Glioblastoma, IDH- and H3-wildtype in young adults: a rare condition with a distinct clinico-radio-histo-molecular and epigenetic landscape

Glioblastoma, IDH- and H3-wildtype in young adults: a rare condition with a distinct clinico-radio-histo-molecular and epigenetic landscape | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Case Report Glioblastoma, IDH- and H3-wildtype in young adults: a rare condition with a distinct clinico-radio-histo-molecular and epigenetic landscape Alexandre ROUX, Arnault TAUZIEDE-ESPARIAT, Giorgia Antonia SIMBOLI, and 19 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7473307/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 16 Oct, 2025 Read the published version in Journal of Neuro-Oncology → Version 1 posted 20 You are reading this latest preprint version Abstract Purpose. Glioblastomas, IDH- and H3-wildtype in young adults is a rare and poorly known entity. We compared newly diagnosed glioblastomas, IDH- and H3-wildtype in young adults (18–39 years) to those in adult patients (> 39 years). Methods. We performed an observational, retrospective, single-centre cohort study at a tertiary neurosurgical oncology centre between January 2006 and December 2022. Results. We included 1.139 adult patients with a newly diagnosed glioblastoma, IDH- and H3-wildtype. Young adults: 1) represent a small proportion of patients with glioblastoma, IDH- and H3-wildtype (n = 33, 2.9%); 2) have a high rate of unclassified cases according to WHO criteria and epigenetics (n = 10, 30.3%); 3) have a longer progression-free survival (p = 0.003) and overall survival (p = 0.001) and; 4) do not have higher surgically-related adverse event rates (p = 0.198). Concerning young adults, surgical resection was associated with improved progression-free and overall survival (p < 0.001 and p < 0.001, respectively). The DNA-methylation class significantly impacts the overall survival (p = 0.028), however, the MGMT methylation status is not significantly associated with either progression-free or overall survival (p = 0.320 and p = 0.639, respectively). Conclusion. Glioblastomas, IDH- and H3-wildtype is a rare histo-molecular subtype in young adults with a better prognosis than older adults. In young adults, DNA-methylation subtypes are different from their adult counterpart and had a significant impact on survival unlike MGMT status. Given the rarity of glioblastoma IDH- and H3-wildtype in young adults, a dedicated management in specialized neurosurgical oncology centres is preferred. Further histo-molecular and epigenetic analyses are required to understand the differences in prognosis compared to adult patients. Glioblastoma IDH-wildtype Neurosurgery Neuro-oncology Young adult Epigenetic Figures Figure 1 Figure 2 Figure 3 Introduction Glioblastoma, isocitrate dehydrogenase ( IDH ) -wildtype (World Health Organization (WHO) grade 4) is the most common primary brain tumour in adults and among the most aggressive of all tumours[ 1 ]. In newly diagnosed glioblastomas, IDH- and H3–wildtype, survival is improved by surgical resection[ 2 ] (with or without Carmustine wafer implantation[ 3 , 4 ]), in association with standard chemoradiotherapy[ 5 ] and, when applicable, tumor-treating fields[ 6 ]. Adolescents and young adults comprise a group aged between 15–39 years according to the definition of the LIVESTRONG Young Adult Alliance and of the NCI Adolescent and Young Adult Oncology Progress Review Group[ 7 ]. In young adults (i.e. 18–39 years), primary brain tumours represent the most common solid tumours and the second most frequent malignancies[ 8 , 9 ]. Glioblastomas, IDH - and H3-wildtype, carry the highest mortality rate among young adult patients[ 10 – 12 ]. Due to their rarity and apparent similar features to adult forms, pediatric and young adult glioblastomas, IDH– and H3–wildtype, are currently classified, graded, and managed according to the same criteria as in older adults. This study population lies at the intersection between the pediatric population, which presents specific histo-molecular and epigenetic subtypes (such as H3 K27-altered, H3 G34-mutant, and pediatric type-HGG), and the adult population. Moreover, young adult patients with a brain tumour have particular requirements related to their age and conditions[ 13 ]. Recent studies mainly focused on epidemiological[ 11 , 12 ], psychological[ 14 – 17 ], neuropsychological[ 18 – 20 ], health-related quality-of-life[ 21 ], family life[ 22 – 25 ], transitional care[ 26 ], or on histo-molecular and epigenetic profiling [ 27 – 32 ]. To date, no study has assessed the clinico-radio-histo-molecular and epigenetic features of glioblastoma, IDH- and H3-wildtype and the management strategy in young adult patients. In the present study, we compared the prognosis and the impact of oncological treatment on newly diagnosed glioblastomas, IDH- and H3-wildtype between young adults (i.e. 18–39 years) and older adult patients (i.e. >39 years) and we detailed the clinico-radio-histo-molecular and epigenetic features in young adults. Methods Study design An observational, retrospective, single-centre cohort study was conducted at an adult tertiary neurosurgical oncology centre between January 2006 and December 2023. The manuscript was written according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist[ 33 ]. Participants Inclusion criteria were: 1) a confirmed histo-molecular diagnosis of glioblastoma, IDH-wildtype and H3-wildtype according to the 2021 WHO classification[ 1 ]; 2) available pre- and early postoperative MRI scans ; and 3) available postoperative follow-up, including adjuvant oncological treatments, morbidity, and survival. Data collection Data were systematically gathered from the medical records using a protocol designed for the study. Clinical characteristics at the time of histo-molecular diagnosis were: sex, age, Karnofsky Performance Status (KPS) score, presenting symptom (i.e. the symptom leading to initial diagnosis), signs of raised intracranial pressure (i.e. headache, nausea/vomiting, coma, diplopia, visual blur, papilledema) at diagnosis, neurological deficit (i.e. motor deficit, sensitive deficit, language disorders, visual disturbances, and frontal syndrome) at diagnosis, epileptic seizures (i.e. partial or generalized with or without confirmation by an electroencephalogram) at diagnosis, and revised Radiation Therapy Oncology Group - Recursive Partitioning Analysis (RTOG-RPA) classification system for glioblastoma [ 34 ]. Imaging characteristics on preoperative MRI were: main tumour location (i.e. where the tumour volume was predominantly located for multiple lobar involvement), mass effect, multifocal tumour, contrast enhancement, cortical or ventricle involvement of the contrast enhancement part, tumour volume (obtained by lesion segmentation on preoperative 3D T1-weighted with gadolinium or FLAIR sequences based on a methodology previously described)[ 35 ]. Treatment-related characteristics were: extent of surgical resection, adverse postoperative events within the first postoperative month (hematoma requiring surgical evacuation, new neurological deficit, postoperative seizures, wound-healing defect, cerebrospinal fluid leak, hydrocephalus, infection, and systemic thromboembolic complications), completion of the standard chemoradiotherapy protocol, and KPS score at the end of first-line oncological treatment. We established the extent of resection by quantifying the volume of residual tumour on early postoperative (within 48 hours) 3D T1-weighted sequence (without and with gadolinium) or FLAIR sequence (for non-contrast enhancing tumours) as per our methodology previously described[ 35 ]. Subtotal resection was defined by removal of ≥ 90–99% of the tumour and total resection defined by removal of 100% of the tumour[ 36 , 37 ]. Histo-molecular and epigenetic analyses were described in the supplementary Methods. Statistical analyses Continuous variables were described as mean ± standard deviation. Categorical variables were described as percentages. Univariable analyses were carried out, computing unadjusted odds ratios, and using the chi-square or Fisher’s exact test for comparing categorical variables, and the unpaired t-test or Mann–Whitney U test for continuous variables, as appropriate. Unadjusted survival curves for Overall Survival (OS) and Progression-Free Survival (PFS) were plotted using the Kaplan-Meier method, with group comparisons assessed using the log-rank tests. Cox proportional hazard models were constructed using a backward stepwise approach, adjusting for predictors previously associated with mortality and recurrence at the p < 0.2 level with mortality and recurrence in unadjusted analysis. A p-value < 0.05 was considered significant. We retained only the variables significant at the p < 0.05 level. Statistical analyses were performed using JMP software (Version 18.2.0; SAS Institute Inc, Cary, North Carolina, USA). Ethics approval The study received required authorizations (IRB#1:2023/36) from the human research institutional review board (IRB00011687). The requirement to obtain informed consent was waived according to French legislation (observational retrospective study). Data Availability Statement Data not provided in the article may be shared (anonymized) at the reasonable request of any qualified investigator for purposes of replicating procedures and results. Results Clinical, imaging, and treatment-related characteristics Patients characteristics are detailed in Table 1 . Over the study period, 1.149 