Co-deleted Tumors Research Articles

Radiogenomics Provides Insights into Gliomas Demonstrating Single-Arm 1p or 19q Deletion.

IDH-mutant gliomas are further divided on the basis of 1p/19q status: oligodendroglioma, IDH-mutant and 1p/19q-codeleted, and astrocytoma, IDH-mutant (without codeletion). Occasionally, testing may reveal single-arm 1p or 19q deletion (unideletion), which remains within the diagnosis of astrocytoma. Molecular assessment has some limitations, however, raising the possibility that some unideleted tumors could actually be codeleted. This study assessed whether unideleted tumors had MR imaging features and survival more consistent with astrocytomas or oligodendrogliomas. One hundred twenty-one IDH-mutant grade 2-3 gliomas with 1p/19q results were identified. Two neuroradiologists assessed the T2-FLAIR mismatch sign and calcifications, as differentiators of astrocytomas and oligodendrogliomas. MR imaging features and survival were compared among the unideleted tumors, codeleted tumors, and those without 1p or 19q deletion. The cohort comprised 65 tumors without 1p or 19q deletion, 12 unideleted tumors, and 44 codeleted. The proportion of unideleted tumors demonstrating the T2-FLAIR mismatch sign (33%) was similar to that in tumors without deletion (49%; P = .39), but significantly higher than codeleted tumors (0%; P = .001). Calcifications were less frequent in unideleted tumors (0%) than in codeleted tumors (25%), but this difference did not reach statistical significance (P = .097). The median survival of patients with unideleted tumors was 7.8 years, which was similar to that in tumors without deletion (8.5 years; P = .72) but significantly shorter than that in codeleted tumors (not reaching median survival after 12 years; P = .013). IDH-mutant gliomas with single-arm 1p or 19q deletion have MR imaging appearance and survival that are similar to those of astrocytomas without 1p or 19q deletion and significantly different from those of 1p/19q-codeleted oligodendrogliomas.

Association of MGMT Promoter Methylation With Survival in Low-grade and Anaplastic Gliomas After Alkylating Chemotherapy

O6-methylguanine-DNA methyltransferase (MGMT [OMIM 156569]) promoter methylation (mMGMT) is predictive of response to alkylating chemotherapy for glioblastomas and is routinely used to guide treatment decisions. However, the utility of MGMT promoter status for low-grade and anaplastic gliomas remains unclear due to molecular heterogeneity and the lack of sufficiently large data sets. To evaluate the association of mMGMT for low-grade and anaplastic gliomas with chemotherapy response. This cohort study aggregated grade II and III primary glioma data from 3 prospective cohort studies with patient data collected from August 13, 1995, to August 3, 2022, comprising 411 patients: MSK-IMPACT, EORTC (European Organization of Research and Treatment of Cancer) 26951, and Columbia University. Statistical analysis was performed from April 2022 to January 2023. MGMT promoter methylation status. Multivariable Cox proportional hazards regression modeling was used to assess the association of mMGMT status with progression-free survival (PFS) and overall survival (OS) after adjusting for age, sex, molecular class, grade, chemotherapy, and radiotherapy. Subgroups were stratified by treatment status and World Health Organization 2016 molecular classification. A total of 411 patients (mean [SD] age, 44.1 [14.5] years; 283 men [58%]) met the inclusion criteria, 288 of whom received alkylating chemotherapy. MGMT promoter methylation was observed in 42% of isocitrate dehydrogenase (IDH)-wild-type gliomas (56 of 135), 53% of IDH-mutant and non-codeleted gliomas (79 of 149), and 74% of IDH-mutant and 1p/19q-codeleted gliomas (94 of 127). Among patients who received chemotherapy, mMGMT was associated with improved PFS (median, 68 months [95% CI, 54-132 months] vs 30 months [95% CI, 15-54 months]; log-rank P < .001; adjusted hazard ratio [aHR] for unmethylated MGMT, 1.95 [95% CI, 1.39-2.75]; P < .001) and OS (median, 137 months [95% CI, 104 months to not reached] vs 61 months [95% CI, 47-97 months]; log-rank P < .001; aHR, 1.65 [95% CI, 1.11-2.46]; P = .01). After adjusting for clinical factors, MGMT promoter status was associated with chemotherapy response in IDH-wild-type gliomas (aHR for PFS, 2.15 [95% CI, 1.26-3.66]; P = .005; aHR for OS, 1.69 [95% CI, 0.98-2.91]; P = .06) and IDH-mutant and codeleted gliomas (aHR for PFS, 2.99 [95% CI, 1.44-6.21]; P = .003; aHR for OS, 4.21 [95% CI, 1.25-14.2]; P = .02), but not IDH-mutant and non-codeleted gliomas (aHR for PFS, 1.19 [95% CI, 0.67-2.12]; P = .56; aHR for OS, 1.07 [95% CI, 0.54-2.12]; P = .85). Among patients who did not receive chemotherapy, mMGMT status was not associated with PFS or OS. This study suggests that mMGMT is associated with response to alkylating chemotherapy for low-grade and anaplastic gliomas and may be considered as a stratification factor in future clinical trials of patients with IDH-wild-type and IDH-mutant and codeleted tumors.

