Search

To elucidate the mechanisms of malignant progression of lower-grade glioma, molecular profiling using methylation array, whole-exome sequencing, and RNA sequencing was performed for 122, 36 and 31 gliomas, respectively. This cohort included 24 matched pairs of initial lower-grade gliomas and recurrent tumors, most of which showed malignant progression. Nearly half of IDH-mutant glioblastomas that had progressed from lower-grade gliomas exhibited characteristic partial DNA demethylation in previously methylated genomic regions of their corresponding initial tumors, which had the glioma CpG island methylator phenotype (G-CIMP). In these glioblastomas, cell cycle-related genes, RB and PI3K-AKT pathway genes were frequently altered. Notably, late-replicating domain was significantly enriched in the demethylated regions that were mostly located in non-regulatory regions, suggesting that the loss of DNA methylation during malignant transformation may involve mainly passive demethylation due to a delay in maintenance of methylation during accelerated cell division. Nonetheless, a limited number of genes including IGF2BP3, which potentially drives cell proliferation, were presumed to be upregulated due to demethylation of their promoter. Our data indicated that demethylation of the G-CIMP profile found in a subset of recurrent gliomas reflects accelerated cell divisions accompanied by malignant transformation. Oncogenic genes activated by such epigenetic change represent potential therapeutic targets.

Contains fulltext : 155226.pdf (Publisher’s version ) (Closed access) Temozolomide (TMZ) increases the overall survival of patients with glioblastoma (GBM), but its role in the clinical management of diffuse low-grade gliomas (LGG) is still being defined. DNA hypermethylation of the O (6) -methylguanine-DNA methyltransferase (MGMT) promoter is associated with an improved response to TMZ treatment, while inactivation of the DNA mismatch repair (MMR) pathway is associated with therapeutic resistance and TMZ-induced mutagenesis. We previously demonstrated that TMZ treatment of LGG induces driver mutations in the RB and AKT-mTOR pathways, which may drive malignant progression to secondary GBM. To better understand the mechanisms underlying TMZ-induced mutagenesis and malignant progression, we explored the evolution of MGMT methylation and genetic alterations affecting MMR genes in a cohort of 34 treatment-naive LGGs and their recurrences. Recurrences with TMZ-associated hypermutation had increased MGMT methylation compared to their untreated initial tumors and higher overall MGMT methylation compared to TMZ-treated non-hypermutated recurrences. A TMZ-associated mutation in one or more MMR genes was observed in five out of six TMZ-treated hypermutated recurrences. In two cases, pre-existing heterozygous deletions encompassing MGMT, or an MMR gene, were followed by TMZ-associated mutations in one of the genes of interest. These results suggest that tumor cells with methylated MGMT may undergo positive selection during TMZ treatment in the context of MMR deficiency.

Among diffuse gliomas, oligodendrogliomas show relatively better prognosis, respond well to radiotherapy and chemotherapy, and seldom progress to very aggressive tumors. To elucidate the genetic and epigenetic background for such behavior and tumor evolution during tumor relapse, we comparatively analyzed 12 pairs of primary and recurrent oligodendrogliomas with 1p/19q-codeletion. Initial treatment for these patients was mostly chemotherapy alone. Temozolomide was used for 3, and procarbazine, nimustine and vincristine (PAV chemotherapy) were used for 7 patients. World Health Organization histological grade at recurrence was mostly stable; it was increased in 2, the same in 9, and decreased in 1 cases. Whole-exome sequencing demonstrated that the rate of shared mutation between the primary and recurrent tumors was relatively low, ranging from 3.2-57.9% (average, 33.3%), indicating a branched evolutionary pattern. The trunk alterations that existed throughout the course were restricted to IDH1 mutation, 1p/19q-codeletion, and TERT promoter mutation, and mutation of the known candidate tumor suppressor genes CIC and FUBP1 were not consistently observed between primary and recurrent tumors. Multiple sampling from different regions within a tumor showed marked intratumoral heterogeneity. Notably, in general, the number of mutations was not significantly different after recurrence, remaining under 100, and no hypermutator phenotype was observed. FUBP1 mutation, loss of chr. 9p21, and TCF12 mutation were among a few recurrent de novo alterations that were found at recurrence, indicating that these events were clonally selected at recurrence but were not enough to enhance malignancy. Genome-wide methylation status, measured by Illumina 450 K arrays, was stable between recurrence and the primary tumor. In summary, although oligodendroglioma displays marked mutational heterogeneity, histological malignant transformation accompanying events such as considerable increase in mutation number and epigenetic profile change were not observed at recurrence, indicating that noticeable temporal and spatial genetic heterogeneity in oligodendrogliomas does not result in rapid tumor progression. Electronic supplementary material The online version of this article (doi:10.1186/s40478-017-0422-z) contains supplementary material, which is available to authorized users.

