PATH-01. MOLECULAR PROFILING OF PAEDIATRIC CENTRAL NERVOUS SYSTEM TUMOURS IN AUSTRALASIA – AN UPDATE ON THE AIM BRAIN AND MNP2.0 PROJECTS

Central nervous system (CNS) tumours with BCOR (BCL-6 transcriptional corepressor) internal tandem duplication (ITD) have emerged as a new molecular entity in recent years [1]. This was first reported by Sturm et al. in a study of 323 patients with CNS tumours, where this type of tumour was named 'high-grade neuroepithelial tumour with BCOR ITD' (HGNET BCOR ITD) [2]. In the fifth edition of the WHO classification of CNS tumours, it is now defined as 'a malignant CNS tumour characterized by a predominantly solid growth pattern, uniform oval or spindle-shaped cells with a dense capillary network and focal pseudorosette formation, and an ITD in exon 15 of the BCOR gene'. However, the complete clinicopathological and molecular features, as well as the ideal treatment and prognosis, have not been fully elucidated. Furthermore, in addition to BCOR-ITD, other BCOR gene variants, such as EP300::BCOR [3, 4] and BCOR::CREBBP [5] fusion, have recently been reported, broadening the genetic alteration spectrum for this entity. To date, this tumour has been mainly reported in children and infants, cases in adults are rarely reported and less understood. However, we have recently encountered two cases of adult HGNET harbouring the fusion of EP300::BCOR. Clinical, histopathological and immunohistochemical (IHC) features of both cases were investigated. Comprehensive molecular analyses were conducted, including methylation profiling, Sanger sequencing, targeted next-generation sequencing (NGS) and reverse transcription-polymerase chain reaction (RT-PCR). Both cases exhibited similar imaging and pathological characteristics, and in addition to BCOR gene fusions, deep sequencing revealed other genetic variations that may have significant clinical implications for HGNETs with BCOR fusions. The first patient (Case 1), a previously healthy, 54-year-old male, was asymptomatic and discovered to have a mass in the right frontal lobe during a physical examination 5 days prior. Magnetic resonance imaging (MRI) revealed a large mass with clear boundaries in the right frontal lobe, showing nodular enhancement signals within the tumour and a shift towards the left side of the midline(Figure 1A). Case 1 underwent a total resection, followed by radiation therapy (6000 cGy) and adjuvant temozolomide therapy. At the 16-month follow-up, there were no signs of tumour recurrence. The pathological examination of Case 1 revealed a predominantly ependymoma-like pattern, characterized by abundant perivascular pseudorosettes, where the tumour cells formed a nuclear-free zone around the blood vessels (Figure 1B). The tumour had a well-circumscribed border with sharp demarcation from the adjacent brain tissue. In some areas, short-fascicular or ribbon patterns were observed, and extensive calcified foci were also present (Figure 1D,E). The tumour exhibited high cellularity, nuclear atypia and increased mitosis in some regions (Figure 1C). Immunohistochemical staining showed that the tumour cells were mostly negative for GFAP and S-100, but focally positive for Olig2. Epithelial membrane antigen (EMA) staining revealed faint granular cytoplasmic stain, and Ki-67 was focally up to 30%. Other immunohistochemical markers showed that the tumour cells were diffusely positive for vimentin, CD56 and EGFR; partially positive for SATB2; sporadically positive for NeuN; and negative for BCOR, IDH1R132H and BRAF V600E (VE1) (Figure 1F,G). It was difficult to get an exact diagnosis based on the above results, so a methylation profiling was performed using the EPIC 850k BeadChip array (Illumina, San Diego, CA). By comparing the methylation profile with the selected reference cases from the published cohort (GSE109381) of 2801 previously published CNS tumours [6], this sample was invariably clustered together with the reference methylation class 'CNS tumour with BCOR internal tandem duplication' by unsupervised hierarchical clustering analysis (Figure 1H) and t-SNE analysis (Figure 1I). Methylation-based copy number profiling revealed gains in chromosomes 1q, 5 and 7; more importantly, we observed the chromosome 22q12.31 deletion, where EP300 is located, as previously described by Aldape et al. [7] (Figure 1J). In this case, however, Sanger sequencing did not identify any BCOR-ITD at exon 15. Several months later, we encountered the second patient (Case 2), a 43-year-old female who had been experiencing headaches for 10 days. Her headaches were associated with changes in posture, with pain occurring when lying flat but not when standing. MRI revealed a large, nodular demarcated and heterogeneous mass in the right frontotemporal lobe with an obvious mass effect (Figure 2A). Near-total resection of the lesion was achieved, and the patient received radiation therapy (5200 cGy) supplemented with adjuvant chemotherapy postoperatively. The patient had no signs of tumour progression at the 8-month follow-up. Histologically, Case 2 exhibited diverse appearances with a higher cellularity than Case 1. In some areas, the tumour cells were spindle or ovoid and densely arranged in sheets with branching capillary network (Figure 