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The substantial improvement of treatment results in patients with disseminated forms of renal cell carcinoma (RCC) is associated with the active clinical application of target drugs that affect the molecular genetic mechanisms underlying the development of this disease. Inactivation of the VHL gene and/or the disorders related to other elements of the signaling pathway regulating the processes of proliferation and neoangionesis in tumor tissue (mammalian target of rapamycin; hypoxia-induced factor; vascular endothelial growth factor and its receptor; platelet-derived growth factor receptor; and carboanhydrase IX) are considered to be one of the early and key events in carcinogenesis in clear cell RCC. However, there is presently no consensus of opinion as the prognostic value of these disorders and their impact on the efficiency of drug therapy. The results of the clinical trials assessing potential molecular biological markers are discordant. This is attributable both to the dissimilar clinical characteristics of patients and different methodological approaches to evaluating these or those molecular impairments. There are also other alternative signaling pathways and mechanisms responsible for the formation of primary or secondary drug resistance when target agents are administered. Thus, the quest of potential biomarkers remains an urgent problem as before. This paper analyzes the results of the currently available clinical studies of the role of various biological markers in predicting the efficiency of the present-day medicinal approaches to treating patients with RCC.

Objective: to estimate the rate, predictive and prognostic value of VHL gene alterations in the population of patients with sporadic metastatic renal cell carcinoma (mRCC).Subjects and methods. Paraffin embedded tumor tissue blocks were available from 88 patients with mRCC who had undergone antitumor therapy in 1994- 2010. Of them, 53 patients received only immunotherapy regimens with interferon (IFN)-α and 35 patients had targeted therapy with VEGFR inhibitors. VHL mutations were detected by polymerase chain reaction (PCR) for exons of 1-3, single-strand conformation polymorphism analysis of PCR products, and further sequencing. VHL gene methylation was determined by methyl-sensitive PCR.Results. Somatic mutations and/or promoter hypermethylation of the VHL gene were found in 23 (26%) patients; Of them, VHL gene mutations and promoter hypermethylation were found in 15 patients and 7 patients respectively. Mutation and promoter methylation VHL were simultaneously observed in one case. VHL gene mutations were detected only in patients with clear cell RCC while aberrant promoter methylation was seen in both clear cell and papillary RCC. With a median follow-up of 34 months (range, 2-127 months), the median time to progression (TTP) and median overall survival (OS) for the entire group of patients were 5.8 and 26.7 months, respectively. In patients with and without VHL gene alterations, the median TTP was 5.5 and 6.9 months, respectively (p = 0.15) and the median overall survival time was 22.0 and 34.5 months, respectively (p = 0.98). Moreover, the subgroup analysis revealed that VHL gene inactivation events had no impact on the objective response rate (ORR), TTP and OS in the subgroup of patients who received immunotherapy (n = 53) or antiangiogenic targeted therapy (n = 35) (p > 0.05).Conclusion. VHL gene mutations and/or promotor hypermethylation observed in 26% of patients with mRCC. These VHL gene alterations were neither prognostic nor predictive factors in mRCC patients during immunotherapy with IFN or antiangiogenic therapy with VEGFR inhibitors.