PATH-23. HIGHLY INFILTRATING OLIGODENDROGLIOMAS SHOW DIFFERENT MORPHOLOGY FROM TYPICAL OLIGODENDROGLIOMAS WHILE MAINTAINING GOOD RESPONSE TO CHEMO-RADIATION THERAPY

Abstract Oligodendrogliomas are diffuse gliomas located in the cerebral hemisphere, and the MRI typically show swollen cortex and subcortical white matter by the tumor cells. IDH mutation and 1p/19q co-deletion define oligodendrogliomas in WHO classification, and these genetic alterations are associated with good response to chemo-radiation therapy and better prognosis compared to the IDH-mutant astrocytomas. We reviewed MRI findings of 60 oligodendrogliomas with 1p/19q co-deleted tumors which were diagnosed at Dokkyo Medical University since 1999. Of those, 3 cases showed highly infiltrating pattern in which tumors were more predominant in the white matter than the cortex and the infiltration involved multiple lobes. We retrospectively investigated those 3 cases for histological features, treatment, and clinical outcome. There were 2 males and 1 female. MRI showed faint-brushed Gd enhancement around the center of the tumor-infiltrated area in 1 case, while there was no enhancing lesion in other 2 cases. All three underwent stereotactic biopsy. Histologically, all 3 cases lacked typical oligodendroglioma morphology: the tumor cells have irregular round, oval to elongated nuclei without perinuclear halo and had dense, closed chromatin similar to astrocytoma. Two cases underwent chemotherapy (TMZ and PAV accordingly), without radiation and 1 case underwent chemotherapy with radiation as the primary treatment. Interestingly, all three tumors responded well not only to the primary treatments but also to the radiation therapy administered after recurrence, although all eventually succumbed to the tumor. PFS were 16, 37, 67 months and OS were 104, 70, 115 months for each, which were at the worse end as oligodendrogliomas but are apparently better than astrocytomas. Highly infiltrating oligodendrogliomas appeared to show significantly different MRI and histological features from typical oligodendrogliomas that primarily involve cerebral cortex. The underlying mechanism of such differences might involve specific genetic alterations and/or gene expression alterations that may not affect treatment response.

Can Apparent Diffusion Coefficient Predict the Grade, Genotype, or Proliferation Index of Oligodendrogliomas.

Background:Genetic subsets of oligodendrogliomas (OD) have distinct chromosomal and biophysical profiles. Pretherapeutic tumor grade and genotype analysis is a challenging aspect of management, with 1p/19q codeletion status and grade of oligodendroglioma among the most important considerations for clinical decision making.Methodology:Seventy-three patients with histopathological diagnosis of oligodendroglioma were selected, and their preoperative 1.5T magnetic resonance imaging (MRI) scans were reviewed through parameters including diffusion weighted image, susceptibility-weighted imaging, and apparent diffusion coefficient (ADC). These images were correlated with patients' histopathological and chromosomal testing. Tumor border irregularity, homogeneity, contrast enhancement, and other MRI characteristics were also studied. For analysis, descriptive statistics were generated, and normality was evaluated for ADC value, age, and Ki-67 tumor proliferation index.Objectives:The study aimed to determine the correlation of ADC with Ki-67, grade, and 1p/19q co-deletion in oligodendroglioma at a tertiary care hospital within a low-middle income country.Results:Ki-67 tumor proliferation index was high in 33 tumors. It was found to be statistically significant (P = 0.048) with respect to ADC, showing that 1p/19q co-deleted tumors have a difference in their Ki-67 index. Ki-67 also showed a significant relationship (P < 0.05) with grade of OD. However, there was no statistically significant relationship between 1p19q chromosomal co-deletion and ADC. Linear regression was carried out as the data set was continuous. Univariate analysis showed no significant result with all P values above 0.10.Conclusion:Mean ADC is a viable tool to predict Ki-67 and assist prognostic clinical decisions. However, mean ADC alone cannot predict 1p/19q codeletion and tumor grades in OD. Further supplementation with other radiological modalities may provide greater yield and positive results.

