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• W2803003012 abstract "•The HERBY trial tested the use of bevacizumab in pediatric non-brainstem HGG•Parallel translational biology studies highlighted the diversity of the trial cohort•Elevated levels of CD8+ T cells were seen in PXA-like and hypermutant tumors•MAPK-associated immune signatures predicted response to bevacizumab The HERBY trial was a phase II open-label, randomized, multicenter trial evaluating bevacizumab (BEV) in addition to temozolomide/radiotherapy in patients with newly diagnosed non-brainstem high-grade glioma (HGG) between the ages of 3 and 18 years. We carried out comprehensive molecular analysis integrated with pathology, radiology, and immune profiling. In post-hoc subgroup analysis, hypermutator tumors (mismatch repair deficiency and somatic POLE/POLD1 mutations) and those biologically resembling pleomorphic xanthoastrocytoma ([PXA]-like, driven by BRAF_V600E or NF1 mutation) had significantly more CD8+ tumor-infiltrating lymphocytes, and longer survival with the addition of BEV. Histone H3 subgroups (hemispheric G34R/V and midline K27M) had a worse outcome and were immune cold. Future clinical trials will need to take into account the diversity represented by the term “HGG” in the pediatric population. The HERBY trial was a phase II open-label, randomized, multicenter trial evaluating bevacizumab (BEV) in addition to temozolomide/radiotherapy in patients with newly diagnosed non-brainstem high-grade glioma (HGG) between the ages of 3 and 18 years. We carried out comprehensive molecular analysis integrated with pathology, radiology, and immune profiling. In post-hoc subgroup analysis, hypermutator tumors (mismatch repair deficiency and somatic POLE/POLD1 mutations) and those biologically resembling pleomorphic xanthoastrocytoma ([PXA]-like, driven by BRAF_V600E or NF1 mutation) had significantly more CD8+ tumor-infiltrating lymphocytes, and longer survival with the addition of BEV. Histone H3 subgroups (hemispheric G34R/V and midline K27M) had a worse outcome and were immune cold. Future clinical trials will need to take into account the diversity represented by the term “HGG” in the pediatric population. We validate in the prospective clinical trial setting the biological and clinical diversity of pediatric high-grade glioma previously described in large retrospective series, underpinned by detailed pathological and radiological analysis. Although adding bevacizumab (BEV) to standard temozolomide/radiotherapy did not improve survival across the whole cohort, we identify disease subgroups with MAPK activation to harbor an enhanced CD8+ T cell immune response, which may derive benefit from the addition of BEV. If confirmed in another study, this would represent a useful predictive biomarker for this regimen in these tumors, and points the way for therapeutic strategies for subgroups of children with high-grade glioma. High-grade gliomas (HGGs) in children, like their adult counterparts, continue to have a bleak prognosis, with a median overall survival (OS) of 9–15 months (Cohen et al., 2011Cohen K.J. Pollack I.F. Zhou T. Buxton A. Holmes E.J. Burger P.C. Brat D.J. Rosenblum M.K. Hamilton R.L. Lavey R.S. Heideman R.L. Temozolomide in the treatment of high-grade gliomas in children: a report from the Children's Oncology Group.Neuro Oncol. 2011; 13: 317-323Crossref PubMed Scopus (269) Google Scholar, Jones et al., 2016Jones C. Karajannis M.A. Jones D.T. Kieran M.W. Monje M. Baker S.J. Becher O.J. Cho Y.J. Gupta N. Hawkins C. et al.Pediatric high-grade glioma: biologically and clinically in need of new thinking.Neuro Oncol. 