Analysis of VHL Gene Alterations and their Relationship to Clinical Parameters in Sporadic Conventional Renal Cell Carcinoma

Abstract

PURPOSE: This study aimed to carry out a comprehensive analysis of genetic and epigenetic changes of the von Hippel Lindau (VHL) gene in patients with conventional (clear cell) renal cell carcinoma and to determine their significance relative to clinicopathologic characteristics and outcome. EXPERIMENTAL DESIGN: The VHL status in 86 conventional renal cell carcinomas was determined by mutation detection, loss of heterozygosity (LOH), and promoter methylation analysis, extending our original cohort to a total of 177 patients. Data were analyzed to investigate potential relationships between VHL changes, clinical parameters, and outcome. RESULTS: LOH was found in 89.2%, mutation in 74.6%, and methylation in 31.3% of evaluable tumors; evidence of biallelic inactivation (LOH and mutation or methylation alone) was found in 86.0% whereas no involvement of VHL was found in only 3.4% of samples. Several associations were suggested, including those between LOH and grade, nodal status and necrosis, mutation and sex, and methylation and grade. Biallelic inactivation may be associated with better overall survival compared with patients with no VHL involvement, although small sample numbers in the latter group severely limit this analysis, which requires independent confirmation. CONCLUSIONS: This study reports one of the highest proportions of conventional renal cell carcinoma with VHL changes, and suggests possible relationships between VHL status and clinical variables. The data suggest that VHL defects may define conventional renal cell carcinomas but the clinical significance of specific VHL alterations will only be clarified by the determination of their biological effect at the protein level rather than through genetic or epigenetic analysis alone. (Clin Cancer Res 2009;15(24):7582-92).

Figure 1

Summary of VHL alterations identified in 177 patients with sporadic conventional RCC.

Figure 2

Spectrum of VHL mutations found in sporadic conventional RCC. A, mutations (n=126) reported from analysis of 177 samples in this study; B, cumulative data of 1244 mutations reported in the literature (5, 6, 8-45, 47). All studies have been checked to ensure that data published in multiple studies was not duplicated with some publications omitted for this reason or due to sequences not being available (4, 7, 46). Only conventional (clear cell) RCC cases were included except for one study where the specific pathological subtype of RCC was not indicated (44). Results from patients following trichloroethylene exposure or with end stage renal disease were excluded as previously (9).

Figure 2

Spectrum of VHL mutations found in sporadic conventional RCC. A, mutations (n=126) reported from analysis of 177 samples in this study; B, cumulative data of 1244 mutations reported in the literature (5, 6, 8-45, 47). All studies have been checked to ensure that data published in multiple studies was not duplicated with some publications omitted for this reason or due to sequences not being available (4, 7, 46). Only conventional (clear cell) RCC cases were included except for one study where the specific pathological subtype of RCC was not indicated (44). Results from patients following trichloroethylene exposure or with end stage renal disease were excluded as previously (9).

Figure 3

Cancer-specific survival curves for conventional RCC patients based on presence or absence of A, LOH, B, mutation and C, methylation, for all patients and D, mutation truncation group for the subset of patients with stage I to III disease.