The Translocator Protein (TSPO) Genetic Polymorphism A147T Is Associated with Worse Survival in Male Glioblastoma Patients

SIMPLE SUMMARY: The translocator protein 18 kDa (TSPO) gene is highly expressed in glioblastoma (GBM), the most common primary malignant brain tumor, which remains one of the most difficult tumors to treat. TSPO is located in the outer mitochondrial membrane and binds cholesterol through its C-terminal domain. One frequent single-nucleotide polymorphism (SNP) rs6971, which changes the alanine 147 into threonine (Ala147Thr), has been found in the C-terminal domain of the TSPO region and dramatically alters the affinity with which TSPO binds drug ligands. However, the potential association between the TSPO genetic variants and GBM clinical outcomes is not known. Here, we evaluated the effects of the Ala147Thr SNP localized in this TSPO region on biological, sex-specific, overall, and progression-free GBM survival. Our findings suggest an association between the TSPO rs6971 variant and adverse outcomes in male GBM patients but not in females. These findings also suggest that the TSPO rs6971 SNP could be used as a prognostic marker of survival in GBM patients. ABSTRACT: Glioblastoma (GBM) is the most common primary brain tumor in adults, with few available therapies and a five-year survival rate of 7.2%. Hence, strategies for improving GBM prognosis are urgently needed. The translocator protein 18kDa (TSPO) plays crucial roles in essential mitochondria-based physiological processes and is a validated biomarker of neuroinflammation, which is implicated in GBM progression. The TSPO gene has a germline single nucleotide polymorphism, rs6971, which is the most common SNP in the Caucasian population. High TSPO gene expression is associated with reduced survival in GBM patients; however, the relation between the most frequent TSPO genetic variant and GBM pathogenesis is not known. The present study retrospectively analyzed the correlation of the TSPO polymorphic variant rs6971 with overall and progression-free survival in GBM patients using three independent cohorts. TSPO rs6971 polymorphism was significantly associated with shorter overall survival and progression-free survival in male GBM patients but not in females in one large cohort of 441 patients. We observed similar trends in two other independent cohorts. These observations suggest that the TSPO rs6971 polymorphism could be a significant predictor of poor prognosis in GBM, with a potential for use as a prognosis biomarker in GBM patients. These results reveal for the first time a biological sex-specific relation between rs6971 TSPO polymorphism and GBM.