2016; 19: 153-161Google Scholar, Ostrom et al., 2015Ostrom Q.T. Gittleman H. Fulop J. Liu M. Blanda R. Kromer C. Wolinsky Y. Kruchko C. Barnholtz-Sloan J.S. CBTRUS statistical report: primary brain and central nervous system tumors diagnosed in the United States in 2008–2012.Neuro Oncol. 2015; 17: iv1-iv62Crossref PubMed Scopus (1514) Google Scholar). Recent integrated molecular-profiling initiatives have shown that pediatric HGGs (pHGGs) are biologically distinct from their adult counterparts, with subgroups of the disease marked by recurrent mutations in genes encoding histone H3 variants having different age of incidence, anatomical location, clinical outcome, and a range of biological parameters (Jones and Baker, 2014Jones C. Baker S.J. Unique genetic and epigenetic mechanisms driving paediatric diffuse high-grade glioma.Nat. Rev. Cancer. 2014; 14.: 651-661Crossref Scopus (190) Google Scholar, Mackay et al., 2017Mackay A. Burford A. Carvalho D. Izquierdo E. Fazal-Salom J. Taylor K.R. Bjerke L. Clarke M. Vinci M. Nandhabalan M. et al.Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma.Cancer Cell. 2017; 32: 520-537 e525Abstract Full Text Full Text PDF PubMed Scopus (487) Google Scholar, Paugh et al., 2010Paugh B.S. Qu C. Jones C. Liu Z. Adamowicz-Brice M. Zhang J. Bax D.A. Coyle B. Barrow J. Hargrave D. et al.Integrated molecular genetic profiling of pediatric high-grade gliomas reveals key differences with the adult disease.J. Clin. Oncol. 2010; 28: 3061-3068Crossref PubMed Scopus (466) Google Scholar, Schwartzentruber et al., 2012Schwartzentruber J. Korshunov A. Liu X.Y. Jones D.T. Pfaff E. Jacob K. Sturm D. Fontebasso A.M. Quang D.A. Tonjes M. et al.Driver mutations in histone H3.3 and chromatin remodelling genes in paediatric glioblastoma.Nature. 2012; 482: 226-231Crossref PubMed Scopus (1707) Google Scholar, Sturm et al., 2012Sturm D. Witt H. Hovestadt V. Khuong-Quang D.A. Jones D.T. Konermann C. Pfaff E. Tonjes M. Sill M. Bender S. et al.Hotspot mutations in H3F3A and IDH1 define distinct epigenetic and biological subgroups of glioblastoma.Cancer Cell. 2012; 22: 425-437Abstract Full Text Full Text PDF PubMed Scopus (1283) Google Scholar, Wu et al., 2012Wu G. Broniscer A. McEachron T.A. Lu C. Paugh B.S. Becksfort J. Qu C. Ding L. Huether R. Parker M. et al.Somatic histone H3 alterations in pediatric diffuse intrinsic pontine gliomas and non-brainstem glioblastomas.Nat. Genet. 2012; 44: 251-253Crossref PubMed Scopus (1094) Google Scholar, Wu et al., 2014Wu G. Diaz A.K. Paugh B.S. Rankin S.L. Ju B. Li Y. Zhu X. Qu C. Chen X. Zhang J. et al.The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma.Nat. Genet. 2014; 46: 444-450Crossref PubMed Scopus (687) Google Scholar). Histone wild-type (WT) tumors have widely differing mutational burdens, ranging from infant cases (<3 years) driven by single gene fusion events through to patients with biallelic mismatch repair deficiency harboring some of the highest mutational rates in human cancer (Jones and Baker, 2014Jones C. Baker S.J. Unique genetic and epigenetic mechanisms driving paediatric diffuse high-grade glioma.Nat. Rev. Cancer. 2014; 14.: 651-661Crossref Scopus (190) Google Scholar, Mackay et al., 2017Mackay A. Burford A. Carvalho D. Izquierdo E. Fazal-Salom J. Taylor K.R. Bjerke L. Clarke M. Vinci M. Nandhabalan M. et al.Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma.Cancer Cell. 2017; 32: 520-537 e525Abstract Full Text Full Text PDF PubMed Scopus (487) Google Scholar, Shlien et al., 2015Shlien A. Campbell B.B. de Borja R. Alexandrov L.B. Merico D. Wedge D. Van Loo P. Tarpey P.S. Coupland P. Behjati S. et al.Combined hereditary and somatic mutations of replication error repair genes result in rapid onset of ultra-hypermutated cancers.Nat. Genet. 