2B). The local area showed a high-grade ependymoma-like structure dominated by pseudo-rosettes, as well as Homer Wright rosettes with brisk mitosis (Figure 2C). Palisading necrosis was easily observed (Figure 2D), and microcyst structures and calcifications were frequently present (Figure 2E). Immunohistochemical analysis revealed that the tumour cells were diffusely and strongly positive for vimentin, CD56 and SATB2, weakly positive for BCOR, and focally positive for NeuN and Olig2 (Figure 2F–I). In contrast, staining for GFAP and S-100 was completely negative in Case 2. However, the amount of tumour tissue from Case 2 was insufficient for methylation testing after NGS detection. Targeted NGS results: the DNA-based and RNA-based NGS analyses were used to profile the two samples. In Case 1, the EP300::BCOR fusion was identified at both DNA and RNA levels with breakpoints located in exon 31 of EP300 and exon 6 of BCOR. Additionally, Case 1 showed a BCOR::L3MBTL2 fusion only at the RNA level with breakpoints in exon 4 of BCOR and exon 2 of L3MBTL2. No other genetic alterations were identified in this case. In Case 2, the EP300::BCOR fusion was also identified at both DNA and RNA levels with breakpoints in exon 31 of EP300 and exon 4 of BCOR. Furthermore, additional molecular alterations in Case 2 included a TP53 p.R273C missense mutation, a NOTCH3 p.G37E point mutation and PDGFRA amplification at the DNA level, as well as a PDGFRA (exon 9) and FIP1L1 (exon 4) fusion at the RNA level. The graphical depiction of the BCOR fusion products for both cases is shown in Figures 1K,I and 2J. RT-PCR was performed to further validate all BCOR fusion transcripts mentioned above. Agarose electrophoresis and Sanger sequencing of the amplified products confirmed the presence of the breakpoints detected by RNA-seq (Figures 1M and 2K). No BCOR-ITD was detected in either sample. The two adult cases exhibited comparable radiological and pathologic characteristics that are consistent with those of CNS HGNET-BCOR tumours documented in the literature. Many cases reported in the literatures were located supratentorialy and showed diverse histologic features including ependymoma-like, oligodendroglioma-like or glioblastoma-like [3, 7]. They often demonstrated a low-grade morphology with high-grade transformation [4]. The IHC characteristics of BCOR-fusion tumours were variable. Tumour cells were reported to be immunopositive for Olig2, GFAP, NeuN, EMA, EGFR or beta-catenin, possibly suggesting a potential for multidiretional differentiation [3-5]. Although BCOR IHC staining can be helpful, it often does not correspond with genetic tests. Therefore, methylation profiling combined with NGS detection could significantly enhance the diagnostic accuracy. Recently, Aldape et al. published a retrospective study of gliomas with EP300 and BCOR gene fusions [7]. Their study profiled 21 patients with CNS tumours harbouring BCOR fusions (11 with the EP300 gene, 10 with other or undetermined genes). The median age was 30 years, and 71% of the tumours were well-defined (10 were supratentorial and 5 were in the posterior fossa). Recurring histologic appearances included perivascular pseudorosettes, myxoid changes, calcifications or branching capillary networks. The authors noted a partially overlapping methylation profile between the BCOR-fusion group and the ITD group. They also reported that the median PFS for BCOR-fusion tumours was 45 months, which is favourable compared to the BCOR-ITD tumours [8]. Our two reported cases provide additional evidence for this type of tumour, which may have been underestimated in adults previously. According to our NGS detecting results, besides of fusions of EP300::BCOR, Case 1 also showed a fusion of BCOR::L3MBTL2, which has been previously reported as a confirmed somatic mutation in a 24-year-old female patient diagnosed with high-grade IDH-wild-type glioma [5]. Simultaneous detection of BCOR::L3MBTL2 and EP300::BCOR fusion was also reported in a female patient with uterine sarcoma, which showed moderate nuclear atypia, active mitosis and abundant vascular components [9]. The fusion of FIP1L1::PDGFRA in Case 2 may hold significance for targeted therapy. Previous studies have shown that the FIP1L1-PDGFRA fusion gene is a crucial oncogenic driver of chronic eosinophilic leukemia, which can be effectively targeted by tyrosine kinase inhibitors like imatinib, sunitinib or sorafenib [10]. Treatment with these drugs has resulted in rapid complete remission for patients. Therefore, if the tumour in Case 2 recurs in the future, drugs such as imatinib could be considered as a potential treatment option. In conclusion, BCOR fusion tumours may be distinguished from BCOR-ITD tumours of the CNS by older age, greater glial differentiation, an ependymoma-like appearance and a higher likelihood of a better prognosis. Further studies of additional cases are strongly needed to precisely characterize the classification of CNS tumours with BCOR alterations. With the help of effective molecular assays such as methylation profiling and NGS analysis, an increasing number of adult BCOR fusion tumours may be detected. Data sharing is not applicable to this article as no new data were created or analyzed in this study.