patients were treated for newly diagnosed glioblastoma, IDH- and H3-wildtype (662 men; mean age of 62 ± 12 years, range 19–93). Following histo-molecular and epigenetic reassessment, we excluded 10 patients according to the latest WHO 2021 Classification (Supplementary Fig. 1). Final cohort thus comprised 1.139 patients. Among them, thirty-three patients (2.9%) were considered as “young adults” (i.e. 18–39 years) and 1106 patients (97.1%) were considered as “older adults” (> 39 years) (Supplementary Fig. 2A). Histo-molecular and epigenetic characteristics in young adults In the young adult subgroup (n = 33), the mean age was 33 ± 4.41 years. Based on DNA methylation profiling, twenty-six cases (78.8%) were classified as “adult-type” epigenetic subgroup. Among these, the most common was mesenchymal class (n = 9, 27.2%) – including one atypical mesenchymal case –, followed by RTK1 class (n = 7, 21.2%), RTK2 class (n = 7, 21.2%) and HGG-E class (n = 3, 9.1%). Two cases (6.1%) were classified as pedHGG_RTK1a. Finally, five cases (15.2%) remained not subtyped after DNA-methylation analyses. Integrated clinical, imaging, histo-molecular and epigenetic characteristics are detailed in Fig. 1. Concerning the pedHGG_RTK1a class (n = 2, 6.1%) and the HGG-E class (n = 3, 9.1%), none met at least one molecular criterion for glioblastoma (i.e. 7 gain & 10 loss and/or hTERT promoter mutation and/or EGFR amplification). Three patients (9.1%) were identified as having DNA repair deficiency syndromes (one Lynch syndrome, one CMMRD and one POLE -mutant). One of these was classified as pedHGG_RTK1a, and the other two as HGG-E. Concerning the mesenchymal class (n = 9, 27.2%), 8 cases (88.9%) fulfilled at least one molecular criterion for glioblastoma. Concerning the RTK1 class (n = 7, 21.2%) and RTK2 class (n = 7, 21.2%), all cases had at least one molecular criterion for glioblastoma. Notably, all RTK1 tumours were MGMT -methylated, and all RTK2 tumours were diagnosed in patients older than 30 years. Concerning the not subtyped class (n = 5, 15.2%), one case had uninterpretable NGS results, three had at least one molecular criterion for glioblastoma, and the last one had none. All these cases were located in both hemispheres (mostly in the frontal and the temporal lobes), with one exception of a pedHGG_RTK1a case located in the cerebellum. We found no significant differences between epigenetic subgroups and sex (p = 0.059), presenting symptoms (p = 0.214) and main tumour location (p = 0.674). However, we found a significant impact of age group by epigenetic subgroups (p = 0.019). A simplified graphical summary illustrating the different epigenetic subgroups of HGGs identified is given in Fig. 2. Survival analyses During the follow-up period (median: 10.2 months; range, 0-141), 1039 patients (91.2%) died and 1079 patients (94.7%) experienced disease progression. Among young adults (n = 33), 27 (81.8%) died and 29 (87.9%) experienced disease progression. The median PFS in the entire cohort was 6.5 months (95%CI, 6.0–7.0) in the whole series. PFS results were detailed in the Supplementary Fig. 3 and the Fig. 3. After adjustments using Cox models, young adults (adjusted Hazard Ratio (aHR), 0.64 [95% CI 0.44–0.94], p = 0.015), postoperative KPS score ≥ 70 (aHR, 0.67 [95% CI 0.45–0.98], p = 0.038), surgical resection (aHR, 0.59 [95% CI 0.52–0.68], p < 0.001), and standard chemoradiotherapy protocol (aHR, 0.39 [95% CI 0.34–0.44], p < 0.001) were independently associated with a longer PFS, while contrast enhancement (aHR, 2.27 [95% CI 1.48–3.48], p < 0.001) and postoperative KPS score < 70 (aHR, 1.47 [95% CI 1.27–1.71], p < 0.001) were independently associated with a shorter PFS (Supplementary Table 1). The median OS in the entire cohort was 11.0 months (95%CI, 10.0–12.0). OS survival results were detailed in the Supplementary Fig. 3 and the Fig. 3. After adjustments using Cox models, young adults (aHR, 0.61 [95% CI 0.41–0.90], p = 0.013), epileptic seizures at diagnosis (aHR, 0.78 [95% CI 0.69–0.90], p < 0.001), surgical resection (aHR, 0.50 [95% CI 0.44–0.58], p < 0.001), and standard chemoradiotherapy protocol (aHR, 0.34 [95% CI 0.30–0.39], p < 0.001) were independently associated with a longer OS, while contrast enhancement (aHR, 3.01 [95% CI 1.90–4.77], p < 0.001) and postoperative KPS score < 70 (aHR, 1.82 [95% CI 1.57–2.11], p < 0.001) were independently associated with a shorter OS (Supplementary Table 2). In young adults and after adjustments using Cox models, surgical resection (p = 0.037) and standard chemoradiotherapy protocol (p = 0.027) were independently associated with longer PFS (Supplementary Table 3) and surgical resection (p = 0.012) was independently associated with longer OS (Table 2 ). DNA-methylation class did not significantly impact the PFS (p = 0.054) but significantly impact the OS (p = 0.028). The methylated MGMT status was not associated with longer PFS or OS (p = 0.320 and p = 0.639, respectively). Discussion Key results In this retrospective, single-centre cohort study, we show that glioblastoma, IDH- and H3-wildtype in young adults: 1) is a rare condition, accounting for 2.9% of all cases; 2) has a high rate of unclassified cases according to WHO criteria and epigenetics (n = 10, 30.3%); 3) has longer PFS and OS compared to older adults, the young adult situation representing an independent survival predictor; 4) do not have a significant increase in the rate of adverse postoperative events, and; 5) has a higher rate of awake surgical resection (21.7%) compared to older adults (10.2%). We identify surgical resection as having a significant impact on both PFS and OS. Standard chemoradiotherapy protocol had a significant impact only on PFS. We demonstrate a significant impact of the DNA-methylation class on OS but no significant impact on survival for the MGMT methylation status on PFS or OS. Interpretation In 2013, Leibetseder et al . assessed for the first time outcomes and molecular characteristics of newly diagnosed “glioblastomas” in young adults (18–40 years)[ 10 ]. They found a high frequency of IDH mutations (39.3%) and of MGMT promoter methylation (61.1%), which could explain the observed longer PFS and OS in young adults. However, their study focused on glioblastomas before the era of histo-molecular classifications, which explains the inclusion of IDH-mutant cases[ 38 ]. We recently performed a French multicentre clinico-radio-histo-molecular and epigenetic characterization of high-grade gliomas in adolescents and young adults treated in eight neurosurgical centres[ 27 ]. We demonstrated that: 1) high-grade gliomas in these patients are a heterogeneous subgroup of brain tumours; 2) pediatric subtypes are predominant (H3-mutants, 40%) but adult subtypes are present (IDH-mutants, 27.5%); 3) H3 G34-mutants are an adolescent and young adult-specific histo-molecular subtype, with a higher frequency (13%) in adolescent and young adults than in pediatric (4%) and adult (< 1%) patients[ 27 ]; 4) the extent of surgical resection was an independent predictor of a longer OS, both for pediatric[ 39 ] and adult patients[ 40 ]. The DNA-methylation classes were different from their older adult and pediatric counterparts[ 41 ] with a mix between the different specific methylation classes of these ages. We found a higher frequency of “adult-type” (78.8%) epigenetic subgroups. The most frequent methylation class was the mesenchymal class (n = 9, 27.2%) followed by RTK1 (n = 7, 21.2%), RTK2 classes (n = 7, 21.2%) and HGG-E class (n = 3, 9.1%), which is a different distribution compared with a previous study[ 41 ]. However, in the mesenchymal class, we had one atypical mesenchymal subtype, which remained less specific of older adults than classical mesenchymal[ 41 ]. Drexler et al . in 2023, based on a large series (n = 345) of adult patients with a glioblastoma, IDH- and H3-wildtype, found no significant differences between the mesenchymal, the RTK1 and the RTK2 classes[ 42 ]. Interestingly, they identified the first- and second-line gross-total resection as a strong predictive factors of better PFS and OS in both RTK1 and RTK2 classes but not for mesenchymal class[ 42 ]. Two cases were classified as “pediatric-type” and matched with pedHGG_RTK1a (n = 2, 6.1%). Interestingly, we found a better survival in HGG-E than pedHGG_RTK1a, which was different from a previous study[ 43 ]. Moreover, we found a better survival in “pediatric-type” classes compared to “adult-type” classes. Pereira et al . in 2025, found that HGG-E and atypical mesenchymal classes were significantly associated with shorter OS in multivariate analyses[ 43 ]. They found no other DNA-methylation classes impacting significantly the survival of patients[ 43 ]. Korshunov et al . in 2017, in a series of 87 pediatric patients with a glioblastoma, IDH- and H3-wildtype, identified the “pediatric-type” classes has an independent predictive factors of survival[ 44 ]. They found that pedHGG_RTK2 had a longer survival (median OS 44 months) than pedHGG_RTK1 (median OS 21 months). PedHGG_MYCN had the worst prognosis (median OS 14 months)[ 44 ]. Finally, five cases remained not subtyped after DNA-methylation analyses (n = 5, 15.2%), which remained a higher rate compared to older adults[ 43 ]. All these cases had a good quality control and only one matched with High-grade astrocytoma with piloid features (HGAP) but with a low score (0.71). These results were probably due to the rarity of glioblastoma, IDH- and H3-wildtype in young adults with possibly new DNA-methylation