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BACKGROUND The integration of molecular markers into the WHO 2016 classification has clarified the complex diagnosis of gliomas. Among these biomarkers, the TERT promoter mutation and the loss of ATRX (ATRX loss) are mutually exclusive alterations associated with re-activation of telomerase or alternative lengthening of telomeres (ALT), respectively. Strangely, 25% of gliomas display neither or both these alterations, a situation referred to as abnormal telomere maintenance mechanism (aTMM). MATERIAL AND METHODS To investigate the TMM actually involved in gliomas, the C-circle (CC) assay was adapted to tumor (FFPE and frozen) samples. RESULTS We constructed a CC-based algorithm able to identify the TMM of 284 gliomas with either TERT or ATRX alteration, with a sensitivity of 100% and a specificity of 97.3%, and succeeded in deciphering the TMM involved in 122 aTMM gliomas. Additionally, the combination of the TMM, the mutational status of the Isocitrate dehydrogenase 1/2 (IDH) gene, and the histological grading was used as base for a new classification: TeloDIAG. Six subtypes are defined in this classification: tOD, tLGA, tGBM_IDHmt, tGBM, and tAIV, corresponding to oligodendroglioma, IDHmt low grade astrocytoma, IDHmt glioblastoma, and IDHwt glioblastoma, respectively, the last class gathers ALT+ IDHwt glioma. The TeloDIAG diagnosis is 99% concordant with the WHO classification for glioma displaying typical molecular characteristics (N=312). It modified the classification of 38% (N=156) discordant tumors, such as IDHwt Astrocytoma, aTMM tumors, or gliomas with unexpected TMM (e.g. TERTwt oligodendroglioma, ATRX loss GBM). Interestingly, 20% (N=69) of TERTwt, ATRXwt, or IDHwt GBM were actually tAIV, which is remarkable as tAIV-glioma patients’ survival tended to be longer (21.2 months) than tGBM patients’ survival (16.5 months). Importantly, CC in blood sampled from IDHmt astrocytoma patients was detected with a sensitivity of 56% and a specificity of 95% (N = 206). CONCLUSION In sum, the TeloDIAG is a new, simple, and efficient tool helping in glioma diagnosis and a promising option for liquid biopsy

BACKGROUND Lower-grade gliomas (LGG) are divided into three histo-molecular groups: i) IDH-wildtype, ii) IDH mutant and 1p19q intact and iii) IDH mutant and 1p19q co-deleted. The current classification has improved the clinical stratification and its reproducibility. However, LGGs are still associated with an important degree of clinical heterogeneity. We sought to analyze the cross-talk between the spatial distribution and the quantitative imaging features (radiomics) with the clinical evolution and their molecular background (radiogenomics). MATERIAL AND METHODS We performed a retrospective multicentric study from 4 cohorts of high-grades gliomas (POLA Network, TCGA, REMBRANDT and LGG-1p19q), totaling 900 gliomas. We performed N4 and WhiteStripe imaging corrections to standardize MRI intensities. We used ITK-SNAP to obtain a mask of the different habitats of the tumor. Then we used PyRadiomics to obtain 2616 radiomic features per sample. We used plsRcox for fitting several Cox model in high-dimensional settings. We assessed the performance of the difference Cox model with the Harrel’s concordance index. We used a Sparse Canonical Correlation analysis to analyze the spatial distribution of the tumors. RESULTS Radiomics features allow identification in an unsupervised manner IDH-mutant gliomas with a median AUC of 0.96 [0.92–0.98]. Interestingly, in the analysis of survival, radiomics features provided additional information to clinical or genetics covariates and the model with only radiomics features obtained a C-Index of 0.78 [0.72–0.82]. In addition, survival model with the best performance in the prediction of overall survival was the one combining radiomics, clinics and genetics features with a C-Index 0.85 [0.82–0.92] and was validated in the other cohorts. The analysis of spatial distribution showed a very strong distribution of 1p19q co-deleted oligodendrogliomas in the frontal lobes. CONCLUSION Radiomics features may provide additional relevant clinical information by improving the prognosis of LGG. Radiomics allow non-invasive prediction of the most relevant molecular alterations of LGG.

BACKGROUND: The aim of this study was to correlate MRI features and molecular characteristics in anaplastic oligodendrogliomas (AOs). METHODS: The MRI characteristics of 50 AO patients enrolled in the French national network for high-grade oligodendroglial tumors were analyzed. The genomic profiles and IDH mutational statuses were assessed using high-resolution single-nucleotide polymorphism arrays and direct sequencing, respectively. The gene expression profiles of 25 1p/19q-codeleted AOs were studied on Affymetrix expression arrays. RESULTS: Most of the cases were frontal lobe contrast-enhanced tumors (52%), but the radiological presentations of these cases were heterogeneous, ranging from low-grade glioma-like aspects (26%) to glioblastoma-like aspects (22%). The 1p/19q codeletion (n = 39) was associated with locations in the frontal lobe (P = .001), with heterogeneous intratumoral signal intensities (P = .003) and with no or nonmeasurable contrast enhancements (P = .01). The IDH wild-type AOs (n = 7) more frequently displayed ringlike contrast enhancements (P = .03) and were more frequently located outside of the frontal lobe (P = .01). However, no specific imaging pattern could be identified for the 1p/19q-codeleted AO or the IDH-mutated AO. Within the 1p/19q-codeleted AO, the contrast enhancement was associated with larger tumor volumes (P = .001), chromosome 9p loss and CDKN2A loss (P = .006), genomic instability (P = .03), and angiogenesis-related gene expression (P < .001), particularly for vascular endothelial growth factor A and angiopoietin 2. CONCLUSION: In AOs, the 1p/19q codeletion and the IDH mutation are associated with preferential (but not with specific) imaging characteristics. Within 1p/19q-codeleted AO, imaging heterogeneity is related to additional molecular alterations, especially chromosome 9p loss, which is associated with contrast enhancement and larger tumor volume.

