The kynurenine pathway (KP) is responsible for majority of the TRP metabolism in the central nervous system, and in glioma patients, this pathway becomes highly deregulated. Therefore, we aimed at comprehensive expression analysis of all KP enzymes in different grades of astrocytoma patients and their correlation with clinical outcome.
Twenty nine astrocytoma patients and healthy controls (n = 20) were enrolled in this study. Patients were segregated into pilocytic (PA), diffuse (DA), anaplastic (AA) and glioblastoma multiforme (GBM). Transcriptional analysis of all KP key enzymes was evaluated by Real-time PCR. Ki-67 proliferation index was evaluated by immunohistochemistry.
We report the first comprehensive expression analysis of all KP enzymes in patients with different grades of astrocytoma. Our data revealed a significant correlation between tumor volume and relative mRNA expression levels of IDO-2 (n = 7, Spearman’s rho= 0.8571, P = 0.0137) and AFMID (n = 20, Spearman’s rho= 0.05805, P = 0.0073). One-way ANOVA analysis showed significantly higher mRNA expression levels of KMO in AA patients (P < 0.009). There was also a significant correlation of relative mRNA expression levels of various KP enzymes in PA, DA, AA and GBM patients in comparison to controls (P < 0.05). The mean of proliferation index of Ki-67 was significantly higher (P < 0.001) in GBM as compared to PA, DA and AA patients. ROC analysis suggested Ki-67 is substantially good determinant for predicting death in different grades of astrocytoma (AUC=0.812, 95% CI 0.64 to 0.97). Youden index showed Ki-67 cut-off (4.75) has sensitivity (0.88) and specificity (0.69) for predicting death. Logistic regression analysis showed significant association of Ki-67 with mortality (OR = 15.75, 95% CI 2.3 to 104.55, P = 0.004). Kaplan-Meier survival analysis showed significant less survival in patients with higher Ki-67 proliferative index.
This study provides an important insight of various kynurenine pathway (KP) enzymes and proliferation index of Ki-67 which correlates with clinical outcome and demonstrates the clinical relevance of KP enzymes in patients with different grades of astrocytoma.
Clinical trial identification
Legal entity responsible for the study
All India Institute of Medical Sciences (AIIMS), New Delhi, India.
Department of Science and Technology (DST), Government of India, New Delhi.
All authors have declared no conflicts of interest.