PROGNOSTIC VALUE OF VHL GENE ALTERATION IN PATIENTS WITH METASTATIC RENAL CELL CARCINOMA

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.

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