2015; 47: 257-262Crossref PubMed Scopus (243) Google Scholar, Wu et al., 2014Wu G. Diaz A.K. Paugh B.S. Rankin S.L. Ju B. Li Y. Zhu X. Qu C. Chen X. Zhang J. et al.The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma.Nat. Genet. 2014; 46: 444-450Crossref PubMed Scopus (687) Google Scholar). The rapid advances in our understanding of pHGGs have come predominantly from the accumulation of numerous disparate retrospective collections, a reflection of the rarity of the disease. Clinical trial cohorts with ancillary biomarker analyses have been relatively limited in their scope, and historically have focused on single-marker analyses. These include the Children's Oncology Group ACNS0126 (radiotherapy [RT]/temozolomide [TMZ]) (Cohen et al., 2011Cohen K.J. Pollack I.F. Zhou T. Buxton A. Holmes E.J. Burger P.C. Brat D.J. Rosenblum M.K. Hamilton R.L. Lavey R.S. Heideman R.L. Temozolomide in the treatment of high-grade gliomas in children: a report from the Children's Oncology Group.Neuro Oncol. 2011; 13: 317-323Crossref PubMed Scopus (269) Google Scholar) and ACNS0423 (RT/TMZ followed by TMZ and lomustine) (Jakacki et al., 2016Jakacki R.I. Cohen K.J. Buxton A. Krailo M.D. Burger P.C. Rosenblum M.K. Brat D.J. Hamilton R.L. Eckel S.P. Zhou T. et al.Phase 2 study of concurrent radiotherapy and temozolomide followed by temozolomide and lomustine in the treatment of children with high-grade glioma: a report of the Children's Oncology Group ACNS0423 study.Neuro Oncol. 2016; 18: 1442-1450Crossref PubMed Scopus (83) Google Scholar) studies, which report on the frequency and clinical correlations of O6-methylguanine-DNA methyltransferase (MGMT) expression (ACNS0126) (Jakacki et al., 2016Jakacki R.I. Cohen K.J. Buxton A. Krailo M.D. Burger P.C. Rosenblum M.K. Brat D.J. Hamilton R.L. Eckel S.P. Zhou T. et al.Phase 2 study of concurrent radiotherapy and temozolomide followed by temozolomide and lomustine in the treatment of children with high-grade glioma: a report of the Children's Oncology Group ACNS0423 study.Neuro Oncol. 2016; 18: 1442-1450Crossref PubMed Scopus (83) Google Scholar, Pollack et al., 2006Pollack I.F. Hamilton R.L. Sobol R.W. Burnham J. Yates A.J. Holmes E.J. Zhou T. Finlay J.L. O6-methylguanine-DNA methyltransferase expression strongly correlates with outcome in childhood malignant gliomas: results from the CCG-945 Cohort.J. Clin. Oncol. 2006; 24: 3431-3437Crossref PubMed Scopus (156) Google Scholar), IDH1 mutation (ACNS0423) (Pollack et al., 2011Pollack I.F. Hamilton R.L. Sobol R.W. Nikiforova M.N. Lyons-Weiler M.A. LaFramboise W.A. Burger P.C. Brat D.J. Rosenblum M.K. Holmes E.J. et al.IDH1 mutations are common in malignant gliomas arising in adolescents: a report from the Children's Oncology Group.Childs Nerv. Syst. 2011; 27: 87-94Crossref PubMed Scopus (128) Google Scholar), as well as phosphorylated Akt expression (Pollack et al., 2010aPollack I.F. Hamilton R.L. Burger P.C. Brat D.J. Rosenblum M.K. Murdoch G.H. Nikiforova M.N. Holmes E.J. Zhou T. Cohen K.J. et al.Akt activation is a common event in pediatric malignant gliomas and a potential adverse prognostic marker: a report from the Children's Oncology Group.J. Neurooncol. 2010; 99: 155-163Crossref PubMed Scopus (36) Google Scholar) and microsatellite instability (both) (Pollack et al., 2010bPollack I.F. Hamilton R.L. Sobol R.W. Nikiforova M.N. Nikiforov Y.E. Lyons-Weiler M.A. LaFramboise W.A. Burger P.C. Brat D.J. Rosenblum M.K. et al.Mismatch repair deficiency is an uncommon mechanism of alkylator resistance in pediatric malignant gliomas: a report from the Children's Oncology Group.Pediatr. Blood Cancer. 