classes requiring further analyses. Most of them had criteria for molecular glioblastoma (n = 4/5, 80.0%), two cases had MDM2/CDK4 amplifications (and one with PDGFRA amplification). No other molecular alterations were found after NGS. Here, we identified 3 cases with DNA repair deficiency syndromes due to Lynch syndrome (n = 1), Constitutional mismatch repair deficiency (CMMRD) (n = 1) and POLE mutation (n = 1). One of them was classified as pedHGG_RTK1a and the last two ones as HGG-E and represented a higher proportion of hypermutated glioblastomas (9.1%) compared to the rate in the adult population (1.6%)[ 45 ]. Their identification is crucial since they can influence prognosis and treatment options, including the use of immunotherapy[ 45 ]. In our study, we found no significant differences concerning MGMT promoter methylation status between young adults and older adults. However, the MGMT promoter methylation status had a significant impact on survival (PFS and OS) in older adults but not in young adults. Drexler et al . reported a significant impact on survival of MGMT promoter methylation status only for RTK1 and RTK2 classes but not for the Mesenchymal class [ 42 ]. These results could suggest that the DNA-methylation classes had a stronger impact on survival than the MGMT promoter methylation status in daily practice. Reuss et al . in 2024 described a different MGMT promoter methylation status between the different DNA methylation classes, which could also explained the survival differences between classes for patients mostly treated with alkylating chemotherapy[ 41 ]. Generalizability This cohort reflects real-life clinical management of young adults with a newly diagnosed glioblastoma, IDH- and H3-wildtype. This suggests proposing, whenever possible, surgery with a dedicated management maximizing the extent of resection followed by chemoradiotherapy protocol. As for other types of brain tumours, these patients should be referred to specialized neurosurgical teams to improve survival results. We describe the clinico-radio-histo-molecular and epigenetic profile of glioblastoma, IDH- and H3-wildtype, in young adults, which remain different from their pediatric and older counterparts. Limitations The present results should be interpreted with caution given the retrospective, monocentric, and observational study design. For epigenetic classification and copy number profiling, we used two non-disclosed machine learning platforms, one of which is a commercial, proprietary product, which makes it currently impossible to replicate the study from raw data. The rarity of this condition, illustrated by the small number of young adults in a thousand-cases large cohort, limits the power of our multivariate analysis. The absence of patients aged 15 to 18 years is likely explained by the fact that some of these patients are referred to pediatric neurosurgeons, hence limiting the applicability of this study to the entire adolescent and young adult population and precluding its extension to the adolescent population. This can also be explained by the rarity of glioblastoma, IDH- and H3-wildtype, at this age, but also by treatment carried out in a pediatric neurosurgery department. Conclusion Newly diagnosed glioblastoma, IDH- and H3-wildtype, is a rare histo-molecular entity in young adults. Present findings support proposing maximal safe resection whenever possible, given the greater benefit of surgery in this subgroup, and suggests referring these patients to specialized neurosurgical centres to optimize outcomes. The distinct clinico-radiological, histo-molecular, and epigenetic landscape observed in young adults warrants further investigation to elucidate the biological factors underlying their differential prognosis and to guide age-adapted therapeutic strategies. Declarations Competing Interests The authors have no relevant financial or non-financial interests to disclose. Funding The authors declare that no funds, grants, or other support were received during the preparation of this manuscript. Author Contribution All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Alexandre Roux, Arnault Tauziede-Espariat, Giorgia Antonia Simboli, and Johan Pallud. The first draft of the manuscript was written by Alexandre Roux and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript. Acknowledgement Alexandre Roux would like to thank the Nuovo-Soldati Foundation for Cancer Research, the Servier Institute and the Ligue contre le Cancer for their support. Alexandre Roux and Johan Pallud would like to thank Frédéric Dhermain for his help in retrieving follow-up data. References Louis DN, Perry A, Wesseling P et al (2021) The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. 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Pediatr Blood Cancer 65. https://doi.org/10.1002/pbc.26861 Picart T, Barritault M, Poncet D et al (2021) Characteristics of diffuse hemispheric gliomas, H3 G34-mutant in adults. Neuro-Oncol Adv 3:vdab061. https://doi.org/10.1093/noajnl/vdab061 vonelm(2007) pdf Mirimanoff R-O, Gorlia T, Mason W et al (2006) Radiotherapy and temozolomide for newly diagnosed glioblastoma: recursive partitioning analysis of the EORTC 26981/22981-NCIC CE3 phase III randomized trial. J Clin Oncol Off J Am Soc Clin Oncol 24:2563–2569. https://doi.org/10.1200/JCO.2005.04.5963 Roux A, Roca P, Edjlali M et al (2019) MRI Atlas of IDH Wild-Type Supratentorial Glioblastoma: Probabilistic Maps of Phenotype, Management, and Outcomes. Radiology 293:633–643. https://doi.org/10.1148/radiol.2019190491 Vogelbaum MA, Jost S, Aghi MK et al (2012) Application of novel response/progression measures for surgically delivered therapies for gliomas: Response Assessment in Neuro-Oncology (RANO) Working Group. Neurosurgery 70:234–243 discussion 243–244. https://doi.org/10.1227/NEU.0b013e318223f5a7 Lacroix M, Abi-Said D, Fourney DR et al (2001) A multivariate analysis of 416 patients with glioblastoma multiforme: prognosis, extent of resection, and survival. J Neurosurg 95:190–198. https://doi.org/10.3171/jns.2001.95.2.0190 Louis DN, Perry A, Reifenberger G et al (2016) The 2016 World Health Organization Classification of Tumors of the Central Nervous System: a summary. Acta Neuropathol (Berl) 131:803–820. https://doi.org/10.1007/s00401-016-1545-1 MacDonald TJ, Aguilera D, Kramm CM (2011) Treatment of high-grade glioma in children and adolescents. Neuro-Oncol 13:1049–1058. https://doi.org/10.1093/neuonc/nor092 Molinaro AM, Hervey-Jumper S, Morshed RA et al (2020) Association of Maximal Extent of Resection of Contrast-Enhanced and Non-Contrast-Enhanced Tumor With Survival Within Molecular Subgroups of Patients With Newly Diagnosed Glioblastoma. JAMA Oncol. https://doi.org/10.1001/jamaoncol.2019.6143 Reuss DE, Schrimpf D, Cherkezov A et al (2024) Heterogeneity of DNA methylation profiles and copy number alterations in 10782 adult-type glioblastomas, IDH-wildtype. Free Neuropathol 5:7. https://doi.org/10.17879/freeneuropathology-2024-5345 Drexler R, Schüller U, Eckhardt A et al (2023) DNA methylation subclasses predict the benefit from gross total tumor resection in IDH-wildtype glioblastoma patients. Neuro-Oncol 25:315–325. https://doi.org/10.1093/neuonc/noac177 Pereira R, Mackay A, Grabovska Y et al (2025) The spectrum of IDH- and H3-wildtype high-grade glioma subgroups occurring across teenage and young adult patient populations. Clin Cancer Res Off J Am Assoc Cancer Res. https://doi.org/10.1158/1078-0432.CCR-24-1256 Korshunov A, Schrimpf D, Ryzhova M et al (2017) H3-/IDH-wild type pediatric glioblastoma is comprised of molecularly and prognostically distinct subtypes with associated oncogenic drivers. Acta Neuropathol (Berl) 134:507–516. https://doi.org/10.1007/s00401-017-1710-1 Benusiglio PR, Elder F, Touat M et al (2023) Mismatch Repair Deficiency and Lynch Syndrome Among Adult Patients With Glioma. JCO Precis Oncol 7:e2200525. https://doi.org/10.1200/PO.22.00525 Tables Table 1 and 2 are available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table1.docx Table 1. Main characteristics of the study sample (n=1139). Table2.docx Table 2. Predictors of overall survival in young adults (n=33). Unadjusted and adjusted hazard ratios by Cox proportional hazards model. SuppFigure1.jpg Supplementary Figure 1. Patient flow chart. SuppFigure2.jpg Supplementary Figure 2. Frequency distribution by age and illustrating cases. (A) Histogram of the frequency distribution by age. (B) A 36-year-old right-handed man underwent a function-based resection (84.5cm 3 , no residual tumor) for a right temporal non-enhancing IDH- and H3-wildtype glioblastoma. (Mapping performed at 3.5 mA. numbered tags: involuntary movement of the jaw in 1, involuntary movement of the lips in 2, paresthesias of the tongue in 20, paresthesias of the tongue and lips in 21, errors in exploring the visual field using line bisection test in 10, 11, 12, 13, and 14. (C) A 39-year-old right-handed woman underwent a function-based resection (73.4 cm 3 , no residual tumor) for a left frontal IDH- and H3-wildtype glioblastoma. (Mapping performed at 3.5 mA. numbered tags: speech arrest in 10 and 11, involuntary movement of the of the hand in 1 and 2, arrest of voluntary movements of the hand in 3 and 4, arrest of voluntary movements of the hand and of the elbow in 5, 6, and 7, and phonemic paraphasia in 12. (D) A 26-year-old left-handed man underwent a function-based resection (37.9 cm 3 , no residual tumor) for a right frontal IDH- and H3-wildtype glioblastoma. (Mapping performed at 2.0 