Decreased expression of CTR2 predicts poor prognosis of patients with clear cell renal cell carcinoma

Purpose: Clear cell renal cell carcinoma (ccRCC) is well known for its hypervascularity due to the Von Hippel-Lindau/hypoxia-inducible factor dysregulation. Recent findings suggested that copper transporter 2 (CTR2) is also associated with angiogenesis through copper׳s modulation of the hypoxia-inducible factor pathway. Our group thus explored the prognostic role of CTR2 in patients with ccRCC.

Materials and methods: A total of 331 patients with ccRCC who underwent nephrectomy were enrolled between February 2005 and June 2007 at a single institution. The median follow-up was 98.97 months (2.63-120.47mo). Patients׳ samples were collected and stained for CTR2 by immunohistochemistry. The staining intensity was analyzed quantitatively and defined as high/low expression using X-tile software. Stage, Size, Grade, and Necrosis score and University of California Los Angeles Integrated Staging System score were applied to stratify patients׳ risks. Survival analyses were performed through the Kaplan-Meier method and Cox proportional hazard model. After integrating tumoral CTR2 expression with other clinical parameters, 2 nomograms were generated for overall survival (OS) and disease-free survival (DFS) prediction.

Results: CTR2 expression in ccRCC was decreased compared with that in the peritumoral tissue (P<0.001) and negatively correlated with many other clinical parameters. In survival analyses using the Kaplan-Meier method, low tumoral CTR2 expression displayed a dismal prognostic effect both in OS and DFS prediction (P<0.001). Multivariate analyses also revealed the same result after adjusted with other clinical parameters (P<0.001). Stratifying patients into 3 risk levels using the Stage, Size, Grade, and Necrosis score and University of California Los Angeles Integrated Staging System score, decreased CTR2 expression associated with shorter OS and DFS in the low- and intermediate-risk groups. Moreover, the generated nomogram integrating tumoral CTR2 expression performed better in predicting patients׳ OS than using TNM stages alone (c-index = 0.799; 95% CI: 0.752-0.846 vs. 0.691; 95% CI: 0.637-0.745).

Conclusions: CTR2 is a novel prognostic marker for patients with ccRCC both in OS and DFS prediction, and could be incorporated with other clinical parameters for better patient risk stratification.