e14035 Background: Whole genome CpG DNA methylation profiling is proving to be an extremely valuable tool in the diagnostic and prognostic classification of central nervous system (CNS) tumors, and is especially adept at discriminating between very different tumors, or tumor subtypes, that are histologically similar. However, like any bulk assay, reliability of methylation-based classification depends on sufficient tumor cellularity, as admixed nonneoplastic elements (e.g., neurons, glial cells, inflammatory cells) have their own unique methylation profiles, and thus can skew the results. Currently, it is recommended that at least 70% of the analyzed specimen be tumor; however, this is based on subjective estimates from light microscopy. Many neoplastic entities have well-known driver mutations that occur in virtually 100% of tumor cells, and next-generation sequencing (NGS) assays can detect those mutations and report their relative amounts in the form of Variant Allelic Fraction (VAF). Since NGS and methylation profiling are now frequently being done on the same tumor block, we sought to determine whether driver mutation VAF affects the accuracy of methylation profiling, and whether VAF can help establish more rigorous cutoffs for quality assurance. Methods: Using NGS and Infinium Epic850K methylation arrays, we evaluated 62 CNS neoplasms representing a range of entities, including TERT promoter-mutant glioblastoma, IDH-mutant astrocytoma, IDH-mutant oligodendroglioma, SHH-driven medulloblastoma, and CTNNB1-driven adamantinomatous craniopharyngioma. Results: VAFs of each driver mutation ranged between 1-60%. Forty-four of 62 cases (71%) had a methylation classification score ≥0.9, the most widely accepted cutoff for a successful result. A fit-of-mixture analysis via CutoffFinder (PMID: 23251644) suggested that the optimal VAF cutoff is 21%. Forty-one of 46 (89%) cases with a VAF of 21% or higher had a methylation classification score ≥0.9, whereas only 3/16 (19%) at or below 21% were classifiable with methylation profiling ( P< 0.0001 by Fisher’s exact test). Nonlinear regression of VAF versus methylation score by least squares fit produced R2= 0.54, with sum of squares = 2.0. Conclusions: These data indicate that VAF can serve as a useful predictor of classification success via methylation profiling, and should be taken into account when interpreting methylation profiling results.

Background Central nervous system (CNS) tumors are the leading cause of cancer-related deaths in children aged 0–14 years. Despite significant efforts, targeted therapies based on identified pathways have not improved survival rates. Research has shown that the gut microbiota (GM) can influence brain tumor cell proliferation, suggesting that the microbiota–gut–brain axis plays a role in CNS cancer. Our study aims to assess whether the GM composition in pediatric CNS tumors exhibits specific characteristics. Methods The study included 18 pediatric patients, 9 diagnosed with CNS tumors (CNS tumors group) and 9 with other tumor types (extra-CNS tumors group). Microbial DNA was extracted from stool samples, and 16S DNA libraries were generated and sequenced. GM composition was analyzed using amplicon sequence variant (ASV) tables. Results Alpha-diversity analysis, represented by the number of observed features, was lower in the CNS tumors group (P = .0054), while Pielou’s evenness index was similar between groups. LEfSe analysis revealed a significantly reduced abundance of the Firmicutes phylum in CNS tumors group, along with other taxa within this phylum, such as the Clostridia class, Clostridiales order, and Lachnospiraceae family, compared to extra-CNS tumors group. Further analysis using sPLS-DA showed a distinct pattern in GM composition in the CNS tumors group, with lower levels of several taxa, particularly the Firmicutes phylum, Lachnospiraceae family, Clostridiales order, Clostridia class, Ruminococcaceae and Coriobacteriaceae families, and Blautia genus. Conclusions Pediatric patients with CNS tumors have a distinct GM composition. The reduction of specific beneficial microbial taxa may contribute to tumor growth through the microbiota–gut–brain axis.

