Wild-type Lower-grade Gliomas Research Articles

P11.53.B MOLECULAR PROFILING AND ACTIONABLE MUTATIONS IN ADULT PATIENTS WITH IDH WILD TYPE GLIOMAS AND GLIONEURONAL AND NEURONAL TUMORS

Abstract BACKGROUND Next generation sequencing (NGS) assays enable the identification of genetic alterations that may guide a personalized treatment in glioma patients. MATERIAL AND METHODS From July 2021 to March 2023 a NGS analysis (Myriapod® NGS Cancer DNA and RNA panels) was performed in a large prospective cohort of adults with an histological diagnosis of IDH wild type glioma or circumscribed astrocytoma or glioneuronal and neuronal tumor at the Division of Neuro-Oncology, University and City of Health and Science Hospital, Turin, Italy. The aim was to identify potential actionable molecular alterations and provide targeted therapy at recurrence accordingly. RESULTS We collected tumor samples from 221 patients. NGS analysis was available in 211 patients (95.5%), while NGS was not feasible in 10 patients (4.5%). 188 patients out of 211 (89.1%) had an IDH wild type glioblastoma (GBM) (median age 61 years, range 24-84; F/M: 97/91), 6 patients (2.8%) had IDH wild type lower grade gliomas (LGG) (median age 63 years, range 43-78; F/M: 3/3), and 17 patients (8.1%) had circumscribed astrocytoma or glioneuronal and neuronal tumor (median age 37 years, range 18-67; F/M: 13/4). Overall, actionable molecular alterations were found in 13/211 patients (6.2%). In this regard, 7/211 patients (3.3%) had BRAF V600E mutation (3 IDH wild type GBM, 1 IDH wild type LGG, and 3 circumscribed/glioneuronal and neuronal tumor), 4/211 patients (1.9%) had FGFR3-TACC3 fusion (all GBM), 1/211 patients (0.5%) had PIK3CA mutation (GBM), and 1/211 patients (0.5%) had NTRK1 fusion (glioneuronal tumor). Other molecular mutations, including ALK, ERBB2, MET, KIT, KRAS, PDGFRA, and RET have not been detected in our cohort. Three patients with druggable mutations recurred after first-line therapy: 1 patient with BRAF mutated GBM, 1 patient with GBM harboring FGFR3-TACC3 fusion, and 1 patient with NTRK1 fusion positive glioneuronal tumor received specific BRAF/MEK inhibitor (dabrafenib/trametinib), FGFR inhibitor (pemigatinib), and NTRK inhibitor (larotrectinib), respectively. A remarkable activity of BRAF/MEK and NTRK inhibitors was observed (8 months and 5 months, respectively *), while FGFR inhibitor did not display a significant activity to control disease (9 weeks). * ongoing CONCLUSION The incidence of actionable molecular alterations in IDH wild type gliomas and glioneuronal and neuronal tumors was low. However, the possibility of using targeted therapies may lead to an important impact on the outcome.

A 10-Year Survival-Trend Analysis of Low-Grade Glioma and Treatment Patterns from an LMIC.

Objectives The 2021 WHO Classification of Central Nervous System Tumors taxonomy laid further stress on molecular classification and prognostication of glial tumors in comparison to histopathological grading. Research shows that low-grade gliomas (LGGs) can go through malignant differentiation and lead to severe disability and death. Data from various populations will be necessary to ascertain the exact interplay between genotypic predictors of LGG and outcomes. Materials and Methods To assess the molecular pathology for glial tumors in the Pakistani population, the Shaukat Khanum Memorial Cancer Hospital carried out a retrospective chart review of electronic health records from 2008 to 2018, with immunohistochemistry analysis findings from 2010 to 2018. Patients with a pathological diagnosis of a glioma were included. Statistical Analysis Analysis was performed using IBM SPSS Statistics Version 23 and STATA Version 16. A p -value of less than 0.05 was considered statistically significant with 95% confidence intervals reported. Results In all, 281 operable tumors were recorded. The most common procedure was a subtotal resection, and astrocytomas (64.77%) were the most common tumors. Radiation therapy and PCV (procarbazine, CCNU, and vincristine) was received by 85 patients, while radiation therapy and temozolomide were administered to 15 patients. Conclusions Isocitrate dehydrogenase (IDH) wild-type LGG had a lower survival time, while improved survival times were seen for alpha-thalassemia X-linked intellectual disability syndrome (ATRX) retained and 1p19q co-deleted LGGs. Further studies are required to gain a better understanding of lower-grade glial tumor treatment and survival in Pakistan.