2010; 55: 1066-1071Crossref PubMed Scopus (22) Google Scholar). The CCG-945 study (“8 in 1” chemotherapy) (Finlay et al., 1995Finlay J.L. Boyett J.M. Yates A.J. Wisoff J.H. Milstein J.M. Geyer J.R. Bertolone S.J. McGuire P. Cherlow J.M. Tefft M. et al.Randomized phase III trial in childhood high-grade astrocytoma comparing vincristine, lomustine, and prednisone with the eight-drugs-in-1-day regimen. Children’s Cancer Group.J. Clin. Oncol. 1995; 13: 112-123Crossref PubMed Google Scholar) reported on the prognostic significance of p53 expression/mutation (Pollack et al., 2002Pollack I.F. Finkelstein S.D. Woods J. Burnham J. Holmes E.J. Hamilton R.L. Yates A.J. Boyett J.M. Finlay J.L. Sposto R. Children's Cancer GroupExpression of p53 and prognosis in children with malignant gliomas.N. Engl. J. Med. 2002; 346: 420-427Crossref PubMed Scopus (236) Google Scholar), in addition to the presence/absence of 1p19q co-deletion (Pollack et al., 2003bPollack I.F. Finkelstein S.D. Burnham J. Hamilton R.L. Yates A.J. Holmes E.J. Boyett J.M. Finlay J.L. Association between chromosome 1p and 19q loss and outcome in pediatric malignant gliomas: results from the CCG-945 cohort.Pediatr. Neurosurg. 2003; 39: 114-121Crossref PubMed Scopus (52) Google Scholar). This last study (Pollack et al., 2003bPollack I.F. Finkelstein S.D. Burnham J. Hamilton R.L. Yates A.J. Holmes E.J. Boyett J.M. Finlay J.L. Association between chromosome 1p and 19q loss and outcome in pediatric malignant gliomas: results from the CCG-945 cohort.Pediatr. Neurosurg. 2003; 39: 114-121Crossref PubMed Scopus (52) Google Scholar) also highlighted the critical importance of pathological review in the diagnosis of pHGG, and subsequent interpretation of clinical trial results (Gilles et al., 2008Gilles F.H. Tavare C.J. Becker L.E. Burger P.C. Yates A.J. Pollack I.F. Finlay J.L. Pathologist interobserver variability of histologic features in childhood brain tumors: results from the CCG-945 study.Pediatr. Dev. Pathol. 2008; 11: 108-117Crossref PubMed Scopus (41) Google Scholar, Pollack et al., 2003aPollack I.F. Boyett J.M. Yates A.J. Burger P.C. Gilles F.H. Davis R.L. Finlay J.L. Children's Cancer GroupThe influence of central review on outcome associations in childhood malignant gliomas: results from the CCG-945 experience.Neuro Oncol. 2003; 5: 197-207Crossref PubMed Scopus (95) Google Scholar), particularly in midline locations (Eisenstat et al., 2015Eisenstat D.D. Pollack I.F. Demers A. Sapp M.V. Lambert P. Weisfeld-Adams J.D. Burger P.C. Gilles F. Davis R.L. Packer R. et al.Impact of tumor location and pathological discordance on survival of children with midline high-grade gliomas treated on Children's Cancer Group high-grade glioma study CCG-945.J. Neurooncol. 2015; 121: 573-581Crossref PubMed Scopus (24) Google Scholar). It has subsequently become clear that numerous histological subtypes of HGG can harbor distinct genetic drivers and have considerably better clinical outcomes, such as BRAF_V600E mutations in epithelioid glioblastoma (GBM), anaplastic ganglioglioma, and anaplastic pleomorphic xanthoastrocytoma (PXA) (Hatae et al., 2016Hatae R. Hata N. Suzuki S.O. Yoshimoto K. Kuga D. Murata H. Akagi Y. Sangatsuda Y. Iwaki T. Mizoguchi M. Iihara K. A comprehensive analysis identifies BRAF hotspot mutations associated with gliomas with peculiar epithelial morphology.Neuropathology. 2016; 37: 191-199Crossref PubMed Scopus (31) Google Scholar); in the latter two categories, this mutation is also found in lower-grade entities lacking obvious anaplasia. Additional histone WT cases of otherwise uncontroversial HGGs have been found to be biologically and clinically more similar to several types of low-grade glioma (LGG) and PXA (Korshunov et al., 2015Korshunov A. Ryzhova M. Hovestadt V. Bender S. Sturm D. Capper D. Meyer J. Schrimpf D. Kool M. Northcott P.A. et al.Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers.Acta Neuropathol. 