mA. numbered tags: involuntary movement of the jaw and tongue in 1, 2 and 3, involuntary movement of the hand in 4, and involuntary movement of the wrist in 5 identifying the primary motor cortical pathways; paresthesia of the lips in 20 and 21, paresthesia of the thumb in 22, paresthesia of third, fourth, fifth fingers in 23 identifying the sensory cortical pathways; involuntary movements of the jaw 7 identifying subcortical primary motor pathways; arrest of voluntary movements of the mouth in 6 and saccadic lateral deviation of the eyes in 8 identifying cortico-subcortical negative motor networks). SuppFigure3.jpg Supplementary Figure 3. Survival curves according to the Kaplan-Meier method. Progression-free survival (left) and Overall Survival (right). The median progression-free survival (PFS) was 6.5 months (95%CI, 6.0-7.0) in the whole series. (A, left) The median PFS was significantly higher in young adults (11 months; 95%CI, 6.0-14.0) than in older adults (6.5 months; 95%CI, 6.0-7.0) (p=0.003). The median overall survival (OS) was 11.0 months (95%CI, 10.0-12.0) in the whole series. (A, right) The median OS was significantly higher in the young adults (16.2 months; 95%CI, 12.0-29.0) than in the older adults (10.7 months; 95%CI, 10.0-12.0) (p=0.001). (B, left) In the subgroup of patients with a subtotal or total resection as first treatment, the median PFS was significantly higher in young adults (12.9 months; 95%CI, 6.5-19.0) than in older adults (9.0 months; 95%CI, 8.0-10.0, p=0.008). (B, right) In the subgroup of patients with a subtotal or total resection as first treatment, the median OS was significantly higher in young adults (29 months; 95%CI, 13.5-54.0) than in older adults (17.1 months; 95%CI, 16.0-18.5, p=0.007). (C, left) In the subgroup of patients who completed the standard chemoradiation protocol, the median PFS was not significantly different in young adults (12.0 months; 95%CI, 6.5-16.0) than in older adults (10.0 months; 95%CI, 9.1-11.0, p=0.074). (C, right) In the subgroup of patients who completed the standard chemoradiation protocol, the median OS was not significantly different in young adults (16.5 months; 95%CI, 13.5-31.0) than in older adults (17.9 months; 95%CI, 16.5-19.0, p=0.075). SuppTable1.docx Supplementary Table 1. Predictors of progression-free survival in the whole series (n=1.139). Unadjusted and adjusted hazard ratios by Cox proportional hazards model. SuppTable2.docx Supplementary Table 2. Predictors of overall survival in the whole series (n=1.139). Unadjusted and adjusted hazard ratios by Cox proportional hazards model. SuppTable3.docx Supplementary Table 3. Predictors of progression-free survival in young adults (n=33). Unadjusted and adjusted hazard ratios by Cox proportional hazards model. Cite Share Download PDF Status: Published Journal Publication published 16 Oct, 2025 Read the published version in Journal of Neuro-Oncology → Version 1 posted Editorial decision: Revision requested 14 Sep, 2025 Reviews received at journal 13 Sep, 2025 Reviews received at journal 08 Sep, 2025 Reviews received at journal 07 Sep, 2025 Reviews received at journal 07 Sep, 2025 Reviews received at journal 06 Sep, 2025 Reviewers agreed at journal 03 Sep, 2025 Reviewers agreed at journal 03 Sep, 2025 Reviewers agreed at journal 02 Sep, 2025 Reviews received at journal 01 Sep, 2025 Reviewers agreed at journal 01 Sep, 2025 Reviewers agreed at journal 01 Sep, 2025 Reviewers agreed at journal 01 Sep, 2025 Reviews received at journal 01 Sep, 2025 Reviewers agreed at journal 01 Sep, 2025 Reviewers agreed at journal 29 Aug, 2025 Reviewers invited by journal 28 Aug, 2025 Editor assigned by journal 28 Aug, 2025 Submission checks completed at journal 28 Aug, 2025 First submitted to journal 27 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Main characteristics of the study sample (n=1139).\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Table1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7473307/v1/e88eecd2bb1d65a909e7aea4.docx"},{"id":90801787,"identity":"960e50a0-2078-41dd-af71-71f1bbe4b73c","added_by":"auto","created_at":"2025-09-08 10:20:04","extension":"docx","order_by":2,"title":"","display":"","copyAsset":false,"role":"supplement","size":28245,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eTable 2. Predictors of overall survival in young adults (n=33). Unadjusted and adjusted hazard ratios by Cox proportional hazards model.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"Table2.docx","url":"https://assets-eu.researchsquare.com/files/rs-7473307/v1/fbde4e3d4beab15bbde05d77.docx"},{"id":90801812,"identity":"93fdac87-65cd-45cb-b9d0-8fe849880ddf","added_by":"auto","created_at":"2025-09-08 10:20:05","extension":"jpg","order_by":3,"title":"","display":"","copyAsset":false,"role":"supplement","size":366714,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Figure 1. Patient flow chart.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"SuppFigure1.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7473307/v1/4856a78ad990ecc33f885fac.jpg"},{"id":90801807,"identity":"25421de5-9810-4280-a5a4-8b7fbe774f8c","added_by":"auto","created_at":"2025-09-08 10:20:05","extension":"jpg","order_by":4,"title":"","display":"","copyAsset":false,"role":"supplement","size":1572706,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Figure 2. Frequency distribution by age and illustrating cases.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e(A) \u003c/strong\u003eHistogram of the frequency distribution by age. \u003cstrong\u003e(B)\u003c/strong\u003e A 36-year-old right-handed man underwent a function-based resection (84.5cm\u003csup\u003e3\u003c/sup\u003e, no residual tumor) for a right temporal non-enhancing IDH- and H3-wildtype glioblastoma. (Mapping performed at 3.5 mA. numbered tags: involuntary movement of the jaw in 1, involuntary movement of the lips in 2, paresthesias of the tongue in 20, paresthesias of the tongue and lips in 21, errors in exploring the visual field using line bisection test in 10, 11, 12, 13, and 14. \u003cstrong\u003e(C)\u003c/strong\u003e A 39-year-old right-handed woman underwent a function-based resection (73.4 cm\u003csup\u003e3\u003c/sup\u003e, no residual tumor) for a left frontal IDH- and H3-wildtype glioblastoma. (Mapping performed at 3.5 mA. numbered tags: speech arrest in 10 and 11, involuntary movement of the of the hand in 1 and 2, arrest of voluntary movements of the hand in 3 and 4, arrest of voluntary movements of the hand and of the elbow in 5, 6, and 7, and phonemic paraphasia in 12. \u003cstrong\u003e(D)\u003c/strong\u003e A 26-year-old left-handed man underwent a function-based resection (37.9 cm\u003csup\u003e3\u003c/sup\u003e, no residual tumor) for a right frontal IDH- and H3-wildtype glioblastoma. (Mapping performed at 2.0 mA. numbered tags: involuntary movement of the jaw and tongue in 1, 2 and 3, involuntary movement of the hand in 4, and involuntary movement of the wrist in 5 identifying the primary motor cortical pathways; paresthesia of the lips in 20 and 21, paresthesia of the thumb in 22, paresthesia of third, fourth, fifth fingers in 23 identifying the sensory cortical pathways; involuntary movements of the jaw 7 identifying subcortical primary motor pathways; arrest of voluntary movements of the mouth in 6 and saccadic lateral deviation of the eyes in 8 identifying cortico-subcortical negative motor networks).\u003c/p\u003e","description":"","filename":"SuppFigure2.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7473307/v1/8af52fe6dd0a9fd29ca2a103.jpg"},{"id":90801793,"identity":"6e1bc964-4d62-4d59-8835-835978ba2e0e","added_by":"auto","created_at":"2025-09-08 10:20:05","extension":"jpg","order_by":5,"title":"","display":"","copyAsset":false,"role":"supplement","size":375614,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Figure 3. Survival curves according to the Kaplan-Meier method.\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eProgression-free survival (left) and Overall Survival (right). The median progression-free survival (PFS) was 6.5 months (95%CI, 6.0-7.0) in the whole series. \u003cstrong\u003e(A, left)\u003c/strong\u003e The median PFS was significantly higher in young adults (11 months; 95%CI, 6.0-14.0) than in older adults (6.5 months; 95%CI, 6.0-7.0) (p=0.003). The median overall survival (OS) was 11.0 months (95%CI, 10.0-12.0) in the whole series. \u003cstrong\u003e(A, right)\u003c/strong\u003e The median OS was significantly higher in the young adults (16.2 months; 95%CI, 12.0-29.0) than in the older adults (10.7 months; 95%CI, 10.0-12.0) (p=0.001). \u003cstrong\u003e(B, left) \u003c/strong\u003eIn the subgroup of patients with a subtotal or total resection as first treatment, the median PFS was significantly higher in young adults (12.9 months; 95%CI, 6.5-19.0) than in older adults (9.0 months; 95%CI, 8.0-10.0, p=0.008). \u003cstrong\u003e(B, right)\u003c/strong\u003e In the subgroup of patients with a subtotal or total resection as first treatment, the median OS was significantly higher in young adults (29 months; 95%CI, 13.5-54.0) than in older adults (17.1 months; 95%CI, 16.0-18.5, p=0.007). \u003cstrong\u003e(C, left) \u003c/strong\u003eIn the subgroup of patients who completed the standard chemoradiation protocol, the median PFS was not significantly different in young adults (12.0 months; 95%CI, 6.5-16.0) than in older adults (10.0 months; 95%CI, 9.1-11.0, p=0.074). \u003cstrong\u003e(C, right)\u003c/strong\u003e In the subgroup of patients who completed the standard chemoradiation protocol, the median OS was not significantly different in young adults (16.5 months; 95%CI, 13.5-31.0) than in older adults (17.9 months; 95%CI, 16.5-19.0, p=0.075).