Jenkins, Robert B.

Isocitrate dehydrogenase (IDH)–mutant low-grade gliomas are slow-growing brain tumors that frequently progress to aggressive high-grade gliomas that have dismal outcomes. In a recent study, Wu and colleagues provide critical insights into the mechanisms underlying malignant progression by analyzing single-cell gene expression and chromatin accessibility across different tumor grades. Their findings support a two-phase model: In early stages, tumors are primarily driven by oligodendrocyte precursor–like cells and epigenetic alterations that silence tumor suppressors like CDKN2A and activate oncogenes such as PDGFRA. As the disease advances, the tumors become sustained by more proliferative neural precursor–like cells, in which genetic alterations, including PDGFRA, MYCN, and CDK4 amplifications and CDKN2A/B deletion, drive tumor progression. The study further highlights a dynamic regulation of IFN signaling during progression. In low-grade IDH-mutant gliomas, IFN responses are suppressed through epigenetic hypermethylation, which can be reversed with DNA methyltransferase 1 inhibitors or IDH inhibitors, leading to reactivation of the IFN pathway. In contrast, higher grade gliomas evade IFN signaling through genetic deletions of IFN genes. These findings emphasize a broader epigenetic-to-genetic shift in oncogenic regulation that drives glioma progression, provide a valuable framework for understanding the transition from indolent tumors to lethal malignancies, and have implications for therapy and clinical management.

Abstract Background Temozolomide (TMZ) treatment has demonstrated a variable impact on glioma prognosis. This study examines associations of survival with DNA repair gene germline polymorphisms among glioma patients who did and did not have TMZ treatment. Identifying genetic markers which sensitize tumor cells to TMZ could personalize therapy and improve outcomes. Methods We evaluated TMZ-related survival associations of pathogenic germline SNPs and genetically predicted transcript levels within 34 DNA repair genes among 1504 glioma patients from the University of California San Francisco Adult Glioma Study (UCSF AGS) and Mayo Clinic, whose diagnoses spanned pre- and post-TMZ eras within the major known glioma prognostic molecular subtypes. Results Among those who received TMZ, 5 SNPs were associated with overall survival, but not in those who did not receive TMZ. Only rs2308321-G, in MGMT, was associated with decreased survival (hazard ratio = 1.21, P = .019) for all glioma subtypes. Rs73191162-T (near UNG), rs13076508-C (near PARP3), rs7840433-A (near NEIL2), and rs3130618-A (near MSH5) were only associated with survival and TMZ treatment for certain subtypes, suggesting subtype-specific germline chemosensitization. Genetically predicted elevated expression of PNKP, compared to normal brain expression, was associated with markedly poor survival in TMZ-treated patients with isocitrate dehydrogenase (IDH)-mutant and 1p/19q non-codeleted gliomas (P = .015), with a median difference of over 70 months in overall survival times. Similarly, NEIL2 and TDG expressions were associated with altered TMZ-related survival only among certain subtypes. Conclusions Functional germline alterations within DNA repair genes were associated with TMZ sensitivity, measured by overall survival among adults with glioma. These variants should be evaluated in prospective analyses and functional studies.

Abstract Purpose: Current methods for glioma response assessment are limited. This study aimed to assess the technical and clinical feasibility of molecular profiling using longitudinal intracranial cerebrospinal fluid (CSF) from patients with gliomas. Experimental Design: Adults with gliomas underwent longitudinal intracranial CSF collection via Ommaya reservoirs or ventriculoperitoneal shunts. Cell-free DNA (cfDNA) was extracted and analyzed using PredicineCARE for cancer variant profiling and/or PredicineSCORE for low-pass whole-genome sequencing. Results: Five patients (two females and three males; median age, 40 years; range, 32–64 years) underwent longitudinal intracranial CSF collection via Ommaya reservoirs (n = 4) or ventriculoperitoneal shunts (n = 1). In total, 47 CSF samples were obtained (median volume, 4.00 mL; 0.5–5 mL). Forty-one samples (87.2%) yielded sufficient cfDNA for testing. Patient-specific tumor-associated variant allelic frequencies (VAF), and thus tumor fraction, decreased in pre- versus postchemoradiation samples, including through pseudoprogression. These also increased with radiographic progression in three patients, although identifying the time of definitive disease progression from MRIs was a significant limitation. In two patients with isocitrate dehydrogenase (IDH)–mutant gliomas, decreasing IDH1 VAF after resection and chemoradiation correlated with decreased CSF D-2-hydroxyglutarate levels (0.64× and 0.62×, respectively, for the first patient and 0.01× and 0.07× for the other patient), although D-2-hydroxyglutarate and IDH1 VAF were not concordant in one patient thereafter. Moreover, the copy-number burden decreased below the limit of quantification during treatment and increased above the limit at progression. Conclusions: Longitudinal intracranial CSF cfDNA can be obtained in patients with gliomas during their disease course. However, before deploying this technique, numerous questions and challenges should be answered.

