Prognostic Impact of Circulating Vitamin D and Genetic Variants in the Vitamin D Pathway in Glioblastoma

Background Vitamin D (VitD) signaling is implicated in cancer and immune regulation, but its role in glioblastoma (GBM) remains unclear. We investigated the prognostic impact of VitD levels, VDR expression, and polymorphisms in VitD-related genes in GBM. Methods Ninety GBM tumors (62 primary, 28 recurrent) were analyzed. Circulating 25-hydroxyvitamin D (25(OH)D) was measured in 54 cases; tumor VDR mRNA/protein, calcitriol, and CYP24A1/CYP27B1/CYP27A1 proteins were assessed. Whole-exome sequencing identified SNPs in VitD-pathway genes. Associations with overall (OS) and progression-free survival (PFS) were evaluated by Kaplan–Meier and Cox models. Transcriptomic profiles were explored by GSEA. Results Severe 25(OH)D deficiency (<10 ng/mL) was frequent (13 primary, 38.2%; 11, recurrent 55.0%). Patients with <10 ng/mL had significantly shorter OS than patients with higher levels (9 vs. 18 months; HR = 2.55, 95% CI 1.03–6.39, P = .045). High VDR protein was associated with longer PFS (13.1 vs. 4.7 months, P = .027). CYP27B1 variants rs4646536 and rs703842 were associated with shorter OS (∼9–11 vs. ∼23–24 months; P < .05), although statistical significance was attenuated after correction for multiple testing. Transcriptomic analysis showed that CYP27B1 wild-type tumors were enriched for immune-related programs (B/T/NK-cell cytotoxicity, interferon response, antigen presentation; FDR < 0.25), while SNP tumors displayed minimal activation, consistent with poorer outcomes. Conclusions Severe VitD deficiency (<10 ng/mL) and CYP27B1 variants (rs4646536, rs703842) were associated with poorer prognosis in GBM. These exploratory findings suggest that systemic VitD status and genetic variation in its metabolism may influence GBM progression and tumor–immune interactions, warranting validation in independent cohorts.