CTNI-10. ADVANCES IN MANAGEMENT OF LOW-GRADE GLIOMAS

Abstract BACKGROUND Low-grade gliomas (LGGs) are common benign brain tumors that arise from glial cells of the brain. The complex and variable backgrounds of LGGs cause difficulties in assigning therapies. In this report, we compile findings relating to LGG genetics and treatment options in order to create a coherent summary for referential use. METHODS We compiled 70 articles from the past ten years that cover a broad range of topics pertaining to LGGs, including molecular, genetic, epigenetic, morphological, and other diagnostic factors, as well as prognosis and treatment options. RESULTS In order to provide proper treatment, the molecular basis and histology of the tumor must be addressed. The 1p/19q co-deletion indicator has been considered the gold standard of glioma diagnosis, but oft-sighted mutations in the IDH1 and IDH2 genes have given rise to three subgroups of 1p/19q co-deleted tumors, each associated with specific patterns of nervous cells. Other molecular markers and microRNA expression patterns have been studied for possible diagnostic and prognostic methods. Microsurgical resection is the singular treatment with highest overall survival (OS) and quality of life (QOL). Total gross resection is optimal, with patients having a 5-year OS of 100% with 90% tumor resection. Low doses of radiation are as effective as high doses and are better tolerated (with less cognitive deficits). Chemotherapy, specifically temozolomide, offers a favorable toxicity profile and QOL; additionally, seizure reduction is an early and consistent prognostic marker for survival after treatment with temozolomide. CONCLUSIONS The “wait and see” approach for treatment is no longer the standard for LGGs. Immediate treatment after diagnosis is recommended. Gross total resection (if achievable) is the most favorable treatment, with the highest OS and QOL. The use of temozolomide and radiotherapy is recommended. Histological background and genetic markers are vital for determining a treatment plan.

LTBK-12. EORTC 26951, RANDOMIZED STUDY OF ADJUVANT PCV AFTER 59.4 GY RADIOTHERAPY: VERY LONG TERM FOLLOW-UP

Abstract BACKGROUND Between 1995 and 2002 the EORTC Brain Tumor Group conducted a prospective phase III study on adjuvant procarbazine, CCNU and vincristine (PCV) chemotherapy in anaplastic oligodendroglioma (AOD). A mature follow-up presented in 2012 showed survival benefit of the addition of PCV, in particular in 1p/19q co-deleted tumors and tumors with MGMT promoter methylation. We now present very long term follow-up. MATERIALS AND METHODS Patients were eligible if locally diagnosed with a newly diagnosed AOD. They were randomized between radiotherapy (RT, 33 x 1.8 Gy) and the same RT followed by 6 cycles PCV (RT/PCV). Primary endpoints were overall survival (OS) and progression free survival (PFS). 1p/19q status (FISH) was determined in 300 patient. Kaplan- Meier technique and Cox modeling were used for long term survival analysis. Primary analyses were adjusted for known prognostic factors. For other analyses no adjustment was performed. RESULTS With 368 patients included, a median follow-up of 18.4 years and 307 (83%) survival events, median and 20-year survival after RT/PCV versus RT alone were 42.3 mo and 16.8% vs 30.6 months and 10.1% (HR 0.78; 95% CI (0.63, 0.98), adjusted p=0.06). Eighty patients were 1p/19q codel of which 26 (33%) were still alive, in this subgroup median and 20-year survival after RT/PCV versus RT alone were 14 years and 37.1% versus 9.3 years and 13.6% (HR 0.60, 95% CI (0.35, 1.03), unadjusted p=0.06). Twenty year PFS in 1p/19q codel was 31.3% in RT/PCV treated patients and 10.8% in RT only treated patients (HR 0.49, 95% CI (0.29, 0.83), unadjusted p=0.007). In the 1p/19q codel subgroup age, WHO PS and necrosis at pathology were identified to be of independent prognostic value for OS. CONCLUSION This long term analysis confirms the earlier conclusions and provides data on long term survival in this patient group. In 1p/19q codel patients treated with RT/PCV, the 20-year PFS and OS rates are 31% and 37% respectively.

Relevance of calcification and contrast enhancement pattern for molecular diagnosis and survival prediction of gliomas based on the 2016 World Health Organization Classification

ObjectivesThe significance of conventional neuroimaging features for predicting molecular diagnosis and patient survival based on the updated World Health Organization (WHO) classification remains uncertain. We assessed the relevance of neuroimaging features (ring enhancement [RE], non-ring enhancement [non-RE], overall gadolinium enhancement [GdE], and intratumoral calcification [IC]) for molecular diagnosis and survival in glioma patients. Patients and methodsWe evaluated 234 glioma patients according to the updated WHO classification. Isocitrate dehydrogenase (IDH), H3F3A, BRAF hotspot mutations, TERT promotor mutation, and chromosome 1p/19q co-deletion were examined. RE, non-RE, GdE, and IC were evaluated as significant neuroimaging findings. Kaplan-Meier analyses were performed to evaluate overall survival (OS) and the correlations of prognostic factors were evaluated by log-rank tests. Univariate and multivariate analyses were performed to detect prognostic factors for OS. ResultsA total of 207 patients were eligible. In 110 patients presenting RE, 102 (93%) were glioblastoma (GBM), IDH-wild type. In 97 patients without RE, presence of GdE or IC were not significantly different between IDH-mutant and -wild type tumors, whereas presence of GdE was a significant indicator of higher WHO grades. IC was the only significant finding for 1p/19q co-deleted tumors. TERT promoter mutation was observed in 7/17 patients with diffuse astrocytic glioma, IDH-wild type; recently-defined as “molecular GBM.” IC, RE, and GdE were observed with lower prevalence in molecular GBMs. While presence of RE, GdE, and absence of IC were significant factors of OS in overall cohort, presence of GdE was not significant in OS in cases without RE, and IDH-mutant tumors. IC was a significant predictor of favorable OS in cases without RE and IDH-wild type tumors. Multivariate analysis also validated these findings. ConclusionGdE alone is not a significant predictor of IDH mutation status, but the pattern of enhancement is a significant predictor with RE demonstrating high sensitivity and specificity for GBM, IDH-wild type. Predicting “molecular GBM” by conventional neuroimaging is difficult. Moreover, GdE is not a significant factor of survival analyzed with pattern of enhancement or molecular stratifications. IC is an important radiographic finding for predicting molecular diagnosis and survival in glioma patients.

