Genomic Landscape of CNS Tumors: A Multi-Platform Analysis

AIMS This study investigated the genomic landscape of Central Nervous System (CNS) cancers, linking molecular al- terations, tumor grade, and patient demographics to advance diagnostic and therapeutic approaches. METHODS A comprehensive molecular analysis was performed on 96 diverse CNS tumor samples. Next-generation se- quencing (NGS) identified SNVs, CNVs, TMB and gene fusions, while immunohistochemistry (IHC) assessed PD- L1 expression and MSI status. All data were integrated with WHO tumor grade and patient demographics (43% female, 57% male). RESULTS The most frequently altered genes across all CNS cancer subtypes were TP53 (43%), TERT (42%), DST (33%), IDH1 (28%), EGFR (21%), and PTEN (21%). Distinct genetic profiles were observed across different WHO grades. Grade 1 tumors (n=1) showed a mutation in NF1. Grade 2 tumors (n=7) were characterized by IDH1 (43%), TERT (29%), and EGFR (14%) alterations. Grade 3 tumors (n=14) frequently harboured IDH1 (57%), TP53 (43%), and TERT (21%) mutations. Grade 4 tumors (n=66) showed prevalent alterations in TERT (51%), EGFR (29%), TP53 (42%), and PTEN (29%). High-grade tumors (Grades 3 and 4) exhibited a higher frequency of TERT, TP53, and PTEN mutations compared to low-grade tumors (Grades 1 and 2). PD-L1 positivity was observed in only 8% (4/51) of evaluable cases, and only 9% (4/45) exhibited high TMB (≥10 mutations/mb). All 49 evaluable cases were microsatellite stable (MSS). CONCLUSION This comprehensive molecular characterization of CNS cancers reveals distinct genetic alterations linked to tu- mor grade and subtype. The differences in genetic landscapes between high- and low-grade tumors underscore the clinical value of molecular profiling, providing actionable insights for treatment strategies. The low PD-L1 positivity, low TMB, and MSS status observed in this cohort suggest limited efficacy of immune checkpoint in- hibitors, highlighting the urgent need to explore alternative therapeutic avenues, including targeted therapies tailored to the identified molecular markers.