Genomic landscape of IDH-wild-type glioblastoma in a patient treated with TNF-alpha inhibitor: Implications for risk stratification and therapeutic decision-making

Background: TNF-alpha inhibitors, such as adalimumab, are widely used for autoimmune diseases, yet their long-term impact on tumorigenesis in genetically susceptible individuals remains unclear. Glioblastoma multiforme (GBM) is an aggressive IDH-wild-type tumor with well-defined molecular drivers, but genomic characterization of GBM arising in TNF-alpha inhibitor-treated patients remains extremely limited. We investigated the genomic profile of a GBM that developed after sequential methotrexate, sulfasalazine, adalimumab, and tofacitinib therapy to explore possible mechanistic links between immunomodulation and tumor evolution. Methods: Tumor tissue underwent immunohistochemistry, targeted next-generation sequencing, and copy-number analysis at two independent clinical laboratories. Genomic results were interpreted in the context of TNF-alpha pathway biology, tumor microenvironment (TME) interactions, and known molecular pathways associated with GBM progression. Results: The tumor demonstrated GFAP and OLIG positivity, Ki-67 of 45%, and strong p53 expression (>90%). Genomic profiling revealed hallmark alterations of IDH-wild-type GBM, including CDKN2A/B deletions, PTEN deletion, and TP53 mutation. Some unusual variants included a KDM6A frameshift variant, an unexpected ATRX mutation with uncertain pathogenicity, and PDPK1 loss. Notably, the tumor lacked a TERT promoter mutation-present in the majority of IDH-wild-type GBMs-suggesting alternative telomere-maintenance pathways. The combination of PTEN loss, TP53 mutation, and CDKN2A/B deletion indicated a highly aggressive molecular phenotype associated with immune evasion within the TME. Several altered pathways intersect with TNF-alpha signaling, raising the possibility of altered tumor-immune interactions under TNF-alpha blockade. Conclusions: This analysis identifies both canonical and atypical genomic alterations in a GBM arising after prolonged TNF-alpha-targeted therapy. The absence of a TERT promoter mutation and the presence of an unusual ATRX variant suggest a nonstandard evolutionary trajectory. Although causality cannot be established, the temporal association with TNF-alpha inhibitor exposure, combined with pathway overlap between TNF-alpha biology, PTEN/TP53 signaling, and immune regulation, warrants further investigation. These findings highlight the importance of genomic risk stratification and consideration of germline predisposition before initiating TNF-alpha inhibitors, as well as the need for systematic genomic profiling of tumors emerging during biologic therapy.