Abstract 4355: Identification and functional characterization of glioma structural variants

Abstract Adult diffuse gliomas are a diverse class of brain tumors that ultimately result in fatal malignant progression. The highly variable disease progression intervals and poor treatment response observed in glioma have been explained, in part, by the extent of heterogeneity within and across gliomas. Somatic structural variants such as deletions, duplications, insertions, inversions, translocations, and extrachromosomal DNA contribute to glioma heterogeneity by generating genomic instability, a hallmark of cancer genomes. While comprehensive approaches such as whole genome sequencing have begun to catalog the glioma structural variant landscape, the molecular mechanisms by which they contribute to tumor progression remains poorly understood. Here, we identified genomic rearrangements in the whole genomes of 147 gliomas and glioma cell lines. Among the whole-genome sequencing samples were 62 glioblastomas (TCGA), 52 low-grade gliomas (TCGA), and our own set of 33 patient-derived glioma sphere-forming cells. On average, glioblastomas demonstrated a greater frequency of high-confidence structural variants (162 per tumor) than low-grade gliomas (130 per tumor, P=0.02) with two glioblastomas displaying evidence of chromothripsis. Across the World Heath Organization's molecular classifications, the IDH-mutant 1p/19q co-deleted tumors demonstrated the lowest structural variant burden when compared with both IDH-wildtype and IDH-mutant non-co-deleted tumors. Structural variant frequencies were found to be similar between patient tumors and an independent set of patient-derived cell lines. Across all samples, a majority of the structural variant breakpoints were found in intronic (42%) and intergenic regions (55%) suggesting that rearrangements predominantly impact distal regulatory regions. To investigate the functional consequences of structural variants in these regions we integrated these samples with available RNA-sequencing and epigenetic data to characterize deregulated transcriptional circuits. Analyses examining the association between genomic rearrangements and chromatin states to determine potential mechanisms of oncogene activation in select tumor and cell line samples are now underway. Together, our study demonstrates the importance of integrating structural variant calls from whole genome sequencing with expression and epigenetic data to define functional genomic rearrangements. Citation Format: Kevin C. Johnson, Floris P. Barthel, Ming Tang, Samirkumar Amin, Qianghu Wang, Erik P. Sulman, Kunal Rai, Roel G.W Verhaak. Identification and functional characterization of glioma structural variants [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4355.

Molecular classification of patients with grade II/III glioma using quantitative MRI characteristics.

Molecular markers of WHO grade II/III glioma are known to have important prognostic and predictive implications and may be associated with unique imaging phenotypes. The purpose of this study is to determine whether three clinically relevant molecular markers identified in gliomas-IDH, 1p/19q, and MGMT status-show distinct quantitative MRI characteristics on FLAIR imaging. Sixty-one patients with grade II/III gliomas who had molecular data and MRI available prior to radiation were included. Quantitative MRI features were extracted that measured tissue heterogeneity (homogeneity and pixel correlation) and FLAIR border distinctiveness (edge contrast; EC). T-tests were conducted to determine whether patients with different genotypes differ across the features. Logistic regression with LASSO regularization was used to determine the optimal combination of MRI and clinical features for predicting molecular subtypes. Patients with IDH wildtype tumors showed greater signal heterogeneity (p = 0.001) and lower EC (p = 0.008) within the FLAIR region compared to IDH mutant tumors. Among patients with IDH mutant tumors, 1p/19q co-deleted tumors had greater signal heterogeneity (p = 0.002) and lower EC (p = 0.005) compared to 1p/19q intact tumors. MGMT methylated tumors showed lower EC (p = 0.03) compared to the unmethylated group. The combination of FLAIR border distinctness, heterogeneity, and pixel correlation optimally classified tumors by IDH status. Quantitative imaging characteristics of FLAIR heterogeneity and border pattern in grade II/III gliomas may provide unique information for determining molecular status at time of initial diagnostic imaging, which may then guide subsequent surgical and medical management.

Remote intracranial recurrence of IDH mutant gliomas is associated with TP53 mutations and an 8q gain.