The Central Brain Tumor Registry of the United States (CBTRUS), in collaboration with the Centers for Disease Control (CDC) and National Cancer Institute (NCI), is the largest population-based registry focused exclusively on primary brain and other central nervous system (CNS) tumors in the United States (US) and represents the entire US population. This report contains the most up-to-date population-based data on primary brain tumors (malignant and non-malignant) and supersedes all previous CBTRUS reports in terms of completeness and accuracy. All rates (incidence and mortality) are age-adjusted using the 2000 US standard population and presented per 100,000 population. The average annual age-adjusted incidence rate (AAAIR) of all malignant and non-malignant brain and other CNS tumors was 23.79 (Malignant AAAIR=7.08, non-Malignant AAAIR=16.71). This rate was higher in females compared to males (26.31 versus 21.09), Blacks compared to Whites (23.88 versus 23.83), and non-Hispanics compared to Hispanics (24.23 versus 21.48). The most commonly occurring malignant brain and other CNS tumor was glioblastoma (14.5% of all tumors), and the most common non-malignant tumor was meningioma (38.3% of all tumors). Glioblastoma was more common in males, and meningioma was more common in females. In children and adolescents (age 0-19 years), the incidence rate of all primary brain and other CNS tumors was 6.14. An estimated 83,830 new cases of malignant and non-malignant brain and other CNS tumors are expected to be diagnosed in the US in 2020 (24,970 malignant and 58,860 non-malignant). There were 81,246 deaths attributed to malignant brain and other CNS tumors between 2013 and 2017. This represents an average annual mortality rate of 4.42. The 5-year relative survival rate following diagnosis of a malignant brain and other CNS tumor was 23.5% and for a non-malignant brain and other CNS tumor was 82.4%.

Blank wordt nooit gezien als een etnische groep, terwijl het dat wel is. Deze scriptie onderzoekt hoe blanke etniciteit wordt gerepresenteerd in films van blanke en zwarte filmmakers.

Genome-wide DNA methylation signatures correlate with and distinguish central nervous system (CNS) tumor types. Since the publication of the initial CNS tumor DNA methylation classifier in 2018, this platform has been increasingly used as a diagnostic tool for CNS tumors, with multiple studies showing the value and utility of DNA methylation-based classification of CNS tumors. A Consortium to Inform Molecular and Practical Approaches to CNS Tumor Taxonomy (cIMPACT-NOW) Working Group was therefore convened to describe the current state of the field and to provide advice based on lessons learned to date. Here, we provide recommendations for the use of DNA methylation-based classification in CNS tumor diagnostics, emphasizing the attributes and limitations of the modality. We emphasize that the methylation classifier is one diagnostic tool to be used alongside previously established diagnostic tools in a fully integrated fashion. In addition, we provide examples of the inclusion of DNA methylation data within the layered diagnostic reporting format endorsed by the World Health Organization (WHO) and the International Collaboration on Cancer Reporting. We emphasize the need for backward compatibility of future platforms to enable accumulated data to be compatible with new versions of the array. Finally, we outline the specific connections between methylation classes and CNS WHO tumor types to aid in the interpretation of classifier results. It is hoped that this update will assist the neuro-oncology community in the interpretation of DNA methylation classifier results to facilitate the accurate diagnosis of CNS tumors and thereby help guide patient management.

