VHL gene mutations in renal cell carcinoma: role as a biomarker of disease outcome and drug efficacy

Abstract

The therapeutic landscape for renal cell carcinoma (RCC) has changed drastically over the past several years with the emergence of molecularly targeted therapies. With previous prognostic and predictive tools based on studies of patients treated with cytokine therapies, confirmation of these prior methods and discovery of new markers in this new era of targeted therapy are of great importance. Alteration of the von Hippel-Lindau gene (VHL) by mutation, loss of heterozygosity, and promoter methylation has been found to be important to RCC pathogenesis. In this review, we discuss the potential role of VHL mutation as a prognostic and predictive marker for RCC.

Figure 1

Under normal oxygen conditions (left side), the VHL protein forms a complex that exhibits E3 ubiqtuitin ligase complex activity, recognizing prolyl hydroxylated HIF-α and marking it with a polyubiquitin tail. The cellular proteasome recognizes and degrades polyubiquinated HIF-α. In the absence of functional VHL (right side), HIF-α accumulates and migrates to the nucleus where it joins with HIF-β and CBP to initiate transactivation of hypoxia inducible genes, leading to the characteristic phenotype of clear cell renal cell cancer (RCC).