A correction to this article has been published and is linked from the HTML and PDF versions of this paper. The error has been fixed in the paper.

Mutations in H3F3A, which encodes histone H3.3, commonly occur in pediatric glioblastoma. Additionally, H3F3A K27M substitutions occur in gliomas that arise at midline locations (eg, pons, thalamus, spine); moreover, this substitution occurs mainly in tumors in children and adolescents. Here, we sought to determine the association between H3F3A mutations and adult thalamic glioma.Genomic H3F3A was sequenced from 20 separate thalamic gliomas. Additionally, for 14 of the 20 gliomas, 639 genes--including cancer-related genes and chromatin-modifier genes--were sequenced, and the Infinium HumanMethylation450K BeadChip was used to examine DNA methylation across the genome.Of the 20 tumors, 18 were high-grade thalamic gliomas, and of these 18, 11 were from patients under 50 years of age (median age, 38 y; range, 17-46), and 7 were from patients over 50 years of age. The H3F3A K27M mutation was present in 10 of the 11 (91%) younger patients and absent from all 7 older patients. Additionally, H3F3A K27M was not detected in the 2 diffuse astrocytomas. Further sequencing revealed recurrent mutations in TP53, ATRX, NF1, and EGFR. Gliomas with H3F3A K27M from pediatric or young adult patients had similar, characteristic DNA methylation profiles. In contrast, thalamic gliomas with wild-type H3F3A had DNA methylation profiles similar to those of hemispheric glioblastomas.We found that high-grade thalamic gliomas from young adults, like those from children and adolescents, frequently had H3F3A K27M.

Low-grade gliomas often undergo malignant progression, and these transformations are a leading cause of death in patients with low-grade gliomas. However, the molecular mechanisms underlying malignant tumor progression are still not well understood. Recent evidence indicates that epigenetic deregulation is an important cause of gliomagenesis; therefore, we examined the impact of epigenetic changes during malignant progression of low-grade gliomas. Specifically, we used the Illumina Infinium Human Methylation 450K BeadChip to perform genome-wide DNA methylation analysis of 120 gliomas and four normal brains. This study sample included 25 matched-pairs of initial low-grade gliomas and recurrent tumors (temporal heterogeneity) and 20 of the 25 recurring tumors recurred as malignant progressions, and one matched-pair of newly emerging malignant lesions and pre-existing lesions (spatial heterogeneity). Analyses of methylation profiles demonstrated that most low-grade gliomas in our sample (43/51; 84%) had a CpG island methylator phenotype (G-CIMP). Remarkably, approximately 50% of secondary glioblastomas that had progressed from low-grade tumors with the G-CIMP status exhibited a characteristic partial demethylation of genomic DNA during malignant progression, but other recurrent gliomas showed no apparent change in DNA methylation pattern. Interestingly, we found that most loci that were demethylated during malignant progression were located outside of CpG islands. The information of histone modifications patterns in normal human astrocytes and embryonal stem cells also showed that the ratio of active marks at the site corresponding to DNA demethylated loci in G-CIMP-demethylated tumors was significantly lower; this finding indicated that most demethylated loci in G-CIMP-demethylated tumors were likely transcriptionally inactive. A small number of the genes that were upregulated and had demethylated CpG islands were associated with cell cycle-related pathway. In summary, we demonstrated that characteristic DNA demethylation occurred during malignant progression of a subset of low-grade gliomas. The mechanisms underlying and consequences of such DNA demethylation should be studied further.

