Activation of the kynurenine pathway predicts poor outcome in patients with clear cell renal cell carcinoma

To investigate the expression of the kynurenine (KYN) pathway components and the prognostic role of the KYN-to-tryptophan ratio (KTR) in a cohort of patients with clear cell renal cell carcinoma (ccRCC).

The expression of KYN pathway components was investigated by tissue microarray-based immunohistochemistry, indirect immunofluorescence, and confocal microscopy analysis in 100 ccRCC cases and 30 normal renal samples. The role of this pathway in sustaining cancer cell proliferation, migration, and chemoresistance was evaluated. In addition, tryptophan and KYN concentrations and their ratio were measured in serum of 195 patients with ccRCC using a sandwich enzyme-linked immunosorbent assay. The role of KTR as a prognostic factor for ccRCC cancer-specific survival (CSS) and progression-free survival (PFS) was assessed.

Tissue microarray-based immunohistochemistry and indirect immunofluorescence staining showed an increased signal for KYN pathway components in ccRCC. Kaplan-Meier curves showed significant differences in CSS and PFS among groups of patients with high vs. low KTR. In particular, patients with high KTR values had a 5-year survival rate of 76.9% as compared with 92.3% for subjects with low levels (P  < 0.0001). Similar findings were observed for PFS (72.8% vs. 96.8% at 5y). At multivariate analysis, KTR was an independent adverse prognostic factor for CSS (hazard ratio  = 1.24, P  =  0.001), and PFS (hazard ratio  =  1.14, P  =  0.001).

The involvement of the KYN pathway enzymes and catabolites in ccRCC occurs via both immune and nonimmune mechanisms. Our data suggest that KTR could serve as a marker of ccRCC aggressiveness and as a prognostic factor for CSS and PFS.

Urologic oncology. 2017 Mar 27 [Epub ahead of print]

Giuseppe Lucarelli, Monica Rutigliano, Matteo Ferro, Andrea Giglio, Angelica Intini, Francesco Triggiano, Silvano Palazzo, Margherita Gigante, Giuseppe Castellano, Elena Ranieri, Carlo Buonerba, Daniela Terracciano, Francesca Sanguedolce, Anna Napoli, Eugenio Maiorano, Franco Morelli, Pasquale Ditonno, Michele Battaglia

Department of Emergency and Organ Transplantation-Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy. Electronic address: ., Department of Emergency and Organ Transplantation-Urology, Andrology and Kidney Transplantation Unit, University of Bari, Bari, Italy., Department of Urology, European Institute of Oncology, Milan, Italy., Department of Emergency and Organ Transplantation-Nephrology, Dialysis and Transplantation Unit, University of Bari, Bari, Italy., Department of Medical and Surgical Sciences, Clinical Pathology Unit, University of Foggia, Foggia, Italy., Department of Clinical Medicine, Medical Oncology Unit, Federico II University, Naples, Italy., Department of Translational Medical Sciences, Federico II University, Naples, Italy., Department of Pathology, University of Foggia, Foggia, Italy., Department of Pathology, University of Bari, Bari, Italy., Casa Sollievo della Sofferenza Hospital, Medical Oncology Unit, San Giovanni Rotondo, Italy.

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