Phospholipase Cγ1 (PLCG1) overexpression is associated with tumor growth and poor survival in IDH wild-type lower-grade gliomas in adult patients

AbstractGliomas are the most common and recalcitrant intracranial tumors, approximately a quarter of which are classified as lower-grade gliomas (WHO II–III). Although the prognosis of lower-grade gliomas (LGGs) is significantly better than that of higher-grade gliomas, as a highly heterogeneous tumor type, the prognosis of LGGs varies greatly based on the molecular diagnosis. IDH wild-type used to be regarded as a dismal prognostic biomarker in LGGs; however, several studies revealed that IDH wild-type LGGs might not always be equivalent to glioblastoma (WHO IV). Hence, we hypothesize that underlying biological events in LGGs can result in different prognosis. In our study, transcriptome profiling was performed in 24 samples of LGG, and the results showed that the expression of phospholipase Cγ1 (PLCG1) was significantly correlated with IDH1/2 status and patients' clinical outcome. Furthermore, the cancer genome atlas (TCGA) and the Chinese glioma genome atlas (CGGA) databases verified that elevated PLCG1 expression was associated with tumor progression and poor survival in LGG patients. Moreover, PLCG1-targeted siRNA dramatically affected the growth, migration and invasiveness of IDH wild-type LGG cell lines. In in vitro and in vivo experiments, the PLC-targeted drug significantly suppressed the tumor growth of IDH wild-type LGG cell lines in vitro and tumors in mouse models. Taken together, our results demonstrated that higher PLCG1 expression was associated with tumor growth and worse prognosis in IDH wild-type LGGs and PLCG1 could serve as a potential therapeutic target for IDH wild-type LGG patients.The mRNA expression levels of phospholipase Cγ1 (PLCG1) are much higher in IDH wild-type (IDHwt) lower-grade gliomas (LGGs) than in that of IDH mutant (IDHmut) LGGs. Higher PLCG1expression in IDHwt LGGs indicates poor clinical outcome. PLCG1 amplification may act as the key mechanism of PLCG1 upregulation. Depletion of PLCG1 expression can inhibits proliferation and invasion of IDHwt LGG cell lines in vitro and in vivo. The PLC inhibitor U73122 may therefore be a potential therapeutical agent for IDHwt LGGs.

History of atopy confers improved outcomes in IDH mutant and wildtype lower grade gliomas.

A history of atopy or allergy has been shown to be protective against the development of glioma, however the effect of atopy on patient outcomes, especially in conjunction with the survival benefit associated with IDH mutation, has not yet been investigated, and is the focus of the study we present here. Low grade glioma (LGG) data from the TCGA was downloaded, along with IDH, TERT, 1p/19q and ATRX mutational status and genetic alterations. History of asthma, eczema, hay fever, animal, or food allergies, as documented in TCGA, was used to determine patient atopy status. Patients with missing variables were excluded from the study. 374 LGG studies were included. Patients with a history of atopy demonstrated longer overall survival (OS) compared to those without (145.3 vs. 81.5months, p = 00.0195). IDH mutant patients with atopy had longer OS compared those without atopy (158.8 vs. 85months, p = 0.035). Multivariate cox regression analysis demonstrated that the effects of atopy on survival were independent of IDH and histological grade, (p = 0.002, HR 0.257, 95% 0.109-0.604), (p = < 0.001, HR 0.217, 95% 0.107-0.444), and (p = 0.004, HR 2.72, 95% 1.373-5.397), respectively. In terms of treatment outcomes, patients with atopy did not differ in treatment response compared to their counterpart. Pathway analysis demonstrated an upstream activation of the BDNF pathway (p = 0.00027). A history of atopy confers a survival benefit in patients with diffuse low-grade glioma. Activation of the BDNF pathway may drive the observed differences.

MRI Features May Predict Molecular Features of Glioblastoma in Isocitrate Dehydrogenase Wild-Type Lower-Grade Gliomas.