BACKGROUND: Intracranial germ cell tumors (iGCTs) are rare in the Western countries, however they are the second most common brain tumors in patients under 14 in Japan. Unlike other common pediatric brain tumors, the biology of iGCTs is largely unknown. METHODS: We performed a whole exome sequencing in a large series of iGCTs to elucidate their molecular pathogenesis. A total of 198 germ cell tumors (GCTs) including 133 iGCTs (69 pure germinomas, 56 NGGCTs and 8 metastatic tumors) as well as 65 testicular germ cell tumors (tGCTs) (39 seminomas and 26 non-seminoma GCTs) were collected from 13 centers participating in the Intracranial Germ Cell Tumor Consortium in Japan. Somatic mutations in all coding exons were investigated by whole exome sequencing (WES) in 41 tumors and the matched normal DNAs. Based on the WES data, 41 candidate genes were selected according to the frequency and/or significance of the mutations found. All coding exons of these 41 genes spanning over 160kb were PCR-amplified in a further 157 GCTs and sequenced using the IonTorrent system. The results were integrated with the patients' clinical information that was available for 124 iGCT patients. RESULTS: On average, 15.4 non-synonymous somatic mutations were observed in each tumor, ranging from 1 to 140 by WES in 41 iGCTs. The combined WES and IonTorrent screenings showed that KIT was the most frequently mutated gene in both iGCTs (27%) and tGCTs (18%). MTOR was the second most frequently mutated also in both iGCTs (7%) and tGCTs (6%). RAS mutations (KRAS, HRAS, NRAS) were altogether found in 13% of iGCTs and 12% of tGCTs. These mutations were mutually exclusive to each other and also to KIT mutations. Collectively, the genes involved in the MAPK pathway (e.g., KIT, RAS, NF1) and the PI3K/MTOR pathway (e.g., MTOR, PTEN) were mutated in 44% and 13% of all GCTs. Among the iGCTs, these alterations were significantly more common among pure germinomas than NGGCTs. The mutated MTOR protein was shown to have increased kinase activity, which was suppressed by specific MTOR inhibitors. CONCLUSIONS: Our comprehensive mutational genomic analysis of GCTs revealed that alterations of the MAPK and/or PI3K/MTOR pathways play a critical role in the pathogenesis of both iGCTs and tGCTs, although the extent of their involvement depends on the histopathological subtypes. Our findings will hopefully lead to the development of a targeted therapy for treatment-resistant iGCTs. SECONDARY CATEGORY: Tumor Biology.

Back with a Vengeance After surgery, gliomas (a type of brain tumor) recur in nearly all patients and often in a more aggressive form. Johnson et al. (p. 189 , published online 12 December 2013) used exome sequencing to explore whether recurrent tumors harbor different mutations than the primary tumors and whether the mutational profile in the recurrences is influenced by postsurgical treatment of patients with temozolomide (TMZ), a chemotherapeutic drug known to damage DNA. In more than 40% of cases, at least half of the mutations in the initial glioma were undetected at recurrence. The recurrent tumors in many of the TMZ-treated patients bore the signature of TMZ-induced mutagenesis and appeared to follow an evolutionary path to high-grade glioma distinct from that in untreated patients.

BACKGROUND: Mutations in the H3F3A gene, which encodes histone H3.3, were recently reported in cases of pediatric glioblastoma. H3F3A K27M mutations occur in gliomas that arise at midline locations, including the pons, thalamus, and spine; moreover, this particular mutation is found mainly in tumors in children and adolescents. In this study, we aimed to determine the association between H3F3A mutations and adult thalamic glioma. METHODS: Genomic H3F3A was sequenced from 20 separate thalamic gliomas. Additionally, for 14 of the 20 gliomas, 639 genes—including cancer-related genes and chromatin-modifier genes—were sequenced, and the Infinium HumanMethylation450K BeadChip was used to examine DNA methylation across the genome. RESULTS: Of the 20 tumors, 18 were high-grade thalamic gliomas, and of these 18, 11 were from patients under 50 years of age (median age, 38 years; range, 17–46), and seven were from patients more than 50 years of age. Among the 18 high-grade thalamic gliomas, the H3F3A K27M mutation was present in 10 (91%) of the 11 tumors from patients under 50 years of age, and was absent in all seven tumors from patients over 50 years of age. The H3F3A K27M mutation was not detected in two diffuse astrocytomas. By additional sequencing, recurrent mutations were identified in TP53, ATRX, NF1 and EGFR. In addition, a KDM6A mutation was found in one case of diffuse astrocytoma and a CREBBP mutation was identified in one case of glioblastoma with the H3F3A K27M mutation. Gliomas with H3F3A K27M from pediatric or young-adult patients had similar, characteristic DNA methylation profiles. In contrast, thalamic gliomas with wild-type H3F3A had DNA methylation profiles similar to those of hemispheric glioblastomas. The patients with high-grade thalamic gliomas harboring the H3F3A K27M mutation that occur frequently in young adults had a poor prognosis similar to those with wild-type H3F3A tumors that occur mainly in older adults. CONCLUSIONS: We found that high-grade thalamic gliomas from young adults, like those from children and adolescents, frequently had H3F3A K27M. SECONDARY CATEGORY: Neuropathology & Tumor Biomarkers.