Abstract BACKGROUND Both radiation and temozolomide (TMZ) have meaningful single-modality anti-tumor activity against low-grade gliomas. ECOG-ACRIN E3F05 tested whether combined therapy with radiation and temozolomide is more effective than radiation alone in patients with grade II gliomas. METHODS Patients with grade II gliomas (central pathology review performed post hoc), no prior radiation/chemotherapy, and either age > 40, uncontrolled symptoms/seizures, or progression after initial observation were randomized 1:1 to radiation 50.4 Gy alone in 28 fractions (Arm A) versus radiation 50.4 Gy with concomitant and 12 four-week cycles of post-radiation TMZ (Arm B). Randomization was stratified by 1p/19q codeletion status, age, KPS, pre-operative tumor diameter, and contrast enhancement. The primary endpoint was progression-free survival (PFS); overall survival (OS), quality of life, cognition, severe toxicities, and impact of codeletion status were secondary objectives. RESULTS The trial opened 1/09. Accrual was stopped in 1/14 after RTOG 9802 reported benefit from the addition of PCV chemotherapy to radiation in grade II gliomas. A total of 172 subjects were enrolled. Median age was 44 (range 19-78) and 54% male. 1p/19q codeletion was present in 44%. NCI CTCAE (version 4) grade 3+ toxicity was more common in participants treated with TMZ: thrombocytopenia (11%) and neutropenia (5%) versus none in the radiation alone arm. With a median follow-up of 117 months, OS was superior in Arm B (HR 0.54, 95% CI 0.31-0.95, stratified log-rank p value 0.03). OS HRs were 0.56 and 0.53 for subjects with and without 1p/19q codeleted tumors, respectively. PFS did not differ between Arms A and B (HR 0.76, 95% CI 0.44-1.28, p = 0.30). Five and ten-year OS were 78% and 70% in Arm B versus 70% and 47% in Arm A. CONCLUSION The addition of temozolomide to radiation improves overall survival in both co-deleted and non-co-deleted grade II gliomas.

Abstract Background Brain tumors represent a significant global health challenge, with rising incidence and mortality impacting individuals worldwide and contributing to cancer-related morbidity and mortality. In Africa, this burden is exacerbated by limited access to advanced diagnostics, treatment options, and multidisciplinary care, compounded by the absence of standardized cancer registration and tumor biobanking. The introduction of molecular diagnostics, as outlined in the 2021 World Health Organization central nervous system (CNS) tumor classification, adds complexity to brain tumor management, particularly in regions with scarce resources. Methods To address these issues, the Brain Tumor Consortium for Africa (BTCA) was established in 2023, bringing together experts to improve CNS tumor diagnosis, patient care, and research. The initial project, conducted via an electronic questionnaire, aimed to assess neuro-oncology capacity across Sub-Saharan Africa. Results The study revealed significant gaps, with a limited number of institutions incorporating molecular subtyping into their diagnostic algorithms. The consortium’s efforts focus on enhancing local data use, informing public policy, and promoting collaboration to advance neuro-oncology practices in Africa. By fostering a network enlisting the expertise of collaborators in the fields of neurosurgery, neurology, neuropathology, anatomic pathology, and medical and radiation oncology, the BTCA seeks to improve brain tumor management through better diagnostics, infrastructure, and policy advocacy. Future directions include expanding molecular diagnostic capabilities, standardizing brain tumor biobanking, enhancing data collection, and advocating for improved brain tumor care in national health agendas. Conclusions The BTCA represents a pioneering model of collaboration and innovation in addressing the unique challenges of brain tumor care in Africa.

Abstract Clinical management of IDH wildtype glioblastoma (GBM) and tumefactive multiple sclerosis (tMS) is drastically different. GBM requires maximal safe resection followed by chemoradiation, while tMS outcome is worsened by surgery and radiotherapy. Noninvasive methods are needed to help with accurate diagnosis of tumor and non-tumor etiologies. To develop an MRI-based classification model, tMS subjects diagnosed prior to January 1, 2020, were matched to tMS by age at diagnosis, sex, index MRI date, and 2D/3D acquisition. Inclusion criteria included one cm minimal lesion size and pre-operative post-contrast T1 and T2 images available for analysis. A 3D-DenseNet121 was used to develop a classification model using prespecified parameters: 650 epochs, batch size 16, learning rate 10-3, cross-entropy loss, and AdamW optimizer. The stopping rule was defined as three sequential differences in epoch cross-entropy loss <0.02. Models were developed using both T1gd and T2, as well as from only T1gd and only T2. Training included 220 subjects (110 GBM, 110 tMS). A 2-stage validation design was used, which included both retrospective and prospective cohorts. Stage 1 consisted of 272 retrospective GBM (diagnosed prior to January 1, 2020). Stage 2 consisted of 69 and 34 prospective (diagnosed after January 1, 2020) GBM and tMS, respectively. External validation on the 272 retrospective GBM demonstrated accuracy of 91%, 84%, and 78% for T1gd+T2, T1gd only, and T2 only, respectively. External validation on the 69 prospective GBM demonstrated an accuracy of 87%, 64%, and 67% for T1gd+T2, T1gd only, and T2 only, respectively. The 34 prospective tMS demonstrated accuracy of 76%, 76%, and 82% for T1gd+T2, T1gd only, and T2 only, respectively. This shows the feasibility of deep learning to aid in differential diagnosis of brain lesions. Future work entails the integration of germline variants into the classification model, including variants associated with the risk of glioma or MS.