\u003c/p\u003e","description":"","filename":"SuppFigure3.jpg","url":"https://assets-eu.researchsquare.com/files/rs-7473307/v1/ea6981e9a3227c78c6a2424f.jpg"},{"id":90803020,"identity":"b875f73e-3109-4c56-a227-df02b1150c0b","added_by":"auto","created_at":"2025-09-08 10:28:05","extension":"docx","order_by":6,"title":"","display":"","copyAsset":false,"role":"supplement","size":28274,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Table 1. Predictors of progression-free survival in the whole series (n=1.139). Unadjusted and adjusted hazard ratios by Cox proportional hazards model.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"SuppTable1.docx","url":"https://assets-eu.researchsquare.com/files/rs-7473307/v1/ed8d5468aadd60da8e868c95.docx"},{"id":90801815,"identity":"26b3e946-5f93-449a-b508-dc26c2a81d38","added_by":"auto","created_at":"2025-09-08 10:20:06","extension":"docx","order_by":7,"title":"","display":"","copyAsset":false,"role":"supplement","size":27932,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Table 2. Predictors of overall survival in the whole series (n=1.139). Unadjusted and adjusted hazard ratios by Cox proportional hazards model.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"SuppTable2.docx","url":"https://assets-eu.researchsquare.com/files/rs-7473307/v1/45bb6c7a0aff357d5cb4293d.docx"},{"id":90801802,"identity":"b894551a-df94-4b8c-8d6a-57991c691339","added_by":"auto","created_at":"2025-09-08 10:20:05","extension":"docx","order_by":8,"title":"","display":"","copyAsset":false,"role":"supplement","size":28367,"visible":true,"origin":"","legend":"\u003cp\u003e\u003cstrong\u003eSupplementary Table 3. Predictors of progression-free survival in young adults (n=33). Unadjusted and adjusted hazard ratios by Cox proportional hazards model.\u003c/strong\u003e\u003c/p\u003e","description":"","filename":"SuppTable3.docx","url":"https://assets-eu.researchsquare.com/files/rs-7473307/v1/a851058779f08f747b3c9c3c.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Glioblastoma, IDH- and H3-wildtype in young adults: a rare condition with a distinct clinico-radio-histo-molecular and epigenetic landscape","fulltext":[{"header":"Introduction","content":"\u003cp\u003eGlioblastoma, \u003cem\u003eisocitrate dehydrogenase (\u003c/em\u003eIDH\u003cem\u003e)\u003c/em\u003e-wildtype (World Health Organization (WHO) grade 4) is the most common primary brain tumour in adults and among the most aggressive of all tumours[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. In newly diagnosed glioblastomas, IDH- and H3\u0026ndash;wildtype, survival is improved by surgical resection[\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] (with or without Carmustine wafer implantation[\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]), in association with standard chemoradiotherapy[\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e] and, when applicable, tumor-treating fields[\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e]. Adolescents and young adults comprise a group aged between 15\u0026ndash;39 years according to the definition of the LIVESTRONG Young Adult Alliance and of the NCI Adolescent and Young Adult Oncology Progress Review Group[\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e]. In young adults (i.e. 18\u0026ndash;39 years), primary brain tumours represent the most common solid tumours and the second most frequent malignancies[\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e, \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e]. Glioblastomas, IDH\u003cem\u003e-\u003c/em\u003e and H3-wildtype, carry the highest mortality rate among young adult patients[\u003cspan additionalcitationids=\"CR11\" citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e]. Due to their rarity and apparent similar features to adult forms, pediatric and young adult glioblastomas, IDH\u0026ndash; and H3\u0026ndash;wildtype, are currently classified, graded, and managed according to the same criteria as in older adults. This study population lies at the intersection between the pediatric population, which presents specific histo-molecular and epigenetic subtypes (such as H3 K27-altered, H3 G34-mutant, and pediatric type-HGG), and the adult population. Moreover, young adult patients with a brain tumour have particular requirements related to their age and conditions[\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e]. Recent studies mainly focused on epidemiological[\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e], psychological[\u003cspan additionalcitationids=\"CR15 CR16\" citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e], neuropsychological[\u003cspan additionalcitationids=\"CR19\" citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e], health-related quality-of-life[\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e], family life[\u003cspan additionalcitationids=\"CR23 CR24\" citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e], transitional care[\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e], or on histo-molecular and epigenetic profiling [\u003cspan additionalcitationids=\"CR28 CR29 CR30 CR31\" citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e]. To date, no study has assessed the clinico-radio-histo-molecular and epigenetic features of glioblastoma, IDH- and H3-wildtype and the management strategy in young adult patients.\u003c/p\u003e\u003cp\u003eIn the present study, we compared the prognosis and the impact of oncological treatment on newly diagnosed glioblastomas, IDH- and H3-wildtype between young adults (i.e. 18\u0026ndash;39 years) and older adult patients (i.e. \u0026gt;39 years) and we detailed the clinico-radio-histo-molecular and epigenetic features in young adults.\u003c/p\u003e"},{"header":"Methods","content":"\u003cdiv id=\"Sec4\" class=\"Section2\"\u003e\u003ch2\u003eStudy design\u003c/h2\u003e\u003cp\u003eAn observational, retrospective, single-centre cohort study was conducted at an adult tertiary neurosurgical oncology centre between January 2006 and December 2023. The manuscript was written according to the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) checklist[\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\n\u003ch3\u003eParticipants\u003c/h3\u003e\n\u003cp\u003eInclusion criteria were: 1) a confirmed histo-molecular diagnosis of glioblastoma, IDH-wildtype and H3-wildtype according to the 2021 WHO classification[\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]; 2) available pre- and early postoperative MRI scans ; and 3) available postoperative follow-up, including adjuvant oncological treatments, morbidity, and survival.\u003c/p\u003e\n\u003ch3\u003eData collection\u003c/h3\u003e\n\u003cp\u003eData were systematically gathered from the medical records using a protocol designed for the study. Clinical characteristics at the time of histo-molecular diagnosis were: sex, age, Karnofsky Performance Status (KPS) score, presenting symptom (i.e. the symptom leading to initial diagnosis), signs of raised intracranial pressure (i.e. headache, nausea/vomiting, coma, diplopia, visual blur, papilledema) at diagnosis, neurological deficit (i.e. motor deficit, sensitive deficit, language disorders, visual disturbances, and frontal syndrome) at diagnosis, epileptic seizures (i.e. partial or generalized with or without confirmation by an electroencephalogram) at diagnosis, and revised Radiation Therapy Oncology Group - Recursive Partitioning Analysis (RTOG-RPA) classification system for glioblastoma [\u003cspan citationid=\"CR34\" class=\"CitationRef\"\u003e34\u003c/span\u003e]. Imaging characteristics on preoperative MRI were: main tumour location (i.e. where the tumour volume was predominantly located for multiple lobar involvement), mass effect, multifocal tumour, contrast enhancement, cortical or ventricle involvement of the contrast enhancement part, tumour volume (obtained by lesion segmentation on preoperative 3D T1-weighted with gadolinium or FLAIR sequences based on a methodology previously described)[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Treatment-related characteristics were: extent of surgical resection, adverse postoperative events within the first postoperative month (hematoma requiring surgical evacuation, new neurological deficit, postoperative seizures, wound-healing defect, cerebrospinal fluid leak, hydrocephalus, infection, and systemic thromboembolic complications), completion of the standard chemoradiotherapy protocol, and KPS score at the end of first-line oncological treatment. We established the extent of resection by quantifying the volume of residual tumour on early postoperative (within 48 hours) 3D T1-weighted sequence (without and with gadolinium) or FLAIR sequence (for non-contrast enhancing tumours) as per our methodology previously described[\u003cspan citationid=\"CR35\" class=\"CitationRef\"\u003e35\u003c/span\u003e]. Subtotal resection was defined by removal of \u0026ge;\u0026thinsp;90\u0026ndash;99% of the tumour and total resection defined by removal of 100% of the tumour[\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e, \u003cspan citationid=\"CR37\" class=\"CitationRef\"\u003e37\u003c/span\u003e]. Histo-molecular and epigenetic analyses were described in the supplementary Methods.