2015; 129: 669-678Crossref PubMed Scopus (223) Google Scholar), highlighting the importance of an integrated diagnosis combining molecular and histological features. The HERBY trial (study BO25041; clinicaltrials.gov NCT01390948) was a phase II, open-label, randomized, multicenter, comparator study of the addition of the anti-angiogenic agent bevacizumab (BEV) to RT and TMZ in patients between the ages of 3 and 18 years with newly diagnosed non-brainstem HGG (Grill et al., 2018Grill J. Massimino M. Bouffet E. Azizi A.A. McCowage G. Canete A. Saran F. Le Deley M.C. Varlet P. Morgan P.S. et al.Phase II, open-label, randomized, multicenter trial (HERBY) of bevacizumab in pediatric patients with newly diagnosed high-grade glioma.J. Clin. Oncol. 2018; 36: 951-958Crossref PubMed Scopus (71) Google Scholar). Central confirmation of HGG diagnosis was mandatory before randomization, followed by consensus review by five independent expert neuropathologists. Real-time panel radiological assessment was also incorporated. An exploratory endpoint of the study was to establish a biospecimen repository for correlative molecular profiling. In addition to its role in tumor angiogenesis, vascular endothelial growth factor (VEGF) restricts immune cell activity, and BEV has been demonstrated to facilitate recruitment of T cells to infiltrate tumors (Wallin et al., 2016Wallin J.J. Bendell J.C. Funke R. Sznol M. Korski K. Jones S. Hernandez G. Mier J. He X. Hodi F.S. et al.Atezolizumab in combination with bevacizumab enhances antigen-specific T-cell migration in metastatic renal cell carcinoma.Nat. Commun. 2016; 7: 12624Crossref PubMed Scopus (442) Google Scholar), as well as increase the ratio of CD8+CD3+ T cells in adult GBM specimens (Scholz et al., 2016Scholz A. Harter P.N. Cremer S. Yalcin B.H. Gurnik S. Yamaji M. Di Tacchio M. Sommer K. Baumgarten P. Bahr O. et al.Endothelial cell-derived angiopoietin-2 is a therapeutic target in treatment-naive and bevacizumab-resistant glioblastoma.EMBO Mol. Med. 2016; 8: 39-57Crossref PubMed Scopus (106) Google Scholar). We therefore also sought to explore the immune profile of cases within the HERBY cohort. The total HERBY cohort comprised 121 randomized patients at diagnosis (3–18 years) plus 3 infant cases (<3 years) at relapse. Of these, 113 patients consented to the translational research program (Table S1). Tumor tissue was collected from either resection (n = 93) or biopsy (n = 20), although 24 cases failed to provide sufficient quantity or quality of sample for molecular analysis. For the remaining 89 cases, material was available in the form of either fresh-frozen material (n = 36), formalin-fixed paraffin-embedded pathology specimens (n = 79), or both (n = 26). These were subjected to Sanger sequencing for H3F3A (n = 89), exome sequencing (n = 86), Illumina 450k methylation BeadChip profiling (n = 74), CD8 immunohistochemistry (n = 70), methylation-specific PCR for MGMT promoter methylation (n = 36), a capture-based sequencing panel for common fusion gene detection (n = 68), and RNA sequencing (RNA-seq) (n = 20) (Figure 1A). The translational research cohort, representing a subset (91%) of the randomized trial, displayed equivalent clinical characteristics to the full dataset (Grill et al., 2018Grill J. Massimino M. Bouffet E. Azizi A.A. McCowage G. Canete A. Saran F. Le Deley M.C. Varlet P. Morgan P.S. et al.Phase II, open-label, randomized, multicenter trial (HERBY) of bevacizumab in pediatric patients with newly diagnosed high-grade glioma.J. Clin. Oncol. 