Low-grade glioma, especially astrocytomas often undergo malignant progression, and these transformations are a leading cause of death in patients with low-grade gliomas. However, the mechanisms underlying malignant tumor transformation are still not well understood. Recent evidence indicates that epigenetic deregulation is an important cause of gliomagenesis; therefore, we examined the epigenetic changes during malignant progression of gliomas. We used the Illumina Infinium Human Methylation 450K BeadChip to perform genome-wide DNA methylation analysis of 124 gliomas and four normal brains. These tumors comprised 37 grade IV gliomas, 32 grade III gliomas, and 55 grade II gliomas. This study sample included 26 matched-pairs of initial lower grade gliomas and recurrent tumors and 21 of the 26 recurring tumors recurred as malignant progressions. Analyses of methylation profiles demonstrated that most low-grade gliomas in our sample (84%) had a CpG island methylator phenotype (G-CIMP). Remarkably, approximately 25% of recurrent malignant gliomas that had progressed from low-grade tumors with the G-CIMP status exhibited a characteristic partial demethylation of genomic DNA during malignant progression, but other recurrent gliomas showed no apparent change in DNA methylation pattern. Interestingly, we found that most loci that were demethylated during malignant progression were located outside of CpG islands. The information of histone modifications patterns in normal human astrocytes and embryonal stem cells also showed that the ratio of active marks at the site corresponding to DNA demethylated loci in G-CIMP-demethylated tumors was significantly lower; this finding indicated that most demethylated loci in G-CIMP-demethylated tumors were likely transcriptionally inactive. A small number of the genes that were upregulated and had demethylated CpG islands were associated with cell cycle-related pathway. Here, we demonstrated that partial DNA demethylation occurred during malignant transfomrmation of a subset of lower grade gliomas. Citation Format: Mukasa Akitake, Kuniaki Saito, Koki Aihara, Genta Nagae, Mayu Omata, Ryohei Otani, Shunsaku Takayangi, Shota Tanaka, Yoshitaka Narita, Keisuke Ueki, Ryo Nishikawa, Motoo Nagane, Hiroyuki Aburatani, Nobuhito Saito. DNA methylation profile analysis of gliomas revealed a change in methylation status during malignant progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1072. doi:10.1158/1538-7445.AM2015-1072

Low-grade gliomas frequently recur after surgical resection and may undergo malignant progression to a higher grade with a significantly worse prognosis. Understanding the origin and evolution of recurrences is critical for effectively treating residual disease to delay or prevent recurrence. Here, we extend previous work by sequencing the exomes of over 30 initial low-grade gliomas and their patient-matched recurrences to reconstruct the patterns of clonal evolution. We also sequence multiple spatially distinct samples from both initial low-grade and recurrent high-grade tumors to extensively dissect intratumoral heterogeneity. We identify a broad spectrum of genetic relatedness within tumor pairs, with the unexpected loss of canonical driver mutations upon recurrence. Therefore, resected portions of initial tumors can differ dramatically from tumorigenic portions of adjacent residual disease. The identification of common ancestral clones additionally reveals the order in which key driver mutations are acquired, allowing for a model of low-grade astrocytoma gliomagenesis. We have also previously shown that the treatment of low-grade gliomas with temozolomide induces hypermutation and alters the function of key cancer genes and their cognate pathways, potentially driving malignant progression. We extend that finding with an analysis of the evolution and intratumoral heterogeneity of additional hypermutated glioblastoma recurrences. These evolutionary trajectories have immediate ramifications for the use of mutagenic chemotherapies such as temozolomide, and for personalizing therapy to eliminate residual disease.