Abstract Brain tumors constitute significant morbidity and mortality in sub-Saharan Africa (SSA). There is no previous large-scale effort focusing on brain tumor genetics in SSA. This project aims to map out the current neuro-oncology capacity in terms of workforce and available services in SSA. This is an ongoing online survey among a cross section of neuro-oncology practitioners spread across SSA countries to capture information on the distribution, number of available neuro-oncology care practitioners, capacity for neuropathology and molecular diagnosis, management of brain tumors, cancer registration, and tumor biobanking. The survey was disseminated by the Society for Neuro-oncology in SSA (SNOSSA). There were 83 respondents representing 15 countries and 52 health institutions: 46 tertiary, 4 secondary, 1 private and 1 other. Here, we present data on the 52 institutions. The prevalence of specialties was 87% neurosurgery, 75% anatomic pathology, 69% medical oncology, 64% neurology, 60% radiation oncology, and 39% neuropathology. For radiologic evaluation, 81% of institutions were reported to have both CT and MRI, 17% CT only, and one institution neither. For molecular testing, 46% have access to IHC or NGS testing, whereas 52% were reported to have neither. A neuro-oncology tumor board was reported at 58% of institutions. A general cancer registry is available in 64% of institutions, 31% have a brain tumor specific registry and 10% have a brain tumor biorepository. This study shows that SSA has substantial potential in neuro-oncology care practice capacity and facilities. Most significant gaps remain in areas such as neuropathology and molecular testing, which makes widespread implementation of the WHO 2021 diagnosis challenging. Understanding the prevalence of CNS tumor subtypes is also difficult due to low number of brain tumor registries and biobanks in SSA. The present findings reveal strategic opportunities, especially in neuropathology, tumor registries, biobanks, and infrastructure for IHC and NGS in SSA.

Abstract Most TERT promoter (TERTp) clinically relevant sequence variants in CNS tumors are the canonical C228T and C250T mutations. Non-canonical TERTp mutations have been reported mainly in non-CNS tumors. We describe 12 CNS tumors with non-canonical TERTp variants interpreted as clinically relevant. Using clinical targeted NGS panels (2020-2024), we detected c.-100_-79dup (n=2), c.-92_-91insGGCGGCCCCGCCCCTTCCTTTC (n=1), c.-118_-117insTCCCCGGCCCAGCCCCTTCCGGG (n=1), c.-123_-76dup (n=1), c.-110_-89dup (n=2), and c.-57A>C (n=5). Most cases had chromosomal microarray (n=11) and/or methylation array data analyzed using the NCI/Bethesda v.2 classifier (n=9). All non-canonical TERTp variants occurred at a variant allele frequency suggestive of somatic clonal origin (mean, 34%; range, 18-46), and in adults (mean age, 60 years; range, 36-88). Except for the c.-57A>C variant, all non-canonical TERTp variants occurred in tumors with histological and/or molecular diagnostic features of glioblastoma, IDH-wildtype (GBM), often epigenetically aligning to this tumor type. All five tested cases matched to superfamily glioblastoma (score ≥ 0.9), with three to class GBM_RTK_I (>0.9 in 2, 0.86 in 1) and two to GBM_RTK_II (>0.9). The size and sequence of such variants suggest that these may be functionally equivalent to canonical mutations or generate favorable TERTp activation motif conformations like previously reported activating duplications. The c.-57A>C variant is a well-established oncogenic mutation observed in other cancer types but has not been reported in CNS tumors. We describe five cases with the c.-57A>C variant: one GBM matching to methylation class GBM_MES_TYP (0.99); two oligodendroglioma, IDH-mutant and 1p/19q-codeleted, one of which had methylation data matching to class O_IDH (0.99); one diffuse glioma, IDH-mutant, which was partially 1p/19q-codeleted and matched to class O_IDH (0.99); and one anaplastic meningioma, aligning to superfamily meningioma (0.99)/MNG_MAL (0.79). Our findings show that non-canonical TERTp variants typically occur in tumor types that often harbor TERTp canonical mutations, expanding the spectrum of TERTp clinically relevant variants that are molecular biomarkers in CNS tumors.