2018; 36: 951-958Crossref PubMed Scopus (71) Google Scholar), with no difference in the primary endpoint of 1-year event-free survival (EFS) with the addition of BEV to the standard therapy of TMZ and RT (median 12.0 versus 8.3 months, p = 0.372, log rank test), with an additional small (n = 3) infant cohort treated with BEV at relapse (Figure 1B). The cohort contained 66 (58%) hemispheric and 47 (42%) non-brainstem midline tumors, with the latter location conferring a significantly shorter EFS (median 8.0 versus 14.7 months, p = 0.00201, log rank test) (Figure 1C). Histone mutation status was a significant predictor of worse prognosis compared with WT (median EFS = 11.3 months) for H3F3A_K27M (24/89, 27%; median EFS = 7.9 months; p = 0.0063, log rank test) and also trended toward shorter survival for H3F3A_G34R/V (7/89, 8%; median EFS = 8.3 months; p = 0.096, log rank test) (Figure 1D). We used the Heidelberg brain tumor classifier on Illumina 450k methylation array data to assign a molecular subgroup to each of 74 samples for which such data were available (Table S2). After excluding low-scoring assignments (<0.2), we used a simplified system to classify tumors as either H3K27M (n = 18), H3G34R/V (n = 6), or IDH1 (n = 4) (integrating gene mutation data in low-scoring cases); as resembling PXA-like (n = 9) or other LGG-like (n = 3); and aggregating the remaining tumors (HGG-WT, n = 34) (Figure 2A). IDH1 tumors represented the oldest patients (median = 17.2 years, others = 11.2, p = 0.0107, t test), with LGG-like representing the youngest category (median = 5.7 years, p = 0.0098, t test) (Figure 2B). These two subgroups each had significantly better outcome in terms of EFS (p = 0.0281 and p = 0.0386, log rank test), although not OS (p = 0.0935 and p = 0.129, log rank test) (Figure 2C), when compared individually to the remaining tumors. The PXA-like showed a trend toward longer OS (p = 0.0867, log rank test) compared with the rest. When IDH1, PXA-like, and LGG-like tumors were excluded from the analysis, the significant differences between histone mutant and HGG-WT groups were absent (H3K27M, p = 0.257 EFS and p = 0.0746 OS; H3G34R/V, p = 0.552 EFS and p = 0.116 OS, log rank test). Twelve out of 78 (15%) samples harbored a methylated MGMT promoter, although this was largely restricted to the H3G34R/V (n = 3, p = 0.0249, Fishers exact test) and IDH1 (n = 3, p = 0.0062, Fisher’s exact test) subgroups (Figure S1A), and was not significantly associated with survival (Figure S1B) in these uniformly TMZ-treated patients. We used a 450k methylation array and exome-sequencing coverage to derive DNA copy-number profiles for 86 pHGG (Figure S2A), including focal amplifications/deletions, as well as whole-arm chromosomal gains/losses (Table S3). Taken with the somatic single-nucleotide variants (SNVs) and small insertion/deletions from whole-exome sequencing (Table S3), and candidate gene fusion events from capture-based panel sequencing (n = 68) and RNA-seq (n = 20) (Table S3), we derived an integrated map of genetic alterations across the translational research cohort (Figure 3A). The most common alteration was TP53 mutation (39/82, 48%), followed by ATRX deletion/mutation (25/82, 30%), PDGFRA amplification/mutation (17/82, 21%), and CDKN2A/B deletion (15/82, 18%). Additional recurrent alterations in receptor tyrosine kinases (EGFR, MET, ERBB3, IGF1R, and NTRK2), phosphatidylinositol 3-kinase (PI3K)/mammalian target of rapamycin (PTEN, PIK3CA, TSC2, and PIK3R1), and MAP-kinase (NF1, BRAF, PTPN11, and PTPN12) pathways were common, as were amplifications/mutations in various genes associated with cell-cycle regulation (RB1, CDK4, MDM2, and CCND2). Taking a minimum variant allele frequency of 5% as a threshold, the median number of somatic mutations per sample was 15 (range = 0–337) (Figure 3B), with the exception of four cases for whom there were more than 100-fold