Intracranial germ cell tumors (iGCTs) are the second most common central nervous system tumors in patients under 14 in Japan. The majority of germinomas respond well to combined chemo- and radiotherapy, however non-germinoma germ cell tumors (NGGCTs) may show resistance to therapy and have a poor clinical outcome. Despite their clinical significance, the biology of iGCTs is mostly unknown. The aim of this study is to elucidate the molecular pathogenesis of iGCTs through a comprehensive genomic analysis. A total of 198 germ cell tumors (GCTs) including 133 iGCTs (69 pure germinomas, 56 NGGCTs and 8 metastatic tumors) as well as 65 testicular germ cell tumors (tGCTs) (39 seminomas and 26 non-seminoma GCTs) were collected from 13 centers participating in the Intracranial Germ Cell Tumor Consortium in Japan. Matched normal DNA was available for 70 iGCTs and 4 tGCTs. Somatic mutations in all coding exons were investigated by whole exome sequencing (WES) using SureSelectXT Human All Exon v4 and a GAIIx or HiSeq 2000 system in 41 tumors and the matched normal DNAs. Targeted sequencing with a set of custom made PCR primers was performed using either an IonTorrent PGM or Proton System. The results were integrated with the patients' clinical information that was available for 124 iGCT patients. Mutations in selected candidate genes were further evaluated in an independent tumor cohort using the IonTorrent PGM system. On average, 15.4 non-synonymous somatic mutations were observed in each tumor, ranging from 1 to 140 by WES in 41 iGCTs. Based on the WES data, 41 candidate genes were selected according to the frequency and/or significance of the mutations found. All coding exons of these 41 genes spanning over 160kb were PCR-amplified in a further 157 GCTs using the IonTorrent system. The combined WES and IonTorrent screenings showed that KIT was the most frequently mutated gene in both iGCTs (27%) and tGCTs (18%). MTOR was the second most frequently mutated also in both iGCTs (7%) and tGCTs (6%). RAS mutations (KRAS, HRAS, NRAS) were altogether found in 13% of iGCTs and 12% of tGCTs. These mutations were mutually exclusive to each other and also to KIT mutations. Collectively, the genes involved in the MAPK pathway (e.g., KIT, RAS, NF1) and the PI3K/MTOR pathway (e.g., MTOR, PTEN) were mutated in 44% and 13% of all GCTs. These alterations were significantly more common among pure germinomas than NGGCTs. The mutated MTOR protein was shown to have increased kinase activity, which was suppressed by a specific MTOR inhibitor. Our comprehensive mutational genomic analysis of GCTs revealed that alterations of the MAPK and/or PI3K/MTOR pathways play a critical role in the pathogenesis of both iGCTs and tGCTs, although the extent of their involvement depends on the histopathological subtypes. Our findings will hopefully lead to the development of a targeted therapy for treatment-resistant iGCTs. Citation Format: Koichi Ichimura, Shintaro Fukushima, Yasushi Totoki, Yuko Matsushita, Ayaka Otsuka, Arata Tomiyama, Tohru Niwa, Ryuichi Sakai, Toshikazu Ushijima, Taishi Nakamura, Tomonari Suzuki, Kouhei Fukuoka, Takaaki Yanagisawa, Kazuhiko Mishima, Yoichi Nakazato, Fumie Hosoda, Yoshitaka Narita, Soichiro Shibui, Akihiko Yoshida, Hirokazu Takami, Akitake Mukasa, Koki Aihara, Nobuhito Saito, Toshihiro Kumabe, Masayuki Kanamori, Teiji Tominaga, Keiichi Kobayashi, Saki Shimizu, Motoo Nagane, Toshihiko Iuchi, Masahiro Mizoguchi, Koji Yoshimoto, Kaoru Tamura, Taketoshi Maehara, Kazuhiko Sugiyama, Mitsutoshi Nakada, Keiichi Sakai, Yonehiro Kanemura, Masahiro Nonaka, Kiyotaka Yokogami, Hideo Takeshima, Nobutaka Kawahara, Tatsuya Takayama, Masahiro Yao, Hiromi Nakamura, Natsuko Hama, Masao Matsutani, Tatsuhiro Shibata, Ryo Nishikawa. Whole exome and targeted sequencing identified the MAPK and PI3K pathways as the main targets in intracranial and testicular germ cell tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 4264. doi:10.1158/1538-7445.AM2014-4264