Isocitrate dehydrogenase (IDH) wild-type lower-grade gliomas (histologic grades II and III) with epidermal growth factor receptor (EGFR) amplification or telomerase reverse transcriptase (TERT) promoter mutation are reported to behave similar to glioblastoma. We aimed to evaluate whether MR imaging features could identify a subset of IDH wild-type lower-grade gliomas that carry molecular features of glioblastoma. In this multi-institutional retrospective study, pathologically confirmed IDH wild-type lower-grade gliomas from 2 tertiary institutions and The Cancer Genome Atlas constituted the training set (institution 1 and The Cancer Genome Atlas, 64 patients) and the independent test set (institution 2, 57 patients). Preoperative MRIs were analyzed using the Visually AcceSAble Rembrandt Images and radiomics. The molecular glioblastoma status was determined on the basis of the presence of EGFR amplification and TERT promoter mutation. Molecular glioblastoma was present in 73.4% and 56.1% in the training and test sets, respectively. Models using clinical, Visually AcceSAble Rembrandt Images, and radiomic features were built to predict the molecular glioblastoma status in the training set; then they were validated in the test set. In the test set, a model using both Visually AcceSAble Rembrandt Images and radiomic features showed superior predictive performance (area under the curve = 0.854) than that with only clinical features or Visually AcceSAble Rembrandt Images (areas under the curve = 0.514 and 0.648, respectively; P < . 001, both). When both Visually AcceSAble Rembrandt Images and radiomics were added to clinical features, the predictive performance significantly increased (areas under the curve = 0.514 versus 0.863, P < .001). MR imaging features integrated with machine learning classifiers may predict a subset of IDH wild-type lower-grade gliomas that carry molecular features of glioblastoma.

DZIP3 is a key factor to stratify IDH1 wild-type lower-grade gliomas.

Background: Malignant glioma is the most common form of primary malignant brain cancer. Heterogeneity is the hallmark of glioma. DAZ-interacting zinc finger 3 (DZIP3), acts as an RNA-binding RING-type ubiquitin ligase; however, its function in glioma is yet unclear.Results: The DZIP3 expression was related to the World Health Organization (WHO) grade and isocitrate dehydrogenase 1(IDH1) status, as well as the clinical outcome. Malignant cases exhibit lower DZIP3 expression. DZIP3 was an independent predictive factor of good prognosis in all grade and lower grade gliomas (p < 0.0001). Gene enrichment analysis and immunohistochemistry indicated that DZIP3 affected the biological behavior of glioma through the angiogenesis pathway. Moreover, based on DZIP3 expression, IDH1 wild-type lower-grade gliomas could be divided into two groups with different survival time.Conclusion: In conclusion, the loss of DZIP3 may be involved in the mechanism of angiogenesis in the invasive biological process of glioma. These findings laid an understanding of DZIP3-specific clinical features in glioma.Methods: A total of 325 glioma patients from the Chinese Glioma Genome Atlas (CGGA) RNA-seq cohort comprised the training cohort, while 265 patients from the GSE 16011 array cohort formed the validation cohort. The mRNA expression of DZIP3 and clinical characteristics was assessed. DZIP3 protein expression and microvessel density (MVD) were evaluated by immunohistochemistry (IHC).

IDH-wildtype lower-grade diffuse gliomas: the importance of histological grade and molecular assessment for prognostic stratification.

Isocitrate dehydrogenase (IDH) wildtype (wt) grade II gliomas are a rare and heterogeneous entity. Survival and prognostic factors are poorly defined. We searched retrospectively all patients diagnosed with diffuse World Health Organization (WHO) grades II and III gliomas at our center (1989-2020). Out of 517 grade II gliomas, 47 were "diffuse astrocytomas, IDHwt." Tumors frequently had fronto-temporo-insular location (28/47, 60%) and infiltrative behavior. We found telomerase reverse transcriptase (TERT) promoter mutations (23/45, 51%), whole chromosome 7 gains (10/37, 27%), whole chromosome 10 losses (10/41, 24%), and EGFR amplifications (4/43, 9%), but no TP53 mutations (0/22, 0%). Median overall survival (OS) was 59 months (vs 19 mo for IDHwt grade III gliomas) (P < 0.0001). Twenty-nine patients (29/43, 67%) met the definition of molecular glioblastoma according to cIMPACT-NOW update 3. Median OS in this subset was 42 months, which was shorter compared with patients with IDHwt grade II gliomas not meeting this definition (median OS: 57 mo), but substantially longer compared with IDHwt grade III gliomas meeting the definition for molecular glioblastoma (median OS: 17 mo, P < 0.0001). Most patients with IDHwt grade II gliomas met cIMPACT criteria because of isolated TERT promoter mutations (16/26, 62%), which were not predictive of poor outcome (median OS: 88 mo). Actionable targets, including 5 gene fusions involving FGFR3, were found in 7 patients (24%). Our findings highlight the importance of histological grading and molecular profiling for the prognostic stratification of IDHwt gliomas and suggest some caution when assimilating IDHwt grade II gliomas to molecular glioblastomas, especially those with isolated TERT promoter mutation.