more, and were excluded from gene-level counts. Two cases were highlighted from the methylation subgrouping as potentially representing non-HGG entities. One case classifying as CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2, methylation classifier score = 0.617), was found to have no evidence of FOXR2 alterations. A further case, a compact and necrotic tumor with perivascular radiating arrangements (Figure S2B), displayed a methylation classifier score strongly indicative of a high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1, methylation classifier score = 0.713) (Figure S2C). We identified a candidate alteration in this case fusing exon 1 of MN1 (22q12.1) to exon 3 of CARD6 (5p13.1) (Figure S2D), and thus appears most likely to fall into this categorization. Three cases classified more closely to either pilocytic astrocytoma (n = 2) or desmoplastic infantile ganglioglioma (DIG) (n = 1) by 450k methylation profiling. The first two harbored mitogen-activated protein kinase (MAPK) dysregulation in the form of either BRAF_V600E or intragenic FGFR1 duplication (Figure S2E). Histologically, after Pathology Committee re-review, no piloid features were seen, and anaplastic features were evident (Figure S2F). The DIG-like case was found in the infant cohort (2.7 years). None of these three patients died during the course of follow-up, and, although numbers are small, were all found in the right frontal and temporo-parietal lobes with central predominance (Figure S2G). There were four cases with IDH1 hotspot mutations (Figure S3A). Three were classified as WHO-grade III anaplastic astrocytoma (AA), IDH1_R132-positive by immunohistochemistry, with concurrent TP53 and ATRX mutations. The remaining case was originally classified as a mixed oligo-astrocytoma, which, by virtue of the presence of IDH1_R132 and TERT promoter mutation (C228T), as well as copy-number loss of chromosomes 1p and 19q, would be described as an oligodendroglioma according to WHO 2016 (Figure S3B). Across the whole cohort, IDH1 mutation conferred a significantly longer EFS (p = 0.0398, log rank test), although not OS (p = 0.110, log rank test) (Figure S3C), and were restricted to the frontal lobes (Figure S3D). After excluding IDH1 mutant cases, the remaining H3F3A and BRAF WT cases (n = 38) represented a heterogeneous mix of genomic profiles, with recurrent deletions/mutations in the common pHGG tumor suppressor genes TP53 (n = 11), ATRX (n = 5), CDKN2A/B (n = 7), NF1 (n = 8), RB1 (n = 7), and PTEN (n = 5), but also with an enrichment of gene amplifications in PDGFRA (n = 5, with KIT and KDR, n = 4), CDK4 (n = 7, with MDM2, n = 4), EGFR (n = 4), MET (n = 2), CCND2 (n = 3), and MYCN (n = 3) (Figure S3E). The most common methylation subclass in these cases was designated GBM_RTK_MYCN (n = 6); however, it included only one of those with MYCN amplification, and with no other common amplifications or mutations. Seven cases harbored none of the recurrently altered genes previously described in pHGG, and clearly represent a subgroup that warrants further investigation. Together, these cases had bilateral hemispheric distribution with predominant deep right cerebral localization (Figure S3F). Histone mutations have been shown to be present in approximately half of all pHGGs (Mackay et al., 2017Mackay A. Burford A. Carvalho D. Izquierdo E. Fazal-Salom J. Taylor K.R. Bjerke L. Clarke M. Vinci M. Nandhabalan M. et al.Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma.Cancer Cell. 2017; 32: 520-537 e525Abstract Full Text Full Text PDF PubMed Scopus (487) Google Scholar), with a clear negative impact on survival for K27M (Karremann et al., 2018Karremann M. Gielen G.H. Hoffmann M. Wiese M. Colditz N. Warmuth-Metz M. Bison B. Claviez A. van Vuurden D.G. von Bueren A.O. et al.Diffuse high-grade gliomas with H3 K27M mutations carry a dismal prognosis independent of tumor location.Neuro Oncol. 