\u003c/p\u003e\n\u003ch3\u003eStatistical analyses\u003c/h3\u003e\n\u003cp\u003eContinuous variables were described as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation. Categorical variables were described as percentages. Univariable analyses were carried out, computing unadjusted odds ratios, and using the chi-square or Fisher\u0026rsquo;s exact test for comparing categorical variables, and the unpaired t-test or Mann\u0026ndash;Whitney U test for continuous variables, as appropriate. Unadjusted survival curves for Overall Survival (OS) and Progression-Free Survival (PFS) were plotted using the Kaplan-Meier method, with group comparisons assessed using the log-rank tests. Cox proportional hazard models were constructed using a backward stepwise approach, adjusting for predictors previously associated with mortality and recurrence at the p\u0026thinsp;\u0026lt;\u0026thinsp;0.2 level with mortality and recurrence in unadjusted analysis. A p-value\u0026thinsp;\u0026lt;\u0026thinsp;0.05 was considered significant. We retained only the variables significant at the p\u0026thinsp;\u0026lt;\u0026thinsp;0.05 level. Statistical analyses were performed using JMP software (Version 18.2.0; SAS Institute Inc, Cary, North Carolina, USA).\u003c/p\u003e\n\u003ch3\u003eEthics approval\u003c/h3\u003e\n\u003cp\u003eThe study received required authorizations (IRB#1:2023/36) from the human research institutional review board (IRB00011687). The requirement to obtain informed consent was waived according to French legislation (observational retrospective study).\u003c/p\u003e\u003cdiv id=\"Sec9\" class=\"Section2\"\u003e\u003ch2\u003eData Availability Statement\u003c/h2\u003e\u003cp\u003eData not provided in the article may be shared (anonymized) at the reasonable request of any qualified investigator for purposes of replicating procedures and results.\u003c/p\u003e\u003c/div\u003e"},{"header":"Results","content":"\u003cdiv id=\"Sec11\" class=\"Section2\"\u003e\u003ch2\u003eClinical, imaging, and treatment-related characteristics\u003c/h2\u003e\u003cp\u003ePatients characteristics are detailed in Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. Over the study period, 1.149 patients were treated for newly diagnosed glioblastoma, IDH- and H3-wildtype (662 men; mean age of 62\u0026thinsp;\u0026plusmn;\u0026thinsp;12 years, range 19\u0026ndash;93). Following histo-molecular and epigenetic reassessment, we excluded 10 patients according to the latest WHO 2021 Classification (Supplementary Fig.\u0026nbsp;1). Final cohort thus comprised 1.139 patients. Among them, thirty-three patients (2.9%) were considered as \u0026ldquo;young adults\u0026rdquo; (i.e. 18\u0026ndash;39 years) and 1106 patients (97.1%) were considered as \u0026ldquo;older adults\u0026rdquo; (\u0026gt;\u0026thinsp;39 years) (Supplementary Fig.\u0026nbsp;2A).\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec12\" class=\"Section2\"\u003e\u003ch2\u003eHisto-molecular and epigenetic characteristics in young adults\u003c/h2\u003e\u003cp\u003eIn the young adult subgroup (n\u0026thinsp;=\u0026thinsp;33), the mean age was 33\u0026thinsp;\u0026plusmn;\u0026thinsp;4.41 years. Based on DNA methylation profiling, twenty-six cases (78.8%) were classified as \u0026ldquo;adult-type\u0026rdquo; epigenetic subgroup. Among these, the most common was mesenchymal class (n\u0026thinsp;=\u0026thinsp;9, 27.2%) \u0026ndash; including one atypical mesenchymal case \u0026ndash;, followed by RTK1 class (n\u0026thinsp;=\u0026thinsp;7, 21.2%), RTK2 class (n\u0026thinsp;=\u0026thinsp;7, 21.2%) and HGG-E class (n\u0026thinsp;=\u0026thinsp;3, 9.1%). Two cases (6.1%) were classified as pedHGG_RTK1a. Finally, five cases (15.2%) remained not subtyped after DNA-methylation analyses. Integrated clinical, imaging, histo-molecular and epigenetic characteristics are detailed in Fig.\u0026nbsp;1.\u003c/p\u003e\u003cp\u003eConcerning the pedHGG_RTK1a class (n\u0026thinsp;=\u0026thinsp;2, 6.1%) and the HGG-E class (n\u0026thinsp;=\u0026thinsp;3, 9.1%), none met at least one molecular criterion for glioblastoma (i.e. 7 gain \u0026amp; 10 loss and/or \u003cem\u003ehTERT\u003c/em\u003e promoter mutation and/or \u003cem\u003eEGFR\u003c/em\u003e amplification). Three patients (9.1%) were identified as having DNA repair deficiency syndromes (one Lynch syndrome, one CMMRD and one \u003cem\u003ePOLE\u003c/em\u003e-mutant). One of these was classified as pedHGG_RTK1a, and the other two as HGG-E.\u003c/p\u003e\u003cp\u003eConcerning the mesenchymal class (n\u0026thinsp;=\u0026thinsp;9, 27.2%), 8 cases (88.9%) fulfilled at least one molecular criterion for glioblastoma. Concerning the RTK1 class (n\u0026thinsp;=\u0026thinsp;7, 21.2%) and RTK2 class (n\u0026thinsp;=\u0026thinsp;7, 21.2%), all cases had at least one molecular criterion for glioblastoma. Notably, all RTK1 tumours were \u003cem\u003eMGMT\u003c/em\u003e-methylated, and all RTK2 tumours were diagnosed in patients older than 30 years. Concerning the not subtyped class (n\u0026thinsp;=\u0026thinsp;5, 15.2%), one case had uninterpretable NGS results, three had at least one molecular criterion for glioblastoma, and the last one had none.\u003c/p\u003e\u003cp\u003eAll these cases were located in both hemispheres (mostly in the frontal and the temporal lobes), with one exception of a pedHGG_RTK1a case located in the cerebellum.\u003c/p\u003e\u003cp\u003eWe found no significant differences between epigenetic subgroups and sex (p\u0026thinsp;=\u0026thinsp;0.059), presenting symptoms (p\u0026thinsp;=\u0026thinsp;0.214) and main tumour location (p\u0026thinsp;=\u0026thinsp;0.674). However, we found a significant impact of age group by epigenetic subgroups (p\u0026thinsp;=\u0026thinsp;0.019). A simplified graphical summary illustrating the different epigenetic subgroups of HGGs identified is given in Fig.\u0026nbsp;2.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec13\" class=\"Section2\"\u003e\u003ch2\u003eSurvival analyses\u003c/h2\u003e\u003cp\u003eDuring the follow-up period (median: 10.2 months; range, 0-141), 1039 patients (91.2%) died and 1079 patients (94.7%) experienced disease progression. Among young adults (n\u0026thinsp;=\u0026thinsp;33), 27 (81.8%) died and 29 (87.9%) experienced disease progression.\u003c/p\u003e\u003cp\u003eThe median PFS in the entire cohort was 6.5 months (95%CI, 6.0\u0026ndash;7.0) in the whole series. PFS results were detailed in the Supplementary Fig.\u0026nbsp;3 and the Fig.\u0026nbsp;3.\u003c/p\u003e\u003cp\u003eAfter adjustments using Cox models, young adults (adjusted Hazard Ratio (aHR), 0.64 [95% CI 0.44\u0026ndash;0.94], p\u0026thinsp;=\u0026thinsp;0.015), postoperative KPS score\u0026thinsp;\u0026ge;\u0026thinsp;70 (aHR, 0.67 [95% CI 0.45\u0026ndash;0.98], p\u0026thinsp;=\u0026thinsp;0.038), surgical resection (aHR, 0.59 [95% CI 0.52\u0026ndash;0.68], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and standard chemoradiotherapy protocol (aHR, 0.39 [95% CI 0.34\u0026ndash;0.44], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were independently associated with a longer PFS, while contrast enhancement (aHR, 2.27 [95% CI 1.48\u0026ndash;3.48], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and postoperative KPS score\u0026thinsp;\u0026lt;\u0026thinsp;70 (aHR, 1.47 [95% CI 1.27\u0026ndash;1.71], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were independently associated with a shorter PFS (Supplementary Table\u0026nbsp;1).\u003c/p\u003e\u003cp\u003eThe median OS in the entire cohort was 11.0 months (95%CI, 10.0\u0026ndash;12.0). OS survival results were detailed in the Supplementary Fig.\u0026nbsp;3 and the Fig.\u0026nbsp;3.\u003c/p\u003e\u003cp\u003eAfter adjustments using Cox models, young adults (aHR, 0.61 [95% CI 0.41\u0026ndash;0.90], p\u0026thinsp;=\u0026thinsp;0.013), epileptic seizures at diagnosis (aHR, 0.78 [95% CI 0.69\u0026ndash;0.90], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), surgical resection (aHR, 0.50 [95% CI 0.44\u0026ndash;0.58], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001), and standard chemoradiotherapy protocol (aHR, 0.34 [95% CI 0.30\u0026ndash;0.39], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were independently associated with a longer OS, while contrast enhancement (aHR, 3.01 [95% CI 1.90\u0026ndash;4.77], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) and postoperative KPS score\u0026thinsp;\u0026lt;\u0026thinsp;70 (aHR, 1.82 [95% CI 1.57\u0026ndash;2.11], p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) were independently associated with a shorter OS (Supplementary Table\u0026nbsp;2).\u003c/p\u003e\u003cp\u003eIn young adults and after adjustments using Cox models, surgical resection (p\u0026thinsp;=\u0026thinsp;0.037) and standard chemoradiotherapy protocol (p\u0026thinsp;=\u0026thinsp;0.027) were independently associated with longer PFS (Supplementary Table\u0026nbsp;3) and surgical resection (p\u0026thinsp;=\u0026thinsp;0.012) was independently associated with longer OS (Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e). DNA-methylation class did not significantly impact the PFS (p\u0026thinsp;=\u0026thinsp;0.054) but significantly impact the OS (p\u0026thinsp;=\u0026thinsp;0.028). The methylated \u003cem\u003eMGMT\u003c/em\u003e status was not associated with longer PFS or OS (p\u0026thinsp;=\u0026thinsp;0.320 and p\u0026thinsp;=\u0026thinsp;0.639, respectively).