Radiomics risk score may be a potential imaging biomarker for predicting survival in isocitrate dehydrogenase wild-type lower-grade gliomas.

Isocitrate dehydrogenase wild-type (IDHwt) lower-grade gliomas of histologic grades II and III follow heterogeneous clinical outcomes, which necessitates risk stratification. We aimed to evaluate whether radiomics from MRI would allow prediction of overall survival in patients with IDHwt lower-grade gliomas and to investigate the added prognostic value of radiomics over clinical features. Preoperative MRIs of 117 patients with IDHwt lower-grade gliomas from January 2007 to February 2018 were retrospectively analyzed. The external validation cohort consisted of 33 patients from The Cancer Genome Atlas. A total of 182 radiomic features were extracted. Radiomics risk scores (RRSs) for overall survival were derived from the least absolute shrinkage and selection operator (LASSO) and elastic net. Multivariable Cox regression analyses, including clinical features and RRSs, were performed. The integrated areas under the receiver operating characteristic curves (iAUCs) from models with and without RRSs were calculated for comparisons. The prognostic value of RRS was assessed in the validation cohort. The RRS derived from LASSO and elastic net independently predicted survival with hazard ratios of 9.479 (95% confidence interval [CI], 3.220-27.847) and 6.148 (95% CI, 3.009-12.563), respectively. Those RRSs enhanced model performance for predicting overall survival (iAUC increased to 0.780-0.797 from 0.726), which was externally validated. The RRSs stratified IDHwt lower-grade gliomas in the validation cohort with significantly different survival. Radiomics has the potential for noninvasive risk stratification and can improve prediction of overall survival in patients with IDHwt lower-grade gliomas when integrated with clinical features. • Isocitrate dehydrogenase wild-type lower-grade gliomas with histologic grades II and III follow heterogeneous clinical outcomes, which necessitates further risk stratification. • Radiomics risk scores derived from MRI independently predict survival even after incorporating strong clinical prognostic features (hazard ratios 6.148-9.479). • Radiomics risk scores derived from MRI have the potential to improve survival prediction when added to clinical features (integrated areas under the receiver operating characteristic curves increased from 0.726 to 0.780-0.797).

Prognostic Value of Preoperative MRI Metrics for Diffuse Lower-Grade Glioma Molecular Subtypes.

Despite the improved prognostic relevance of the 2016 WHO molecular-based classification of lower-grade gliomas, variability in clinical outcome persists within existing molecular subtypes. Our aim was to determine prognostically significant metrics on preoperative MR imaging for lower-grade gliomas within currently defined molecular categories. We undertook a retrospective analysis of 306 patients with lower-grade gliomas accrued from an institutional data base and The Cancer Genome Atlas. Two neuroradiologists in consensus analyzed preoperative MRIs of each lower-grade glioma to determine the following: tumor size, tumor location, number of involved lobes, corpus callosum involvement, hydrocephalus, midline shift, eloquent cortex involvement, ependymal extension, margins, contrast enhancement, and necrosis. Adjusted hazard ratios determined the association between MR imaging metrics and overall survival per molecular subtype, after adjustment for patient age, patient sex, World Health Organization grade, and surgical resection status. For isocitrate dehydrogenase (IDH) wild-type lower-grade gliomas, tumor size (hazard ratio, 3.82; 95% CI, 1.94-7.75; P < .001), number of involved lobes (hazard ratio, 1.70; 95% CI, 1.28-2.27; P < .001), hydrocephalus (hazard ratio, 4.43; 95% CI, 1.12-17.54; P = .034), midline shift (hazard ratio, 1.16; 95% CI, 1.03-1.30; P = .013), margins (P = .031), and contrast enhancement (hazard ratio, 0.34; 95% CI, 0.13-0.90; P = .030) were associated with overall survival. For IDH-mutant 1p/19q-codeleted lower-grade gliomas, tumor size (hazard ratio, 2.85; 95% CI, 1.06-7.70; P = .039) and ependymal extension (hazard ratio, 6.34; 95% CI, 1.07-37.59; P = .042) were associated with overall survival. MR imaging metrics offers prognostic information for patients with lower-grade gliomas within molecularly defined classes, with the greatest prognostic value for IDH wild-type lower-grade gliomas.