Most IDH mutant gliomas harbor either 1p/19q co-deletions or TP53 mutation; 1p/19q co-deleted tumors have significantly better prognoses than tumors harboring TP53 mutations. To investigate the clinical factors that contribute to differences in tumor progression of IDH mutant gliomas, we classified recurrent tumor patterns based on MRI and correlated these patterns with their genomic characterization. Accordingly, in IDH mutant gliomas (N = 66), 1p/19 co-deleted gliomas only recurred locally, whereas TP53 mutant gliomas recurred both locally and in remote intracranial regions. In addition, diffuse tensor imaging suggested that remote intracranial recurrence in the astrocytomas, IDH-mutant with TP53 mutations may occur along major fiber bundles. Remotely recurrent tumors resulted in a higher mortality and significantly harbored an 8q gain; astrocytomas with an 8q gain resulted in significantly shorter overall survival than those without an 8q gain. OncoScan® arrays and next-generation sequencing revealed specific 8q regions (i.e., between 8q22 and 8q24) show a high copy number. In conclusion, only tumors with TP53 mutations showed patterns of remote recurrence in IDH mutant gliomas. Furthermore, an 8q gain was significantly associated with remote intracranial recurrence and can be considered a poor prognostic factor in astrocytomas, IDH-mutant.

Genetically Defined Oligodendroglioma Is Characterized by Indistinct Tumor Borders at MRI.

In 2016, the World Health Organization revised the brain tumor classification, making IDH mutation and 1p/19q codeletion the defining features of oligodendroglioma. To determine whether imaging characteristics previously associated with oligodendroglial tumors are still applicable, we evaluated the MR imaging features of genetically defined oligodendrogliomas. One hundred forty-eight adult patients with untreated World Health Organization grade II and III infiltrating gliomas with histologic oligodendroglial morphology, known 1p/19q status, and at least 1 preoperative MR imaging were retrospectively identified. The association of 1p/19q codeletion with tumor imaging characteristics and ADC values was evaluated. Ninety of 148 (61%) patients had 1p/19q codeleted tumors, corresponding to genetically defined oligodendroglioma, and 58/148 (39%) did not show 1p/19q codeletion, corresponding to astrocytic tumors. Eighty-three of 90 (92%) genetically defined oligodendrogliomas had noncircumscribed borders, compared with 26/58 (45%) non-1p/19q codeleted tumors with at least partial histologic oligodendroglial morphology (P < .0001). Eighty-nine of 90 (99%) oligodendrogliomas were heterogeneous on T1- and/or T2-weighted imaging. In patients with available ADC values, a lower mean ADC value predicted 1p/19q codeletion (P = .0005). Imaging characteristics of World Health Organization 2016 genetically defined oligodendrogliomas differ from the previously considered characteristics of morphologically defined oligodendrogliomas. We found that genetically defined oligodendrogliomas were commonly poorly circumscribed and were almost always heterogeneous in signal intensity.

Chapter 22 - Low-grade and anaplastic oligodendroglioma

Anaplastic oligodendrogliomas have long attracted interest because of their sensitivity to chemotherapy, in particular in the subset of 1p/19q co-deleted tumors. Recent molecular studies have shown that all 1p/19q co-deleted tumors have IDH mutations and most of them also have TERT mutations. Because of the presence of similar typical genetic alterations in astrocytoma and glioblastoma, the current trend is to diagnose these tumors on the basis of their molecular profile. Further long-term follow-up analysis of both EORTC and RTOG randomized studies on (neo)adjuvant procarbazine, lomustine, vincristine (PCV) chemotherapy have shown that adjuvant chemotherapy indeed improves outcome, and this is now standard of care. It is also equally clear that benefit to PCV chemotherapy is not limited to the 1p/19q co-deleted cases; potential other predictive factors are IDH mutations and MGMT promoter methylation. Moreover, a recent RTOG study on low-grade glioma also noted an improved outcome after adjuvant PCV chemotherapy, thus making (PCV) chemotherapy now standard of care for all 1p/19q co-deleted tumors regardless of grade. It remains unclear whether temozolomide provides the same survival benefit, as no data from well-designed clinical trials on adjuvant temozolomide in this tumor type are available. Another question that remains is whether one can safely leave out radiotherapy as part of initial treatment to avoid cognitive side-effects of radiotherapy. The current data suggest that delaying radiotherapy and treatment with chemotherapy only may be detrimental for overall survival.