\u003c/p\u003e\u003c/div\u003e"},{"header":"Discussion","content":"\u003cdiv id=\"Sec15\" class=\"Section2\"\u003e\u003ch2\u003eKey results\u003c/h2\u003e\u003cp\u003eIn this retrospective, single-centre cohort study, we show that glioblastoma, IDH- and H3-wildtype in young adults: 1) is a rare condition, accounting for 2.9% of all cases; 2) has a high rate of unclassified cases according to WHO criteria and epigenetics (n\u0026thinsp;=\u0026thinsp;10, 30.3%); 3) has longer PFS and OS compared to older adults, the young adult situation representing an independent survival predictor; 4) do not have a significant increase in the rate of adverse postoperative events, and; 5) has a higher rate of awake surgical resection (21.7%) compared to older adults (10.2%). We identify surgical resection as having a significant impact on both PFS and OS. Standard chemoradiotherapy protocol had a significant impact only on PFS. We demonstrate a significant impact of the DNA-methylation class on OS but no significant impact on survival for the \u003cem\u003eMGMT\u003c/em\u003e methylation status on PFS or OS.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec16\" class=\"Section2\"\u003e\u003ch2\u003eInterpretation\u003c/h2\u003e\u003cp\u003eIn 2013, Leibetseder \u003cem\u003eet al\u003c/em\u003e. assessed for the first time outcomes and molecular characteristics of newly diagnosed \u0026ldquo;glioblastomas\u0026rdquo; in young adults (18\u0026ndash;40 years)[\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. They found a high frequency of IDH mutations (39.3%) and of \u003cem\u003eMGMT\u003c/em\u003e promoter methylation (61.1%), which could explain the observed longer PFS and OS in young adults. However, their study focused on glioblastomas before the era of histo-molecular classifications, which explains the inclusion of IDH-mutant cases[\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e]. We recently performed a French multicentre clinico-radio-histo-molecular and epigenetic characterization of high-grade gliomas in adolescents and young adults treated in eight neurosurgical centres[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]. We demonstrated that: 1) high-grade gliomas in these patients are a heterogeneous subgroup of brain tumours; 2) pediatric subtypes are predominant (H3-mutants, 40%) but adult subtypes are present (IDH-mutants, 27.5%); 3) H3 G34-mutants are an adolescent and young adult-specific histo-molecular subtype, with a higher frequency (13%) in adolescent and young adults than in pediatric (4%) and adult (\u0026lt;\u0026thinsp;1%) patients[\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e]; 4) the extent of surgical resection was an independent predictor of a longer OS, both for pediatric[\u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e] and adult patients[\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eThe DNA-methylation classes were different from their older adult and pediatric counterparts[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e] with a mix between the different specific methylation classes of these ages. We found a higher frequency of \u0026ldquo;adult-type\u0026rdquo; (78.8%) epigenetic subgroups. The most frequent methylation class was the mesenchymal class (n\u0026thinsp;=\u0026thinsp;9, 27.2%) followed by RTK1 (n\u0026thinsp;=\u0026thinsp;7, 21.2%), RTK2 classes (n\u0026thinsp;=\u0026thinsp;7, 21.2%) and HGG-E class (n\u0026thinsp;=\u0026thinsp;3, 9.1%), which is a different distribution compared with a previous study[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. However, in the mesenchymal class, we had one atypical mesenchymal subtype, which remained less specific of older adults than classical mesenchymal[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e]. Drexler \u003cem\u003eet al\u003c/em\u003e. in 2023, based on a large series (n\u0026thinsp;=\u0026thinsp;345) of adult patients with a glioblastoma, IDH- and H3-wildtype, found no significant differences between the mesenchymal, the RTK1 and the RTK2 classes[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. Interestingly, they identified the first- and second-line gross-total resection as a strong predictive factors of better PFS and OS in both RTK1 and RTK2 classes but not for mesenchymal class[\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. Two cases were classified as \u0026ldquo;pediatric-type\u0026rdquo; and matched with pedHGG_RTK1a (n\u0026thinsp;=\u0026thinsp;2, 6.1%). Interestingly, we found a better survival in HGG-E than pedHGG_RTK1a, which was different from a previous study[\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. Moreover, we found a better survival in \u0026ldquo;pediatric-type\u0026rdquo; classes compared to \u0026ldquo;adult-type\u0026rdquo; classes. Pereira \u003cem\u003eet al\u003c/em\u003e. in 2025, found that HGG-E and atypical mesenchymal classes were significantly associated with shorter OS in multivariate analyses[\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. They found no other DNA-methylation classes impacting significantly the survival of patients[\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. Korshunov \u003cem\u003eet al\u003c/em\u003e. in 2017, in a series of 87 pediatric patients with a glioblastoma, IDH- and H3-wildtype, identified the \u0026ldquo;pediatric-type\u0026rdquo; classes has an independent predictive factors of survival[\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. They found that pedHGG_RTK2 had a longer survival (median OS 44 months) than pedHGG_RTK1 (median OS 21 months). PedHGG_MYCN had the worst prognosis (median OS 14 months)[\u003cspan citationid=\"CR44\" class=\"CitationRef\"\u003e44\u003c/span\u003e]. Finally, five cases remained not subtyped after DNA-methylation analyses (n\u0026thinsp;=\u0026thinsp;5, 15.2%), which remained a higher rate compared to older adults[\u003cspan citationid=\"CR43\" class=\"CitationRef\"\u003e43\u003c/span\u003e]. All these cases had a good quality control and only one matched with High-grade astrocytoma with piloid features (HGAP) but with a low score (0.71). These results were probably due to the rarity of glioblastoma, IDH- and H3-wildtype in young adults with possibly new DNA-methylation classes requiring further analyses. Most of them had criteria for molecular glioblastoma (n\u0026thinsp;=\u0026thinsp;4/5, 80.0%), two cases had \u003cem\u003eMDM2/CDK4\u003c/em\u003e amplifications (and one with \u003cem\u003ePDGFRA\u003c/em\u003e amplification). No other molecular alterations were found after NGS.\u003c/p\u003e\u003cp\u003eHere, we identified 3 cases with DNA repair deficiency syndromes due to Lynch syndrome (n\u0026thinsp;=\u0026thinsp;1), Constitutional mismatch repair deficiency (CMMRD) (n\u0026thinsp;=\u0026thinsp;1) and \u003cem\u003ePOLE\u003c/em\u003e mutation (n\u0026thinsp;=\u0026thinsp;1). One of them was classified as pedHGG_RTK1a and the last two ones as HGG-E and represented a higher proportion of hypermutated glioblastomas (9.1%) compared to the rate in the adult population (1.6%)[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e]. Their identification is crucial since they can influence prognosis and treatment options, including the use of immunotherapy[\u003cspan citationid=\"CR45\" class=\"CitationRef\"\u003e45\u003c/span\u003e].\u003c/p\u003e\u003cp\u003eIn our study, we found no significant differences concerning \u003cem\u003eMGMT\u003c/em\u003e promoter methylation status between young adults and older adults. However, the \u003cem\u003eMGMT\u003c/em\u003e promoter methylation status had a significant impact on survival (PFS and OS) in older adults but not in young adults. Drexler \u003cem\u003eet al\u003c/em\u003e. reported a significant impact on survival of \u003cem\u003eMGMT\u003c/em\u003e promoter methylation status only for RTK1 and RTK2 classes but not for the Mesenchymal class [\u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e]. These results could suggest that the DNA-methylation classes had a stronger impact on survival than the \u003cem\u003eMGMT\u003c/em\u003e promoter methylation status in daily practice. Reuss \u003cem\u003eet al\u003c/em\u003e. in 2024 described a different \u003cem\u003eMGMT\u003c/em\u003e promoter methylation status between the different DNA methylation classes, which could also explained the survival differences between classes for patients mostly treated with alkylating chemotherapy[\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e].\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec17\" class=\"Section2\"\u003e\u003ch2\u003eGeneralizability\u003c/h2\u003e\u003cp\u003eThis cohort reflects real-life clinical management of young adults with a newly diagnosed glioblastoma, IDH- and H3-wildtype. This suggests proposing, whenever possible, surgery with a dedicated management maximizing the extent of resection followed by chemoradiotherapy protocol. As for other types of brain tumours, these patients should be referred to specialized neurosurgical teams to improve survival results. We describe the clinico-radio-histo-molecular and epigenetic profile of glioblastoma, IDH- and H3-wildtype, in young adults, which remain different from their pediatric and older counterparts.