MR image phenotypes may add prognostic value to clinical features in IDH wild-type lower-grade gliomas.

To identify significant prognostic magnetic resonance imaging (MRI) features and their prognostic value when added to clinical features in patients with isocitrate dehydrogenase wild-type (IDHwt) lower-grade gliomas. Preoperative MR images of 158 patients (discovery set = 112, external validation set = 46) with IDHwt lower-grade gliomas (WHO grade II or III) were retrospectively analyzed using the Visually Accessible Rembrandt Images feature set. Radiologic risk scores (RRSs) for overall survival were derived from the least absolute shrinkage and selection operator and elastic net. Multivariable Cox regression analysis, including age, Karnofsky Performance score, extent of resection, WHO grade, and RRS, was performed. The added prognostic value of RRS was calculated by comparing the integrated area under the receiver operating characteristic curve (iAUC) between models with and without RRS. The presence of cysts, pial invasion, and cortical involvement were favorable prognostic factors, while ependymal extension, multifocal or multicentric distribution, nonlobar location, proportion of necrosis > 33%, satellites, and eloquent cortex involvement were significantly associated with worse prognosis. RRS independently predicted survival and significantly enhanced model performance for survival prediction when integrated to clinical features (iAUC increased to 0.773-0.777 from 0.737), which was successfully validated on the validation set (iAUC increased to 0.805-0.830 from 0.735). MRI features associated with prognosis in patients with IDHwt lower-grade gliomas were identified. RRSs derived from MRI features independently predicted survival and significantly improved performance of survival prediction models when integrated into clinical features. • Comprehensive analysis of MRI features conveys prognostic information in patients with isocitrate dehydrogenase wild-type lower-grade gliomas. • Presence of cysts, pial invasion, and cortical involvement of the tumor were favorable prognostic factors. • Radiological phenotypes derived from MRI independently predict survival and have the potential to improve survival prediction when added to clinical features.

Increased intratumoral infiltration in IDH wild-type lower-grade gliomas observed with diffusion tensor imaging.

Diffuse lower grade gliomas (LGG) with isocitrate dehydrogenase (IDH) gene mutations (IDHMUT) have a distinct survival advantage compared with IDH wild-type (IDHWT) cases but the mechanism underlying this disparity is not well understood. Diffusion Tensor Imaging (DTI) has identified infiltrated non-enhancing tumor regions that are characterized by low isotropic (p) and high anisotropic (q) diffusion tensor components that associate with poor survival in glioblastoma. We hypothesized that similar regions are more prevalent in IDHWT (vs. IDHMUT) LGG. p and q maps were reconstructed from preoperative DTI scans in N = 41 LGG patients with known IDH mutation and 1p/19q codeletion status. Enhancing and non-enhancing tumor volumes were autosegmented from standard (non-DTI) MRI scans. Percentage non-enhancing tumor volumes exhibiting low p and high q (Vinf) were then determined using threshold values (p = 2 × 10-3mm2/s, q = 3 × 10-4 mm2/s) and compared between IDHWT and IDHMUT LGG, and between IDHMUT LGG with and without 1p/19q codeletion. Vinf volumes were significantly larger in IDHWT LGG than in IDHMUT LGG (35.4 ± 18.3% vs. 15.9 ± 7.6%, P < 0.001). Vinf volumes did not significantly differ between IDHMUT LGG with and without 1p/19q codeletion (17.1 ± 9.5% vs. 14.8 ± 5.8%, P = 1.0). IDHWT LGG exhibited larger volumes with suppressed isotropic diffusion (p) and high anisotropic diffusion (q) which reflects regions with increased cell density but non-disrupted neuronal structures. This may indicate a greater prevalence of infiltrative tumor in IDHWT LGG.

Adult IDH wild-type lower-grade gliomas should be further stratified.