GENO-19INTEGRATED GENOMIC ANALYSIS OF OLIGODENDROGLIAL TUMORS IDENTIFIES DISTINCT MOLECULAR SUBGROUPS WITHIN 1p/19q CO-DELETED OLIGODENDROGLIOMAS

BACKGROUND: Oligodendroglial tumors are a group of heterogeneous gliomas in terms of clinical, radiological, histological and molecular profiles. Current molecular classification of oligodendroglial tumors identifies 3 groups with distinct clinical outcomes based on two genetic events only: IDH mutation and 1p/19q co-deletion. Integrating data from additional molecular level contributes to refine further this classification and adapt clinical practice accordingly. METHODS: 156 tumors with an oligodendroglial component (Grade II(46), III(100), IV(10)) as well as 22 supportive samples (11 glioblastomas, 2 diffuse astrocytomas, 9 normal brain samples) were profiled transcriptionally (mRNA expression arrays and microRNA sequencing), genomically (SNP arrays) and epigenetically (DNA methylation arrays). Unsupervised consensus classification was performed for each omics separately and by integrating the different omics. RESULTS: A strong correlation was observed between the classification systems obtained from the different omics and 5 subgroups of tumors were robustly identified. The validity of these 5 classes was confirmed on public TCGA data from low grade gliomas (TCGA-LGG). Beyond the 3 well-known molecular classes (1p/19q co-deletion and IDH mutation, IDH mutation only, no IDH mutation and no 1p/19q co-deletion), our multi-omics classification reveals 3 additional subgroups within the group of 1p/19q co-deleted tumors. These 3 subgroups are associated with distinct genomic alterations, distinct expression patterns of cell differentiation markers (from oligodendroglial precursor cells, oligodendrocytes, or neuronal cells), and distinct expression of oncogenic pathways and immune signatures. Follow-up duration of our cohort was not long enough to highlight reliable associations with prognosis but the analysis of TCGA-LGG based on our new 3 subgroups shows a significant association with distinct survival outcomes independently from histologic grade. CONCLUSION: This work represents the first integrative multi-omics analysis of oligodendroglial tumors and enables the refining of their molecular classification. The new classification identifies for the first time distinct molecular subgroups within 1p/19q co-deleted oligodendroglial tumors.

MPTH-10MOLECULAR-GENETIC AND CLINICAL RISK FACTORS FOR PATIENTS WITH GLIOMAS WITH TOTAL 1p19q LOSS

Codeleted gliomas are associated with better response to therapy and longer survival. However, early recurrence occurs at times, and there are cases with short survival despite 1p19q loss. Although several unfavorable prognostic factors are known for low grade gliomas, the risk factors for patients with codeleted gliomas has not been elucidated. We studied 57 codeleted tumors of WHO grade II-III for chromosomal copy number abnormality (CNA) by comparative genomic hybridization (metaphase CGH), promoter methylation of the MGMT gene by methylation-specific PCR as well as clinical factors known to be associated with prognosis of glioma patients. Overall survival (OS) curves were estimated using the Kaplan-Meier method, and compared by grade (grade 2 versus grade 3), age (patients from 50 years up versus under 50 years of age, ), extent of surgery (over 95% removal versus partial removal versus biopsy), tumor maximum diameter (larger than 5cm diameter versus less), copy number abberations detected in more than 10% of all cases, status of MGMT methylation and pathological diagnosis by original institutional diagnosis (oligodendroglial versus astrocytic). As a result, there was no significant difference in OS for age, extent of surgery, maximum tumor diameter, histological feature and status of MGMT methylation. On the other hand, the OS was significantly shorter in the patients with gliomas with gain of 19p (p = 0.011), and gain on 17q and histological grade III showed trends towards poor prognosis (p = 0.055, 0.1, respectively).In conclusion, gain of 19p, gain on 17q, and histological grade III might be unfavorable prognostic factors of gliomas with total 1p19q loss.

IDH mutation, 1p19q codeletion and ATRX loss in WHO grade II gliomas.

Epigenetic, genetic, and molecular studies have identified several diagnostic and prognostic markers in diffuse gliomas. Their importance for evaluating WHO grade II gliomas has yet to be specifically delineated. We analyzed markers, including IDH mutation(IDHmut), 1p19q codeletion(1p19qcodel), ATRX expression loss(ATRX loss) and p53 overexpression, and outcomes in 159 patients with WHO grade II oligodendroglioma, oligoastrocytoma, and astrocytoma (2003-2012). IDHmut was found in 141(91%) and ATRX loss in 64(87%) of IDHmut-noncodel tumors (p = 0.003). All codeleted tumors (n = 66) were IDHmut. Four subgroups were identified: IDHmut-codel, 66(43%); IDHmut-noncodel-ATRX loss, 60(39%); IDHmut-noncodel-ATRXwt, 9(6%); IDHwt, 14(9%). Median survival among 4 groups was significantly different (p = 0.038), particularly in IDHmut-codel (median survival 15.6 years) compared to the remaining 3 groups (p = 0.025). Survival by histology was not significant. Overall (OS), but not progression-free (PFS), survival was significantly longer with gross total resection vs. biopsy only (p = 0.042). Outcomes for patients with subtotal resection were not significantly different from those with biopsy only. Among these uniformly treated patients, OS far exceeds PFS, particularly in those with 1p/19q codeletion. For WHO grade II diffuse glioma, molecular classification using 1p/19qcodel, IDHmut, and ATRX loss more accurately predicts outcome and should be incorporated in the neuropathologic evaluation.