Introduction. Mutations in the H3F3A gene, which encodes histone H3.3, were recently reported in cases of pediatric glioblastoma. H3F3A K27M mutations occur in gliomas that arise at midline locations, including the pons, thalamus, and spine; moreover, this particular mutation is found mainly in tumors in children and adolescents. In this study, we aimed to determine the association between H3F3A mutations and adult thalamic glioma. Methods. Genomic H3F3A was sequenced from 20 separate thalamic gliomas. Of the 20 tumors, 18 were high-grade thalamic gliomas, and of these 18, 11 were from patients under 50 years of age (median age, 38 years; range, 17 - 46), and seven were from patients more than 50 years of age. Additionally, for 14 of the 20 gliomas, 639 genes_including cancer-related genes and chromatin-modifier genes_were sequenced, and the Infinium HumanMethylation450K BeadChip was used to examine DNA methylation across the genome. Results. The H3F3A K27M mutation was present in 10 of (91%) of the 11 younger patients, and absent from all seven older patients. Additionally, H3F3A K27M was not detected in the two diffuse astrocytomas. By additional sequencing, recurrent mutations were identified in TP53, ATRX, NF1, and EGFR. In addition, a KDM6A mutation was found in one case of diffuse astrocytoma and a CREBBP mutation was identified in one case of glioblastoma with the H3F3A K27M mutation. Gliomas with H3F3A K27M from pediatric or young-adult patients had similar, characteristic DNA methylation profiles. In contrast, thalamic gliomas with wild-type H3F3A had DNA methylation profiles similar to those of hemispheric glioblastomas. Conclusion. We found that high-grade thalamic gliomas from young adults, like those from children and adolescents, frequently have the H3F3A K27M mutation. Citation Format: Akitake Mukasa, Koki Aihara, Kengo Gotoh, Kuniaki Saito, Genta Nagae, Shingo Tsuji, Kenji Tatuno, Shogo Yamamoto, Shunsaku Takayanagi, Yoshitaka Narita, Soichiro Shibui, Hiroyuki Aburatani, Nobuhito Saito. Frequent H3F3A K27M mutations in thalamic gliomas from young adult patients. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1356. doi:10.1158/1538-7445.AM2014-1356

BACKGROUND: Among number of genetic markers in gliomas, 1p/19q co-deletion in grade 2-3 gliomas is the most established marker in predicting chemosensitivity and surprisingly better prognosis. The mechanism for such distinct clinical features is not well understood. METHODS: We have retrospectively analyzed the treatment result of 1p/19q codeleted gliomas to elucidate the mechanism underlying such clinical features. For recurrent tumors that were resected, genetic and histological examinations were performed to see the changes in the recurrent tumors. RESULTS: Of 31 gliomas with 1p/19q co-deletion, 5 were not given any adjuvant therapy, 18 were treated with chemotherapy alone, and 7 underwent radiation therapy with chemotherapy. With the median follow-up of 48 months, 12 out of the 31 recurred, but the histological grades remained to be 2 or 3, showing slow growth, and responded to additional therapy well. In 9 cases, genetic testing for 1p/19q, 10q loss was peformed in recurrent tumors, and the alterations remained the same without additional 10q loss, the hallmark of grade 4 gliomas (glioblastoma). Copy number alterations of whole genome was also examined in selected cases, that also showed fewer additional genetic changes compared to the previous studies on astrocytic tumors. CONCLUSIONS: Thus, slow growth and relative genetic stability after genotoxic treatment may be the feature of those gliomas leading to the better prognosis compared to the rest. SECONDARY CATEGORY: Clinical Neuro-Oncology.