Astrocytoma of the isocitrate dehydrogenase (IDH) wild-type gene is described as a provisional entity within the new World Health Organization (WHO) classification. Some groups believe that IDH wild-type lower-grade gliomas, when interrogated for other biomarkers, will mostly turn out to be glioblastoma. We hypothesize that not all IDH wild-type lower-grade gliomas have very poor outcomes and the group could be substratified prognostically. Seven hundred and eighteen adult WHO grades II and III patients with gliomas from our hospitals were re-reviewed and tested for IDH1/2 mutations. One hundred and sixty-six patients with IDH wild-type cases were identified for further studies, and EGFR and MYB amplifications, mutations of histone H3F3A, TERT promoter (TERTp), and BRAF were examined. EGFR amplification, BRAF, and H3F3A mutations were observed in 13.8%, 6.9%, and 9.5% of patients, respectively, in a mutually exclusive pattern in IDH wild-type lower-grade gliomas. TERTp mutations were detected in 26.8% of cases. Favorable outcome was observed in patients with young age, oligodendroglial phenotype, and grade II histology. Independent adverse prognostic values of older age, nontotal resection, grade III histology, EGFR amplification, and H3F3A mutation were confirmed by multivariable analysis. Tumors were further classified into "molecularly" high grade (harboring EGFR, H3F3A, or TERTp) (median overall survival = 1.23 y) and lower grade (lacking all of the 3) (median overall survival = 7.63 y) with independent prognostic relevance. The most favorable survival was noted in molecularly lower-grade gliomas with MYB amplification. Adult IDH wild-type lower-grade gliomas are prognostically heterogeneous and do not have uniformly poor prognosis. Clinical information and additional markers, including MYB, EGFR, TERTp, and H3F3A, should be examined to delineate discrete favorable and unfavorable prognostic groups.

OS11.4 Adult IDH wild-type lower-grade gliomas should be further stratified

IDH wild-type astrocytoma is described as a provisional entity within the new WHO classification. Some groups believe that IDH wild-type lower-grade gliomas, when interrogated for other biomarkers, will mostly turn out to be glioblastoma. We hypothesize that not all IDH wild-type lower-grade gliomas have very poor outcomes and the group could be sub-stratified prognostically. 718 adult WHO Grade II and III gliomas from our hospitals were re-reviewed and tested for IDH1/2 mutations. 166 IDH wild-type cases were identified for further studies and EGFR and MYB amplifications, mutations of histone H3F3A, TERT promoter and BRAF were examined. EGFR amplification, BRAF and H3F3A mutations were observed in 13.3%, 8.6% and 9.1% respectively, in a mutually exclusive pattern in IDH wild-type lower-grade gliomas. TERTp mutations were detected in 26.4% of cases. Favorable outcome was observed in tumors with oligodendroglial phenotype, grade II histology and total resection. Independent adverse prognostic values of older age, non-total resection, grade III histology, EGFR amplification, and H3F3A mutation were confirmed by multivariate analysis. Tumors were further classified into “molecularly” high grade (harboring EGFR, H3F3A or TERTp) (median OS=1.2 years) and lower-grade (lacking all of the three) (median OS=7.6 years) with independent prognostic relevance. The most favorable survival was noted in molecularly lower-grade gliomas with MYB amplification. In summary, adult IDH wild-type lower-grade gliomas are prognostically heterogeneous and do not have uniformly poor prognosis. Clinical information and additional markers including MYB, EGFR, TERTp and H3F3A should be examined to delineate bad and good prognostic groups.

MPTH-24COMBINATION GENETIC SIGNATURE STRATIFIES PROGNOSIS IN LOWER-GRADE GLIOMAS BUT IDH STATUS ALONE DOES NOT SUPERSEDE HISTOLOGIC GRADES

We studied if combination genetic signature potentially stratifies lower-grade gliomas better than histology by investigating 214 lower-grade gliomas for IDH1/2 and TERTp mutations, 1p/19q codeletion and EGFR amplification as to their impact on prognostication. Prognostic association of grading was independent of other prognostic variables including age, histological type, IDH1/2, 1p/19q and TERTp status. No single marker, including IDH1/2, superseded grading in prognostication, indicating grading was still a very important tool. Prognosis was most favorable in 31.7% of patients with IDH1/2 mutation and either 1p/19q codeletion or TERTp mutation (IDHmut-OT), intermediate in 45.8% of patients with IDH1/2 mutation only (IDHmut) and 16.9% of patients without any of the alterations (IDHwt), and poorest in 5.6% of patients with wild-type IDH1/2 and either TERTp mutation or EGFR amplification (IDHwt-ET). Our results suggested not all IDH1/2 wild-type lower-grade gliomas are aggressive and additional biomarkers are required to identify glioblastoma-equivalent tumors. Multivariate analysis revealed independent prognostic values of grading and genetic signature. Grade II IDHwt-ET gliomas exhibited shorter survival than IDH1/2 mutated grade III gliomas, suggesting combination genetic signature potentially superseded grading in prognostication. In summary, biomarker-based stratification is useful in the diagnosis and prognostication of lower-grade gliomas, and should be used together with grading.