BACKGROUND: Low-grade gliomas (LGG) are divided into three histo-molecular groups: i) IDHwt, ii) IDHmut and 1p19q intact and iii) 1p19q co-deleted with IDH1 mutation. The current classification has improved the clinical stratification and its reproducibility. However, LGGs are still associated with an important degree of clinical heterogeneity.We sough to analyze the genomic and genetic heterogeneity by re-analyzing next-generation sequencing data of two different cohorts of LGG to dissect the potential role of clonal architecture on the clinical evolution of LGG. MATERIAL AND METHODS: We have re-analyzed whole-exome sequencing (WES) using LGG TCGA dataset and a cohort of 40 LGG analyzed by WES from the POLA Network. We have obtained the clonal architecture, the mutation burden, the number of clones, the clonal and subclonal distribution of genetic and genomic alterations and the distribution of the somatic signatures. In addition, we have also analyzed 5 1p19q co-deleted samples at different timepoints to further dissect the clonal evolution of this entity. RESULTS: As expected, the mutation burden of LGG is low (median somatic mutation per sample 34). Surprisingly, the number the subclones was higher in the 1p19q co-deleted subgroup.LGG were enriched in somatic signatures associated with hydrolytic deamination of methylated CpG and with deficiency of mismatch repair. Interestingly, only within 1p19q co-deleted gliomas, the number of subclones, the mutant-allele tumor heterogeneity (MATH) score and the signature associated with hydrolytic deamination of methylated CpGwere associated with poorer outcome in univariate analysis. Finally, only the enrichment of the mutational signature associated with hydrolytic deamination of methylated CpG had prognostic impact in 1p19q co-deleted LGG in Cox multivariate analysis afteradjusting by age, mutational clones number, MATH score and loss of CDKN2A loss. CONCLUSION: The clonal architecture of LGG may provide additional clinical relevant data within 1p19q co-deleted tumors. The enrichment of a somatic signature associated with hydrolytic deamination of methylated CpG is independently associated with poor overall survival.

Anaplastic or WHO grade III oligodendrogliomas (AO) are a heterogeneous subgroup of diffuse glial tumors in adults. Three major histomolecular subtypes with clinical relevance have been individualized: (i) 1p/19q co-deleted AO -80% of cases-, (ii) non 1p/19q co-deleted and IDH mutated AO -10% of cases- and (iii) non 1p/19q co-deleted and IDH wild-typeAO -10% of cases-. 1p/19q co-deleted AO, and to a lesser extent IDH mutated AO, have better prognosis and better response to treatment with a median survival of more than 10 years, as shown in two phase III international trials. We have recently shown that loss of heterozygosity (LOH) in chromosome arm 9p, with copy number loss -CL LOH- or without -Copy Neutral LOH- is a frequent event in AO. Interestingly, 9p CN LOH, inducing gene under-expression, has biological significance. In the present study, we address the prognostic value of 9p loss in 1p/19q co-deleted AO. In the present study, 228 AO exhibiting 1p/19q co-deletion were included. All tumors were centrally reviewed in the setting of the French national network for high-grade oligodendroglial tumors (POLA network) that recruits prospectively newly diagnosed anaplastic oligodendroglial tumors. Tumor DNA was analyzed using high-resolution single nucleotide polymorphism array analysis. In the entire series, 70/228 (1/3) harbored 9p loss including CN-LOH, homozygous loss or CL-LOH. 9p loss was associated with a worse prognosis in 1p19q co-deleted AO in univariate analysis (3-years OS of 98% vs. 74%, p < 0.001) whereas PFS at three years was not significantly different (3-years PFS of 88% vs. 66% p = 0.1). After adjustment for age, KPS, and treatment, multivariate analysis demonstrated 9p loss to be an independent prognostic factor for OS, p-value = 0.03, HR = 4.9 [1.2-16], but not for PFS. 1p19q co-deleted AO harboring 9p loss have shorter overall survival compared to their non 9p-lost counterparts in this prospective cohort. Further studies are needed to validate our findings.

The prognosis of low-grade gliomas (LGGs) varies widely, with overall survival (OS) ranging from a few years to decades. Defining reliable prognostic factors in LGGs has been difficult, but the importance of clinical factors, including gender, age, Karnofsky performance status (KPS), symptoms at diagnosis, tumor size, and extent of tumor resection, has been recently recognized.1–4 To date, the only identified molecular alteration of prognostic importance in LGGs is the 1p–19q co-deletion.5,6 Loss of heterozygosity (LOH) on chromosomes 9p and 10q is rare in LGGs. These alterations are classically associated with high-grade tumors (anaplastic gliomas and glioblastomas)7 and have been found to be of prognostic significance in anaplastic gliomas8 but not in glioblastomas.9 In this study, we analyzed the prognostic impact of LOH on 9p and 10q in a series of LGGs.