Molecular classification of diffuse cerebral WHO grade II/III gliomas using genome- and transcriptome-wide profiling improves stratification of prognostically distinct patient groups.

Cerebral gliomas of World Health Organization (WHO) grade II and III represent a major challenge in terms of histological classification and clinical management. Here, we asked whether large-scale genomic and transcriptomic profiling improves the definition of prognostically distinct entities. We performed microarray-based genome- and transcriptome-wide analyses of primary tumor samples from a prospective German Glioma Network cohort of 137 patients with cerebral gliomas, including 61 WHO grade II and 76 WHO grade III tumors. Integrative bioinformatic analyses were employed to define molecular subgroups, which were then related to histology, molecular biomarkers, including isocitrate dehydrogenase 1 or 2 (IDH1/2) mutation, 1p/19q co-deletion and telomerase reverse transcriptase (TERT) promoter mutations, and patient outcome. Genomic profiling identified five distinct glioma groups, including three IDH1/2 mutant and two IDH1/2 wild-type groups. Expression profiling revealed evidence for eight transcriptionally different groups (five IDH1/2 mutant, three IDH1/2 wild type), which were only partially linked to the genomic groups. Correlation of DNA-based molecular stratification with clinical outcome allowed to define three major prognostic groups with characteristic genomic aberrations. The best prognosis was found in patients with IDH1/2 mutant and 1p/19q co-deleted tumors. Patients with IDH1/2 wild-type gliomas and glioblastoma-like genomic alterations, including gain on chromosome arm 7q (+7q), loss on chromosome arm 10q (-10q), TERT promoter mutation and oncogene amplification, displayed the worst outcome. Intermediate survival was seen in patients with IDH1/2 mutant, but 1p/19q intact, mostly astrocytic gliomas, and in patients with IDH1/2 wild-type gliomas lacking the +7q/-10q genotype and TERT promoter mutation. This molecular subgrouping stratified patients into prognostically distinct groups better than histological classification. Addition of gene expression data to this genomic classifier did not further improve prognostic stratification. In summary, DNA-based molecular profiling of WHO grade II and III gliomas distinguishes biologically distinct tumor groups and provides prognostically relevant information beyond histological classification as well as IDH1/2 mutation and 1p/19q co-deletion status.

P-CREB expression in human gliomas: potential use in the differential diagnosis between astrocytoma and oligodendroglioma.

Phosphorylated cyclic-AMP responsive element binding protein (p-CREB) is a transcription factor that is involved in gliomagenesis. For this reason, it was recently proposed as a potential therapeutic target in gliomas; however, gliomas comprise tumors with different biomolecular profile, clinical behavior, and response to chemotherapy. In the present study, we aimed to investigate whether p-CREB expression varies in the 2 main types of gliomas, astrocytomas and oligodendrogliomas. Thus, we analyzed the expression of p-CREB in a series of astrocytomas and oligodendrogliomas of different histologic grades by immunohistochemistry and Western blot analysis. p53 overexpression and the Ki-67 labeling index were also assessed in all the tumors. p-CREB immunohistochemical expression was present in 100% of the astrocytic tumors, but in only 46% of oligodendrogliomas (P = .0033 for grade II; P = .0041 for grade III tumors). Absence of p-CREB immunohistochemical expression was significantly associated with 1p/19q codeletion (P < .0001) and identified 1p/19q codeleted tumors, with 70% sensitivity and 100% specificity (area under the curve = 0.85; P < .0001). In addition, p-CREB expression correlated with higher Ki-67 labeling index (P = .049) and p53 overexpression (P < .0001) as well as with the histologic grade of astrocytomas (P = .044). Immunohistochemical results were further confirmed by Western blot analysis. Our findings demonstrate that astrocytomas and oligodendrogliomas are characterized by distinctive patterns of p-CREB expression. These distinct expression patterns might provide insight into the mechanism of tumorigenesis of glial tumors and represent a useful tool for the differential diagnosis of astrocytoma and oligodendroglioma.

AT-56 * TREATMENT OF LARGE LOW-GRADE OLIGODENDROGLIAL TUMORS WITH UPFRONT PROCARBAZINE, LOMUSTINE, AND VINCRISTINE CHEMOTHERAPY WITH LONG FOLLOW-UP: A RETROSPECTIVE COHORT STUDY WITH GROWTH KINETICS