Background A brain dead donor caused by central nervous system (CNS) tumor is generally included in the donor category for organ transplantation, but it is done in a selective way to prevent possible risk of cancer transmission through donation. In order to evaluate the possibility of tumor transmission from donor with CNS tumor, we reviewed and analyzed 91 recipients from 28 donors with CNS tumor retrospectively. Methods From January 1, 2005 to December 31, 2014, 28 donors with CNS tumor and 91 recipients who received solid organs from these donors were included. Based on KONOS donor data registry, we conducted donors and recipients survey at the hospitals where transplantation had been done. Results Twentyone donors were categorized into four histologic grades by WHO except 7 donors who has no detailed report of CNS tumor classification. Among them, 11 donors were grouped in grade I tumor (52.4%), and 3 were in group II(14.3%), 4 in grade III(19.0%) and 3 in grade IV(14.3%). According to high risk categories defined by the malignancy subcommittee of DTAC committee, intracranial surgery were done in 11 donors, chemo-radiotherapy in 2 patients, and 3 patients had chemo-radiotherapy after surgery. Therefore, 76.2% of those donors were in the highrisk category. A total of 91 transplants (25 livers, 52 kidneys, 7 hearts, 3 lungs, and 4 multi-organ transplants) were performed from donors with CNS tumors, and 85 recipients were finally analyzed after excluding 6 recipients whose current status were not confirmed. Of the 85 recipients, 14 were dead, of which 11 recipients were not associated with brain tumor as a death cause, and remaining 3 recipients, causes of death were unable to identify. However, there were 7 recipients who developed tumor after transplantation. One of them them recurred original recipient tumor (HCC) and remained 6 patients were diagnosed as non-CNS tumor (renal cell carcinoma, carcinoma in situ of cervix, B cell lymphoma, thyroid ca., kaposi’s sarcoma and colon ca). Conclusion Even though the possibility of tumor transmission from donor with CNS tumor is rare, we still have to focus de novo malignancy incidence after transplantation. So we need more precise post-transplant evaluation to detect de novo malignancy in recipients who has organs from CNS tumor.

The Neuropathology Study Group of the Korean Society of Pathologists conducted a nationwide collection of central nervous system (CNS) tumors to evaluate the relative frequency in Korea of CNS tumors belonging to the revised World Health Organization (WHO) classification categories. A total of 3221 histologically proven cases of CNS tumors were collected from 13 institutes between 1997 and 1998. All the cases were classified according to the revised WHO histological types and analyzed for the relative frequency, the distribution of age and sex, and location of tumors. The most frequent type of CNS tumors in Korea was meningiomas, followed by pituitary adenoma, glioblastoma, astrocytoma, and schwannoma. Among the pediatric CNS tumors, pilocytic astrocytoma, medulloblastoma, craniopharyngioma, germ cell tumors, and ependymomas were common types of tumors. Compared with a previous nationwide study, the rates for neuronal/glial tumors, glioblastoma, malignant lymphoma, and cystic lesion were increased, and the rate of embryonal tumors was decreased. The overall male to female ratio was 0.9: 1, which may be attributed to the greater number of female-predominate meningiomas and pituitary adenoma. Compared with Western countries, Koreans had higher rates of pituitary adenoma and meningiomas and lower rate of gliomas. The relative frequency of CNS tumors among Koreans is very similar to that reported in Taiwan. The occurrence rates for various subtypes of CNS tumors in Korea are distinct from those in the United States and Europe and similar in many ways to those in Asian and Mexican population.

Objective: To investigate the relationship between mast cells (MCs) and different central nervous system (CNS) tumors. Methods: It was a comparative immunohistochemical study to investigate the presence, number, and location of MCs in pilocytic astrocytomas, glioblastoma, medulloblastoma, ependymoma, meningioma, and immature and mature teratomas. Means, medians, and standard deviation were obtained. Comparation in the number of MCs in the different tumors was carried out using the Mann-Whitney test (p < 0.05). Results: There was a significant difference in the number of MCs between pilocytic astrocytoma (X = 0), and mature teratoma (X = 65), in relation to the other neoplasms (X = 3-11.4). MCs were identified in meningeal lining in meningiomas, in the perivascular space in ependymomas and in the tumor stroma and perivascular space in the rest of the tumors analyzed. Conclusions: MCs appear to play different roles in CNS tumors. Its absence in pilocytic astrocytomas and its presence in glioblastomas suggests a role in the latter, probably related to angiogenesis. The maximum number of MCs was observed in mature teratomas, specifically in relation to stratified squamous epithelium, possibly in relation to trophic factors that contribute to epithelial renewal and maintenance. These findings call for future research to determine if MCs can be a therapeutic target or are important as a prognostic factor.

