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

Balint Otvos,Matthew M Grabowski,Jill S Barnholtz Sloan,Tomás R Guilarte,Gino Cioffi,Katie M Troike,Arlet M Acanda De La Rocha,Kristin A Waite,Tyler J Alban,Diana J Azzam,Justin D Lathia

doi:10.3390/cancers13184525

Abstract

Simple SummaryThe 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.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.

Highlights

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and accounts for 14.5% of all primary brain and central nervous system (CNS) neoplasms [1]
We observed a significant increase in translocator protein 18kDa (TSPO) gene expression in GBM compared to that of non-tumor brain tissue (p < 0.001) (Figure 1A)
Taken together, our data provide evidence suggesting that the TSPO rs6971 gene variant may be a useful indicator of survival time in GBM patients, with the presence suggesting a poorer survival outlook in male patients

Summary

Introduction

Glioblastoma (GBM) is the most common primary malignant brain tumor in adults and accounts for 14.5% of all primary brain and central nervous system (CNS) neoplasms [1]. In the U.S, the incidence rate for GBM is 3.23 per 100,000 in the population, the highest for malignant tumors, and is 1.6 times higher in males than females [1]. The unfavorable prognosis for GBM can be attributed to numerous features, including the intra- and inter-heterogeneity and intrinsic cell plasticity [3], a high rate of invasion to the brain parenchyma, a hypoxic intratumoral environment [4], the presence of cancer stem cells that contribute to the treatment resistance and recurrence [5], and an immunosuppressive tumor state [6]. Increasing evidence suggests that mitochondrial dysfunction plays a key role in the pathogenic events of GBM due to their role as central regulators of cell metabolism, cell death, oxidative stress, invasion, and inflammation [7]

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