\u003c/p\u003e\u003c/div\u003e\u003cdiv id=\"Sec18\" class=\"Section2\"\u003e\u003ch2\u003eLimitations\u003c/h2\u003e\u003cp\u003eThe present results should be interpreted with caution given the retrospective, monocentric, and observational study design. For epigenetic classification and copy number profiling, we used two non-disclosed machine learning platforms, one of which is a commercial, proprietary product, which makes it currently impossible to replicate the study from raw data. The rarity of this condition, illustrated by the small number of young adults in a thousand-cases large cohort, limits the power of our multivariate analysis. The absence of patients aged 15 to 18 years is likely explained by the fact that some of these patients are referred to pediatric neurosurgeons, hence limiting the applicability of this study to the entire adolescent and young adult population and precluding its extension to the adolescent population. This can also be explained by the rarity of glioblastoma, IDH- and H3-wildtype, at this age, but also by treatment carried out in a pediatric neurosurgery department.\u003c/p\u003e\u003c/div\u003e"},{"header":"Conclusion","content":"\u003cp\u003eNewly diagnosed glioblastoma, IDH- and H3-wildtype, is a rare histo-molecular entity in young adults. Present findings support proposing maximal safe resection whenever possible, given the greater benefit of surgery in this subgroup, and suggests referring these patients to specialized neurosurgical centres to optimize outcomes. The distinct clinico-radiological, histo-molecular, and epigenetic landscape observed in young adults warrants further investigation to elucidate the biological factors underlying their differential prognosis and to guide age-adapted therapeutic strategies.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003ch2\u003eCompeting Interests\u003c/h2\u003e\u003cp\u003eThe authors have no relevant financial or non-financial interests to disclose.\u003c/p\u003e\u003c/p\u003e\u003ch2\u003eFunding\u003c/h2\u003e\u003cp\u003eThe authors declare that no funds, grants, or other support were received during the preparation of this manuscript.\u003c/p\u003e\u003ch2\u003eAuthor Contribution\u003c/h2\u003e\u003cp\u003eAll authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by Alexandre Roux, Arnault Tauziede-Espariat, Giorgia Antonia Simboli, and Johan Pallud. The first draft of the manuscript was written by Alexandre Roux and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\u003ch2\u003eAcknowledgement\u003c/h2\u003e\u003cp\u003eAlexandre Roux would like to thank the Nuovo-Soldati Foundation for Cancer Research, the Servier Institute and the Ligue contre le Cancer for their support. Alexandre Roux and Johan Pallud would like to thank Frédéric Dhermain for his help in retrieving follow-up data.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eLouis DN, Perry A, Wesseling P et al (2021) The 2021 WHO Classification of Tumors of the Central Nervous System: a summary. 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JCO Precis Oncol 7:e2200525. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1200/PO.22.00525\u003c/span\u003e\u003cspan address=\"10.1200/PO.22.00525\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"},{"header":"Tables","content":"\u003cp\u003eTable 1 and 2 are available in the Supplementary Files section.\u003c/p\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"journal-of-neuro-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"neon","sideBox":"Learn more about [Journal of Neuro-Oncology](https://www.springer.com/journal/11060)","snPcode":"11060","submissionUrl":"https://submission.nature.com/new-submission/11060/3","title":"Journal of Neuro-Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"Glioblastoma, IDH-wildtype, Neurosurgery, Neuro-oncology, Young adult, Epigenetic","lastPublishedDoi":"10.21203/rs.3.rs-7473307/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7473307/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cb\u003ePurpose.\u003c/b\u003e\u003c/p\u003e\u003cp\u003eGlioblastomas, IDH- and H3-wildtype in young adults is a rare and poorly known entity. We compared newly diagnosed glioblastomas, IDH- and H3-wildtype in young adults (18\u0026ndash;39 years) to those in adult patients (\u0026gt;\u0026thinsp;39 years).\u003c/p\u003e\u003cp\u003e\u003cb\u003eMethods.\u003c/b\u003e\u003c/p\u003e\u003cp\u003eWe performed an observational, retrospective, single-centre cohort study at a tertiary neurosurgical oncology centre between January 2006 and December 2022.\u003c/p\u003e\u003cp\u003e\u003cb\u003eResults.\u003c/b\u003e\u003c/p\u003e\u003cp\u003eWe included 1.139 adult patients with a newly diagnosed glioblastoma, IDH- and H3-wildtype. Young adults: 1) represent a small proportion of patients with glioblastoma, IDH- and H3-wildtype (n\u0026thinsp;=\u0026thinsp;33, 2.9%); 2) have a high rate of unclassified cases according to WHO criteria and epigenetics (n\u0026thinsp;=\u0026thinsp;10, 30.3%); 3) have a longer progression-free survival (p\u0026thinsp;=\u0026thinsp;0.003) and overall survival (p\u0026thinsp;=\u0026thinsp;0.001) and; 4) do not have higher surgically-related adverse event rates (p\u0026thinsp;=\u0026thinsp;0.198). Concerning young adults, surgical resection was associated with improved progression-free and overall survival (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001 and p\u0026thinsp;\u0026lt;\u0026thinsp;0.001, respectively). The DNA-methylation class significantly impacts the overall survival (p\u0026thinsp;=\u0026thinsp;0.028), however, the \u003cem\u003eMGMT\u003c/em\u003e methylation status is not significantly associated with either progression-free or overall survival (p\u0026thinsp;=\u0026thinsp;0.320 and p\u0026thinsp;=\u0026thinsp;0.639, respectively).\u003c/p\u003e\u003cp\u003e\u003cb\u003eConclusion.\u003c/b\u003e\u003c/p\u003e\u003cp\u003eGlioblastomas, IDH- and H3-wildtype is a rare histo-molecular subtype in young adults with a better prognosis than older adults. In young adults, DNA-methylation subtypes are different from their adult counterpart and had a significant impact on survival unlike \u003cem\u003eMGMT\u003c/em\u003e status. Given the rarity of glioblastoma IDH- and H3-wildtype in young adults, a dedicated management in specialized neurosurgical oncology centres is preferred. Further histo-molecular and epigenetic analyses are required to understand the differences in prognosis compared to adult patients.\u003c/p\u003e","manuscriptTitle":"Glioblastoma, IDH- and H3-wildtype in young adults: a rare condition with a distinct clinico-radio-histo-molecular and epigenetic landscape","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-09-08 10:19:58","doi":"10.21203/rs.3.rs-7473307/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"decision","content":"Revision requested","date":"2025-09-14T12:16:11+00:00","index":"","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-13T23:01:56+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-08T06:33:41+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-07T12:51:16+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-07T06:10:59+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-07T02:42:59+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"137610999703070331400466752193095837687","date":"2025-09-04T00:15:30+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"255983621652056195994090329403513587659","date":"2025-09-03T22:47:35+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"318081215062226182362296151420083414817","date":"2025-09-03T02:33:14+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-02T03:08:06+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"7873446330720008216244509021286427712","date":"2025-09-02T01:55:40+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"260706601807468805716915640002620391950","date":"2025-09-02T00:34:53+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"328302550384798725121073171919660380313","date":"2025-09-01T20:41:54+00:00","index":"hide","fulltext":""},{"type":"editorInvitedReview","content":"","date":"2025-09-01T13:57:33+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"66341362927998197182085198220344281379","date":"2025-09-01T12:04:27+00:00","index":"hide","fulltext":""},{"type":"reviewerAgreed","content":"9901115709174255489063812127002031176","date":"2025-08-29T13:58:42+00:00","index":"hide","fulltext":""},{"type":"reviewersInvited","content":"","date":"2025-08-28T12:48:41+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2025-08-28T12:26:41+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2025-08-28T12:25:43+00:00","index":"","fulltext":""},{"type":"submitted","content":"Journal of Neuro-Oncology","date":"2025-08-27T15:48:19+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"journal-of-neuro-oncology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"neon","sideBox":"Learn more about [Journal of Neuro-Oncology](https://www.springer.com/journal/11060)","snPcode":"11060","submissionUrl":"https://submission.nature.com/new-submission/11060/3","title":"Journal of Neuro-Oncology","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"em","reportingPortfolio":"Springer Hybrid","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"13b188c5-6c4b-47c4-a94e-a39ae2d02e2d","owner":[],"postedDate":"September 8th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[],"tags":[],"updatedAt":"2025-10-20T16:03:52+00:00","versionOfRecord":{"articleIdentity":"rs-7473307","link":"https://doi.org/10.1007/s11060-025-05246-z","journal":{"identity":"journal-of-neuro-oncology","isVorOnly":false,"title":"Journal of Neuro-Oncology"},"publishedOn":"2025-10-16 15:58:14","publishedOnDateReadable":"October 16th, 2025"},"versionCreatedAt":"2025-09-08 10:19:58","video":"","vorDoi":"10.1007/s11060-025-05246-z","vorDoiUrl":"https://doi.org/10.1007/s11060-025-05246-z","workflowStages":[]},"version":"v1","identity":"rs-7473307","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7473307","identity":"rs-7473307","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}