Combination genetic signature stratifies lower-grade gliomas better than histological grade.

We studied if combination genetic signature potentially stratifies lower-grade gliomas better than histology by investigating 214 lower-grade gliomas for IDH1/2 and TERTp mutations, 1p/19q codeletion and EGFR amplification as to their impact on prognostication. Prognostic association of grading was independent of other prognostic variables including age, histological type, IDH1/2, 1p/19q and TERTp status. No single marker, including IDH1/2, superseded grading in prognostication, indicating grading was still a very important tool. Prognosis was most favorable in 31.7% of patients with IDH1/2 mutation and either 1p/19q codeletion or TERTp mutation (IDHmut-OT), intermediate in 45.8% of patients with IDH1/2 mutation only (IDHmut) and 16.9% of patients without any of the alterations (IDHwt), and poorest in 5.6% of patients with wild-type IDH1/2 and either TERTp mutation or EGFR amplification (IDHwt-ET). Our results suggested not all IDH1/2 wild-type lower-grade gliomas are aggressive and additional biomarkers are required to identify glioblastoma-equivalent tumors. Multivariate analysis revealed independent prognostic values of grading and genetic signature. Grade II IDHwt-ET gliomas exhibited shorter survival than IDH1/2 mutated grade III gliomas, suggesting combination genetic signature potentially superseded grading in prognostication. In summary, biomarker-based stratification is useful in the diagnosis and prognostication of lower-grade gliomas, and should be used together with grading.

TERT promoter mutations contribute to subset prognostication of lower-grade gliomas

Recurrent mutations in the promoter region of telomerase reverse transcriptase (TERT) have been found in various cancers including diffuse gliomas. Mutations lead to TERT upregulation and are associated with aggressive clinical behavior in glioblastomas. However, the clinical significance of TERT promoter mutations in lower-grade gliomas remains undetermined. The aim of this study is to evaluate the status of TERT promoter and the respective prognostic significance in a cohort of 237 lower-grade gliomas comprising grades II and III astrocytomas, oligodendrogliomas, and oligoastrocytomas. Mutually exclusive mutations in TERT promoter, C228T and C250T, were identified in 16/105 (15%) diffuse astrocytomas, 16/63 (25%) anaplastic astrocytomas, 13/18 (72%) oligodendrogliomas, 3/3 (100%) anaplastic oligodendrogliomas, 17/45 (38%) oligoastrocytomas, and 2/3 (67%) anaplastic oligoastrocytomas. Mutations co-occurred with 1p/19q codeletion (P<0.001) and are associated with oligodendroglial histology (P<0.001). Kaplan–Meier's survival analysis showed that TERT promoter mutation (P=0.037), Isocitrate dehydrogenase (IDH) mutation (P<0.001), and 1p/19q codeletion (P<0.001) were associated with favorable overall survival (OS). In the subset of 116 IDH-mutated lower-grade gliomas lacking 1p/19q codeletion, 19 TERT promoter-mutated tumors exhibited longer progression-free survival (PFS) (P=0.027) and OS (P=0.004). Consistent with this observation, in the subset of 97 IDH-mutated astrocytomas, 14 TERT promoter-mutated tumors showed longer PFS (P=0.001) and OS (P=0.001). In contrast, among the subset of 74 IDH wild-type lower-grade gliomas with intact 1p/19q, TERT promoter mutation was associated with shorter PFS (P=0.001) and OS (P=0.001). Similarly, in the subset of 65 IDH wild-type astrocytomas, 16 TERT promoter-mutated tumors exhibited unfavorable PFS (P=0.007) and OS (P=0.008). Our results indicate that when combined with IDH status, TERT promoter mutation contributes to prognostic subgroups of lower-grade astrocytic tumors or 1p/19q intact lower-grade gliomas and this may further refine future molecular classification of lower-grade gliomas.

