Familial Glioma in a Father and Son: Integrated Genomic and Multi-compartment Proteomic Profiling

BACKGROUND/AIM: Genetic predisposition to glioblastoma multiforme (GBM) is rare and is often associated with syndromes such as Li-Fraumeni syndrome and neurofibromatosis. However, a subset of cases involves familial aggregation of glioma, and its molecular pathogenesis remains poorly understood. This study aimed to elucidate the proteomic and genomic profiles of familial glioma cases. CASE REPORT: A 60-year-old male (father) and his 35-year-old son presented with gliomas. Clinical histories, imaging, surgical procedures, and histological analyses were documented. Proteomic analysis of tissue, plasma-derived extracellular vesicles (EVs), and urine was performed, and a systems biology approach was used to compare molecular profiles. Computational evaluation and pathway analysis were performed. Gliomas were diagnosed according to World Health Organization (WHO) guidelines. The father was diagnosed with glioblastoma, isocitrate dehydrogenase (IDH)-wildtype, WHO grade 4, with an unmethylated O6-methylguanine-DNA methyltransferase (MGMT) promoter, whereas the son presented with astrocytoma, IDH-mutant, WHO grade 3, with a methylated MGMT promoter. Proteomic analysis identified 1,268 proteins, with approximately 200 differentially abundant proteins (DAPs) in each biological matrix. Pathway analysis highlighted patient-specific differences, including inflammatory markers and GBM-associated proteins, with particularly notable variation in urine samples, including glycoproteins. CONCLUSION: This study provides insight into proteomic differences between familial gliomas, showing that they can develop through distinct molecular profiles and pathogenic pathways despite a shared genetic background. Proteomic analysis across tissue, plasma-derived EVs, and urine revealed tumor-associated proteins that could serve as non-invasive biomarkers, capturing patient-specific molecular features that were less evident in plasma.