Prevalence of von Hippel-Lindau gene mutations in sporadic renal cell carcinoma: results from The Netherlands cohort study.

Kjeld P Van Houwelingen,Jack A Schalken,Leo J Schouten,Boukje Ac Van Dijk,Hanneke Jm Gorissen,Egbert Oosterwijk,Piet A Van Den Brandt,Christina A Hulsbergen-Van De Kaa

doi:10.1186/1471-2407-5-57

Abstract

BackgroundBiallelic von Hippel-Lindau (VHL) gene defects, a rate-limiting event in the carcinogenesis, occur in approximately 75% of sporadic clear-cell Renal Cell Carcinoma (RCC). We studied the VHL mutation status in a large population-based case group.MethodsCases were identified within the Netherlands cohort study on diet and cancer, which includes 120,852 men and women. After 11.3 years of follow-up, 337 incident cases with histologically confirmed epithelial cancers were identified. DNA was isolated from paraffin material collected from 51 pathology laboratories and revised by one pathologist, leaving material from 235 cases. VHL mutational status was assessed by SSCP followed by direct sequencing, after testing SSCP as a screening tool in a subsample.ResultsThe number of mutations was significantly higher for clear-cell RCC compared to other histological types. We observed 131 mutations in 114 out of 187 patients (61%) with clear-cell RCC. The majority of mutations were truncating mutations (47%). The mean tumor size was 72.7 mm for mutated tumors compared to 65.3 mm for wildtype tumors (p = 0.06). No statistically significant differences were observed for nuclear grade, TNM distribution or stage. In other histological types, we observed 8 mutations in 7 out of 48 patients (15%), 1 mutation in 1 of 6 oncocytoma, 3 mutations in 2 of 7 chromophobe RCC, 2 mutations in 2 of 30 papillary RCC, no mutations in 1 collecting duct carcinoma and 2 mutations in 2 of 4 unclassified RCC.ConclusionVHL mutations were detected in 61% of sporadic clear-cell RCC. VHL mutated and wildtype clear-cell RCC did not differ with respect to most parameters.

Highlights

Biallelic von Hippel-Lindau (VHL) gene defects, a rate-limiting event in the carcinogenesis, occur in approximately 75% of sporadic clear-cell Renal Cell Carcinoma (RCC)
PCR-SSCP as a screening tool preceding direct sequencing To evaluate whether PCR-SSCP could be used to distinguish between wildtype and mutated VHL, we determined the VHL status of 20 cases by SSCP and direct sequencing (Table 2)
We are aware that the sampling size is limited, and it is known that SSCP as a screening tool is neither 100% sensitive nor specific

Summary

Introduction

Biallelic von Hippel-Lindau (VHL) gene defects, a rate-limiting event in the carcinogenesis, occur in approximately 75% of sporadic clear-cell Renal Cell Carcinoma (RCC). After its identification it became evident that the VHL gene is involved in the development of sporadic clear-cell RCC. Together with loss of the homologous chromosome 3p allele (3p LOH), VHL mutations are ratelimiting events in the carcinogenesis of clear-cell RCC [3,4]. In approximately 19% of sporadic clear-cell RCC, methylation of the VHL gene promoter appeared to be involved [9]. In approximately 10%–20% of sporadic clear-cell RCC no alteration in the VHL alleles was detected, indicating that other genes are involved in clearcell RCC carcinogenesis, possibly affecting the same signaling pathway as VHL

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