PURPOSE: We treated patients with newly diagnosed and large low-grade oligodendroglial tumors with upfront procarbazine, lomustine (CCNU) and vincristine (PCV) in our institution in order to delay RT. We now report long term follow-up on a cohort of patients treated between 1998 and 2006. METHODS: Patients were treated with PCV in cycles of 6 weeks, for a maximum of 6 cycles. Central pathology review, genotyping on 1p/19q loss and immunohistochemistry on the IDH1 mutational status and MIB-1 labeling was performed. The response to treatment was defined according to the RANO criteria; in addition change over time of mean tumor diameters (growth kinetics) was calculated. RESULTS: Thirty-two patients were treated, 18 of which were diagnosed with 1p/19q co-deleted tumors. Median follow-up duration was 8 years. The median overall survival (OS) was 120 months and the median progression-free survival (PFS) was 46 months. Growth kinetics showed an ongoing decrease of the mean tumor diameter after completion of chemotherapy, during a median time of 35 months (range 5-136 months), but an increase of the mean tumor diameter did not herald progression as detected by RANO criteria. 1p/19q co-deletion was associated with a significant increase in OS (median OS 83 months versus not reached for codeleted tumors; p = 0.003)) and PFS (median PFS 35 months versus 67 months for codeleted tumors; p = 0.024). Patients with combined 1p/19q loss had a 10 year PFS of 34% and the radiotherapy in these patients was postponed for a median period of more than 6 years. CONCLUSION: This long-term follow-up study indicates that upfront PCV chemotherapy is associated with long PFS and OS and delays radiotherapy for a considerable period of time in patients with low-grade oligodendroglial tumors, in particular with combined 1p/19q loss.

GE-08 * TARGETED NEXT GENERATION SEQUENCING OF ARCHIVAL FFPE SAMPLES FROM EORTC STUDY 26951 SHOWS STRONG PROGNOSTIC VALUE OF A MOLECULAR CLASSIFICATION IN LOCALLY DIAGNOSED GRADE III OLIGODENDROGLIOMA

BACKGROUND: Molecular holds promise for an improved classification of glial tumors. We analyzed samples of patients enrolled in EORTC study 26951 on adjuvant PCV in anaplastic oligodendroglial tumors to evaluate 1. The clinical significance of glioma classification with Next Generation Sequencing (NGS); and 2. The prognostic significance of CIC and FUBP mutations. MATERIAL AND METHODS: EORTC 26951 investigated adjuvant PCV in locally diagnosed anaplastic oligodendroglial tumors. NGS was performed on archival formalin fixed paraffin embedded (FFPE) samples using the Ion Torrent Personal Genome Machine for simultaneous detection of mutations in the genes for ATRX, CIC, EGFR, FUBP1, NOTCH1, PTEN, and TP53 and hot spot mutation regions in BRAF, H3F3A, IDH1, IDH2 and PIK3CA as well as imbalances on chromosome 1p, 10q, 7 en 19q. TERT mutations were assessed with PCR. RESULTS: At the time of abstract submission 89 cases have been investigated, more samples are being processed. In 62 tumors an IDH1 mutations was found, in 2 an IDH 2 mutation. Forty-eight tumors (54%) were 1p/19q codeleted, 29 (60%) of these had CIC mutations and 20 (42%) had FUBP mutations. All but one 1p/19q codeleted tumors showed TERT mutations. Ten tumors showed ATRX mutations, 5 also had PTEN mutations. Median OS was 136 months for CIC mutated 1p/19q co-delete tumors, and 95 months for CICwt tumors (p = 0.17); FUBP mutations showed no relation with OS. TERT mutations were found in 60 tumors (67%), OS in TERT mutated but 1p/19q intact tumors was 12 months. IDH mutations, TERT mutations and 1p/19q co-deletion were the most significant prognostic factors, distinguishing between groups with significantly different OS. CONCLUSIONS: The ongoing expansion of this series will show if CIC mutations have prognostic significance. Targeted NGS even on archival FFPE allows a clinically relevant prognostic classification of glioma, while simultaneously identifying relevant druggable targets.

Treatment of large low-grade oligodendroglial tumors with upfront procarbazine, lomustine, and vincristine chemotherapy with long follow-up: a retrospective cohort study with growth kinetics.

We treated patients with newly diagnosed and large low-grade oligodendroglial tumors with upfront procarbazine, CCNU and vincristine (PCV) in order to delay radiotherapy. Patients were treated with PCV for a maximum of 6 cycles. The response to treatment was defined according to the RANO criteria; in addition change over time of mean tumor diameters (growth kinetics) was calculated. Thirty-two patients were treated between 1998 and 2006, 18 of which were diagnosed with 1p/19q co-deleted tumors. Median follow-up duration was 8 years (range 0.5-13 years). The median overall survival (mOS) was 120 months and the median progression-free survival (mPFS) was 46 months. Growth kinetics showed an ongoing decrease of the mean tumor diameter after completion of chemotherapy, during a median time of 35 months, but an increase of the mean tumor diameter did not herald progression as detected by RANO criteria. 1p/19q co-deletion was associated with a significant increase in OS (mOS 83 months versus not reached for codeleted tumors; p = 0.003)) and PFS (mPFS 35 months versus 67 months for codeleted tumors; p = 0.024). Patients with combined 1p/19q loss had a 10 year PFS of 34 % and the radiotherapy in these patients was postponed for a median period of more than 6 years. This long-term follow-up study indicates that upfront PCV chemotherapy is associated with long PFS and OS and delays radiotherapy for a considerable period of time in patients with low-grade oligodendroglial tumors, in particular with combined 1p/19q loss.