P04.06 * TERT PROMOTER MUTATIONS CONTRIBUTE TO SUBSET PROGNOSTICATION OF LOWER GRADE GLIOMAS

Recurrent mutations in the promoter region of TERT (telomerase reverse transcriptase) have been found in various cancers including diffuse gliomas. Mutations lead to TERT upregulation and are associated with aggressive clinical behaviour in glioblastomas. However, the clinical significance of TERT promoter mutations in lower grade gliomas remains undetermined. The aim of this study is to evaluate the status of TERT promoter and the respective prognostic significance in a cohort of 181 lower grade gliomas comprising grades II and III astrocytomas, oligodendrogliomas and oligoastrocytomas. Mutually exclusive mutations in TERT promoter, C228T and C250T, were identified in 12/89 (14%) diffuse astrocytomas, 8/23 (35%) anaplastic astrocytomas, 13/18 (72%) oligodendrogliomas, 3/3 (100%) anaplastic oligodendrogliomas, 17/45 (38%) oligoastrocytomas and 2/3 (67%) anaplastic oligoastrocytomas. Mutations co-occurred with 1p/19q codeletion (p < 0.001), IDH mutation (p = 0.025) and are associated with oligodendroglial histology (p < 0.001). Kaplan-Meier's survival analysis showed that TERT promoter mutation (p = 0.017), IDH mutation (p = 0.004) and 1p/19q codeletion (p < 0.001) were associated with favorable overall survival. In the subset of 90 IDH mutated lower grade gliomas lacking 1p/19q codeletion, 16 TERT promoter mutated tumors exhibited longer overall survival (p = 0.017). Consistent with this observation, in the subset of 71 IDH mutated astrocytomas, 11 TERT promoter mutated tumors showed longer progression-free survival (p = 0.003) and overall survival (p = 0.005). In contrast, among the subset of 46 IDH wild type lower grade gliomas, TERT promoter mutation was associated with shorter progression-free survival (p = 0.001) and overall survival (p = 0.001). Similarly, in the subset of 37 IDH wild type lower grade gliomas with intact 1p/19q, 8 TERT promoter mutated tumors exhibited unfavorable progression-free survival (p = 0.005) and overall survival (p = 0.008). Our results indicate that when combined with IDH status, TERT promoter mutation contributes to prognostic subgroups of lower grade astrocytic tumors or 1p/19q intact lower grade gliomas and this may further refine future molecular classification of lower grade gliomas.

TERT PROMOTER MUTATIONS CONTRIBUTE TO PROGNOSTIC SUBGROUPS OF LOWER GRADE ASTROCYTOMAS

BACKGROUND: Recurrent mutations in the promoter region of TERT (telomerase reverse transcriptase) have been found in various cancers including diffuse gliomas. Mutations lead to TERT upregulation and are associated with aggressive clinical behaviour in glioblastomas. However, the prognostic impact of TERT promoter mutations in lower grade gliomas remains undetermined. METHODS: The aim of this study is to evaluate the status of TERT promoter and the respective clinical significance in a cohort of 181 lower grade gliomas comprising grades II and III astrocytomas, oligodendrogliomas and oligoastrocytomas. RESULTS: Mutually exclusive mutations in TERT promoter, C228T and C250T, were identified in 12/89 (14%) diffuse astrocytomas, 8/23 (35%) anaplastic astrocytomas, 13/18 (72%) oligodendrogliomas, 3/3 (100%) anaplastic oligodendrogliomas, 17/45 (38%) oligoastrocytomas and 2/3 (67%) anaplastic oligoastrocytomas. Mutations co-occurred with 1p/19q codeletion (p < 0.001), IDH mutation (p = 0.025) and are associated with oligodendroglial histology (p < 0.001). Kaplan-Meier's survival analysis showed that IDH mutation (p = 0.027) and 1p/19q codeletion (p = 0.001) were associated with longer progression-free survival. TERT promoter mutation (p = 0.017), IDH mutation (p = 0.004) and 1p/19q codeletion (p < 0.001) were associated with favorable overall survival. In the subset of 90 IDH mutated lower grade gliomas lacking 1p/19q codeletion, 16 TERT promoter mutated tumors exhibited longer overall survival (p = 0.017). Consistent with this observation, in the subset of 71 IDH mutated astrocytomas, 11 TERT promoter mutated tumors showed longer progression-free survival (p = 0.003) and overall survival (p = 0.005). In contrast, among the subset of 46 IDH wild type lower grade gliomas, TERT promoter mutation was associated with shorter progression-free survival (p = 0.001) and overall survival (p = 0.001). Similarly, in the subset of 37 IDH wild type lower grade gliomas with intact 1p19q, 8 TERT promoter mutated tumors exhibited unfavorable progression-free survival (p = 0.005) and overall survival (p = 0.008). IDH included IDH1 and IDH2. CONCLUSIONS: Our results indicate that when combined with IDH status, TERT promoter mutation contributes to prognostic subgroups of lower grade astrocytic tumors (1p/19q intact low grade gliomas) and this may further refine future molecular classification of lower grade gliomas. SECONDARY CATEGORY: Clinical Neuro-Oncology.