Background: SETD2 is a tumor suppressor gene responsible for trimethylation of H3K36, crucial for DNA mismatch repair and homologous recombination. Novel synthetic lethality agents, ATR inhibitors (ATRi), have demonstrated anti-tumor activity in preclinical models and early clinical trials for pan-tumors. SETD2 and H3K36 deficient cells have been demonstrated to display Micro Satellite Instability (MSI) with increased tumor mutational burden (TMB). Deleterious SETD2 alterations occur in 5-10% of brain tumor patients with glioblastoma, IDH wild type, WHO grade 4, (GBM). These patients have a poor prognosis. This study aims to evaluate targeted treatment strategies in central nervous system (CNS) tumors, by investigating the potential of ATRi for tumors harboring deleterious SETD2 alterations and immuno-therapy for tumors with increased mutational burden, with the objective of improving patient outcomes. Materials &amp; methods: This study analyzes genomic profiles from 434 patients diagnosed with central nervous system (CNS) tumors between January 1st, 2019, and February 28th, 2025, enrolled in the prospective Neurogenome and CoPPO studies. Rigshospitalet has one of the largest single-institution datasets with comprehensive data on SETD2 alterations derived from whole exome/genome sequencing including structural variants, copy number variations, and RNA expression. Results: The study cohort included 434 patients with CNS tumors (166 female, 268 male) with a median age at diagnosis of 59 years (interquartile range: 49-66 years). GBM was the predominant tumor type (86%), followed by astrocytoma, IDH mutated (mut), WHO grade 2-4 (12%) and oligodendroglioma, IDH-mut, 1p/19q co-deletion, WHO-grade 2-3 (1.2%). Other CNS tumors were diagnosed in 6 (1.4%) patients. Deleterious SETD2 alterations were found in 13 (3%) patients: 11 with GBM, 1 astrocytoma IDH mut, and 1 oligodendroglioma. Twelve patients had mutations: 6 premature stop codons, 5 frameshift mutations and 1 splice site variant, and one case with biallelic SETD2 loss. Data on tumor mutational burden (TMB) was assessable for 12 SETD2-deficient patients, none exceeding 10mut/mb; mean TMB was 3.3 mut/mb vs. 6.2 mut/mb in the SETD2-wildtype (wt) group. No SETD2-deficient patients had received temozolomide (TMZ) treatment prior to sampling. By contrast, some samples in the SETD2-wt cohort were obtained at relapse, which may have inflated TMB due to TMZ treatment. COSMIC signatures were available for 10 SETD2-deficient patients with none having indications of MSI based on COSMIC signature evaluation. Conclusion: Loss of SETD2 function in primary CNS-tumors is relatively rare and was predominantly driven by mutations, with copy number analysis revealing only 1 biallelic deletion in 434 patients. SETD2 alterations was primarily seen in GBM patients. The SETD2 deficient patients did not exhibit indications of MSI or high TMB. However, the impact of patient relapse samples with TMZ induced mutations in the SETD2-wt cohort is being explored further together with pan-tumor markers for DNA damage repair. Citation Format: Tine Østergaard, Christoffer L. Halvorsen, Dorte S. Nørøxe, Vincent N. Fougner, Iben Spanggaard, Kristoffer S. Rohrberg, Martin Højgaard. Comprehensive genomic profiling in central nervous system tumors reveals low frequency of deleterious alterations in SETD2 without associated increase in mutational burden [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr C037.