2018; 20: 123-131Crossref PubMed Scopus (132) Google Scholar, Khuong-Quang et al., 2012Khuong-Quang D.A. Buczkowicz P. Rakopoulos P. Liu X.Y. Fontebasso A.M. Bouffet E. Bartels U. Albrecht S. Schwartzentruber J. Letourneau L. et al.K27M mutation in histone H3.3 defines clinically and biologically distinct subgroups of pediatric diffuse intrinsic pontine gliomas.Acta Neuropathol. 2012; 124: 439-447Crossref PubMed Scopus (636) Google Scholar, Mackay et al., 2017Mackay A. Burford A. Carvalho D. Izquierdo E. Fazal-Salom J. Taylor K.R. Bjerke L. Clarke M. Vinci M. Nandhabalan M. et al.Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma.Cancer Cell. 2017; 32: 520-537 e525Abstract Full Text Full Text PDF PubMed Scopus (487) Google Scholar), although the situation is less clear for G34R/V mutations (Bjerke et al., 2013Bjerke L. Mackay A. Nandhabalan M. Burford A. Jury A. Popov S. Bax D.A. Carvalho D. Taylor K.R. Vinci M. et al.Histone H3.3. mutations drive pediatric glioblastoma through upregulation of MYCN.Cancer Discov. 2013; 3: 512-519Crossref PubMed Scopus (223) Google Scholar, Korshunov et al., 2015Korshunov A. Ryzhova M. Hovestadt V. Bender S. Sturm D. Capper D. Meyer J. Schrimpf D. Kool M. Northcott P.A. et al.Integrated analysis of pediatric glioblastoma reveals a subset of biologically favorable tumors with associated molecular prognostic markers.Acta Neuropathol. 2015; 129: 669-678Crossref PubMed Scopus (223) Google Scholar, Mackay et al., 2017Mackay A. Burford A. Carvalho D. Izquierdo E. Fazal-Salom J. Taylor K.R. Bjerke L. Clarke M. Vinci M. Nandhabalan M. et al.Integrated molecular meta-analysis of 1,000 pediatric high-grade and diffuse intrinsic pontine glioma.Cancer Cell. 2017; 32: 520-537 e525Abstract Full Text Full Text PDF PubMed Scopus (487) Google Scholar). H3F3A_G34R/V mutant tumors had a tendency to being diffusely infiltrative with predominant deep left temporo-parietal involvement (Figure 4A). There were seven cases with H3F3A_G34 substitutions (six G34R and one G34V), with six out of seven (86%) cases additionally harboring TP53 and/or ATRX mutations (five out of seven, 71% both), while five out of seven (71%) also contained PDGFRA amplification and/or mutation (Figure 4B). There were no other recurrent mutations, although isolated instances of mutations in PI3K signaling (PIK3CA and PTEN) and DNA repair (ERCC1) were observed (Table S3). Histologically, there were four GBM, two AA with multinucleated cells, and one HGG, not otherwise specified (Figure 4C). Tumors were Olig2 negative (7/7) with strong nuclear accumulation of p53 (6/7). Across all tumors within this hemispheric subgroup, patients harboring these mutations trended toward a shorter EFS (median = 8.3 months; p = 0.0572, log rank test) and had a significantly shorter OS (median = 12.0 months; p = 0.00765, log rank test) (Figure 4D), although this association was lost when IDH1, PXA-like, and LGG-like tumors were excluded (p = 0.440 EFS and p = 0.139 OS, log rank test) (Figure S4A). By contrast, K27M substitutions were restricted to midline regions (n = 24). Two patients had distinct, separate lesions in the thalamus and hypothalamus, while the remaining had central thalamic, midbrain, or cerebellar local" @default.
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• W2803003012 title "Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial" @default.
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• W2803003012 doi "https://doi.org/10.1016/j.ccell.2018.04.004" @default.
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