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Genetic and Epigenetic Alterations in the von Hippel-Lindau Gene: the Influence on Renal Cancer Prognosis

Authors' Affiliations: Departments of ¹ Epidemiology and ² Pathology, GROW-School for Oncology and Developmental Biology, Maastricht University, Maastricht, the Netherlands and Departments of ³ Clinical Chemistry, ⁴ Pathology, and ⁵ Urology, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands

Requests for reprints: Kim Smits, Department of Epidemiology, Maastricht University, P.O. Box 616, 6200 MD Maastricht, the Netherlands. Phone: 31-43388-2385; E-mail: kim.smits{at}epid.unimaas.nl.

Background: Inactivation of the von Hippel-Lindau (VHL) gene is considered as an early event in renal cancer tumorigenesis. The prognostic relevance of these changes, however, is not clear and previous results are contradictory. We have evaluated the influence of (epi)genetic alterations in VHL on cause-specific survival in clear-cell renal cell cancer (ccRCC) in a large, population-based group of cases.

Methods: One hundred and eighty-five cases of ccRCC, identified in the Netherlands Cohort Study on diet and cancer diagnosed in the period 1986 to 1997, were included in the analyses. Mortality information until December 2005, including causes of death, were obtained for all cases through linkage with the Central Bureau of Statistics. VHL mutations were determined with PCR single-strand conformational polymorphism and direct sequencing. VHL methylation was determined with methylation-specific PCR. Kaplan-Meier analyses and Cox proportional hazards models were used to assess associations between VHL alterations and cause-specific mortality.

Results: Median follow-up in our population was 6 years. The frequency of loss of function mutations and methylation, separately or combined, did not differ statistically significant between different cancer stages or between tumors with different sizes. We observed no influence of loss of function mutations or methylation of the VHL gene on cause-specific mortality (hazard ratio, 1.08; 95% confidence interval, 0.69-1.68, P = 0.735) as compared with patients with a wild-type or silent mutation in VHL.

Discussion: Our results indicate that (epi)genetic alterations in the VHL gene do not have prognostic value in ccRCC.