BACKGROUND Central nervous system (CNS) tumors exhibit significant racial disparities, with recent studies showing distinct distributions among molecularly classified CNS tumors. African Americans are overrepresented in pituitary adenomas (35%) while underrepresented in IDH wild-type glioblastoma (3% vs. 90% in Caucasians), suggesting ethnic factors contribute to tumor development. However, current large-scale databases including SEER, CBTRUS lack ethnicity annotation with current WHO molecular classification. This prevents analysis of ethnic disparities across the &amp;gt;100 molecularly distinct CNS tumor entities now recognized, representing a critical gap in understanding tumor predisposition and developing precision medicine approaches. METHODS We developed a machine learning classifier to predict ethnic backgrounds of CNS tumor samples using DNA methylation arrays, the same data used for molecular classification. The classifier was trained on an ethnically heterogeneous public dataset comprising healthy blood and brain tumor samples, and will be calibrated on a separate brain tumor dataset to ensure accurate performance for CNS tumor samples. RESULTS Our classifier demonstrated excellent validation performance with log loss of 0.188 and mean AUROC of 0.995 across ethnic groups. Individual performance showed consistently high AUROC (African American = 0.995, Caucasian = 0.994, East Asian/Asian American = 0.998, Hispanic/Latino/South American = 0.993). Mean Brier scores were low at 0.023 overall, indicating good calibration across ethnic groups (African American = 0.012, Caucasian = 0.038, East Asian/Asian American = 0.013, Hispanic/Latino/South American = 0.028). Following calibration, the classifier will be applied to over 150,000 CNS tumor samples to systematically analyze ethnic disparities across CNS tumor subtypes. CONCLUSIONS We developed an accurate ethnicity prediction tool that will enable large-scale analysis of ethnic disparities in molecularly classified CNS tumors. This addresses gaps in current epidemiological analyses and will provide insights into how ethnicity influences tumor biology and molecular classification patterns, potentially informing precision medicine approaches for diverse patient populations.

BackgroundSymptoms in children with incurable central nervous system (CNS) tumours are frequently managed with corticosteroids but 33% of children prescribed corticosteroids experience adverse effects and the overall effect on quality...

ABSTRACTPaediatric central nervous system (CNS) tumours are the second most common childhood malignancy and the leading cause of cancer‐related mortality in this age group. Histopathological diagnosis can be challenging, particularly for rare or ambiguous tumours, and may result in misclassification. To evaluate the utility of DNA methylation profiling in a middle‐income country, we performed the Infinium MethylationEPIC BeadChip (Illumina) on tumours from 182 paediatric patients treated at a reference centre for paediatric oncology in Campinas, state of São Paulo, Brazil. Data were analysed using the DKFZ/Heidelberg CNS tumour classifier (v12.8). After excluding control tissue, 163 samples (89.6%) were suitable for classification; 135 (74.2%) achieved a calibrated score ≥ 0.9 and were assigned to a methylation class family. Methylation profiling resulted in a tumour subtype for 88 cases (65.7%) and changed the diagnosis in 28 cases (20.9%), identifying several rare tumour subtypes that were identified solely through methylation analysis, confirming the value of this method in improving diagnostic accuracy. This study highlights the utility of DNA methylation profiling for paediatric CNS tumours in a resource‐limited setting and provides a cohort from an underrepresented middle‐income population to international molecular databases.

Introduction. The two-week wait (2WW) referral guideline for suspected central nervous system (CNS) tumours was implemented more than a decade ago to facilitate early cancer diagnosis with the aim of improving tumour survival rates. Short-term studies have shown poor compliance and low detection rates of the guideline. This study aimed to provide a decade analysis of referral patterns, and compliance and detection rates of the guideline. Methods. All patients referred via the 2WW pathway for suspected CNS tumour to the Newcastle Department of Neurosurgery from 1st January 2002 to 31st December 2011 were retrospectively identified from the local cancer registry. Data from referral letters, case notes, radiographic images and final outcomes were recorded. Trends in waiting time, time to diagnosis, compliance and detection rate of the guideline in identifying CNS tumours were analysed. Results. Over the last decade, there were no significant changes in trends in waiting time, time to diagnosis and compliance and detection rates of the guideline. Of 85 2WW referrals, 41.2% were non-compliant and 21.2% identified CNS tumours. The detection rate was higher in referrals that complied with the guideline compared to those that did not (32.0% vs 5.2%, p < 0.05). The non-compliant referrals which identified CNS tumours consisted of patients with cognitive decline. The guideline sensitivity and specificity were 88.8% (63.9%–98.1%, 95% CI) and 49.3% (40.0%–61.6%), respectively. Most of CNS tumour diagnoses were made independent of the 2WW pathway (N = 1093, 98.4%). Conclusion. There have not been any major changes in terms of waiting time, time to diagnosis, compliance and detection rates of the 2WW guideline during the last decade. The 2WW pathway generated very few referrals but among these, the positive detection rate was high and the addition of time-based cognitive decline onto the current guideline may further improve the detection rate.

(797) - Risk of Tumor Transmission After Thoracic Allograft Transplantation from Adult Donors with Central Nervous System Neoplasm-A UNOS Database Study