was subdivided into two subgroups according to the predominant cell component comprising >50 % of tumors: the astrocytic predominant type (GBMO-A) and oligodendroglioma predominant type (GBMO-O). Methylation of MGMT, IDH1/2 mutation, and co-deletion of 1p and 19q were found in 31.0, 26.2, and 17.9 % of patients with GBMO, respectively. Clinicopathological and molecular characteristics did not differ significantly between GBMO-A and GBMO-O. However, patients with GBMO-O experienced better outcomes than patients with GBMO-A (p = 0.007). On multivariate analysis the predominant cell type was an independent prognostic factor in overall survival [hazard ratio 4.2 (95 % confidence interval 1.4-12.8), p = 0.011]. When compared to patients with classic GBM, those with GBMO were younger (49.21 vs. 57.47, p = 0.003) and more frequently had tumors with IDH1 mutation (23.8 vs. 4.4 %, p = 0.009). Survival was similar in patients with GBMO and with classic GBM. Based on these results, GBMO may represent a subgroup of GBM that is associated with IDH1 mutation and younger age, although similar to classic GBM in prognosis.

Single-Copy Gain of Chromosome 1q Is a Negative Prognostic Marker in Pediatric Nonependymal, Nonpilocytic Gliomas

Reports of genetic analyses on pediatric gliomas are few, and those tumors have been far less characterized than adult gliomas. To characterize the genetic and biological features of pediatric gliomas. We investigated 23 pediatric nonependymal, nonpilocytic gliomas for chromosomal copy number aberrations (CNAs) by comparative genomic hybridization (CGH), mutations of isocitrate dehydrogenase (IDH) genes by direct sequencing, and proliferative activity and expression of O-methylguanine-DNA methyltransferase (MGMT) by immunohistochemistry. The most frequent CNA was single-copy gain of chromosome 1q, with 10 of 20 successfully investigated tumors showing the abnormality (50%). Other CNAs detected by CGH included gain on 7q (+7q) in 6, +9q in 5, +17q in 5, and + 7p in 4 cases. Gain of entire chromosome 7 was rare (2 cases), and codeletion of 1p and 19q was not detected. Gain of 1q was significantly predictive for shorter progression-free survival (PFS) and overall survival (OS), and even more closely associated with poor clinical outcome than histological grade (P = .0009 for PFS, P = .003 for OS by 1q status; P = .004 for PFS, P = .035 for OS by high-grade vs low-grade). Gain of 1q was also significantly correlated with proliferative activity (P = .0002), and tumors with 1q gain showed a trend toward higher MGMT expression (P = .27). Mutation of IDH1 gene was detected in only 2 of 17 tumors successfully analyzed. Single copy gain of 1q is associated with biological features of pediatric gliomas, and is a negative prognostic marker in patients with those tumors.

High rate of deletion of chromosomes 1p and 19q in insular oligodendroglial tumors

It has been reported recently that oligodendroglial tumors arising in the insula rarely harbor co-deletions of chromosomes 1p and 19q, a molecular signature which is associated with a good prognosis and increased responsiveness to radiation and chemotherapy compared with tumors in which 1p and/or 19q is intact. In the context of this claim, we analyzed a series of insular oligodendroglial tumors in order to determine the frequency of 1p/19q co-deletion in tumors arising in this region. We identified 14 insular cases operated on after 2003 in which testing for losses of 1p and 19q was performed. Of these cases, co-deletion of 1p and 19q occurred in eight (57%). Four (50%) of eight oligodendrogliomas and four (67%) of six oligoastrocytomas demonstrated 1p/19q co-deletions. Seven of the eight tumors with co-deletion of 1p/19q were WHO grade II gliomas. There were no statistical differences between tumors with 1p/19q co-deletion compared to those with 1p and/or 19q intact in terms of age, preoperative KPS, presenting symptoms, left versus right lateralization, tumor location (purely insular versus extension into frontal or temporal lobe), preoperative tumor size. There was a preponderance of females in the co-deletion group, and a greater average extent of resection. In contradistinction to previous reports, loss of 1p/19q occurs commonly in insular oligodendroglial tumors. With respect to 1p/19q, insular gliomas do not appear to be distinct from gliomas arising elsewhere in the brain.

Anaplastic Glioma: How to Prognosticate Outcome and Choose a Treatment Strategy

Anaplastic Glioma: How to Prognosticate Outcome and Choose a Treatment Strategy