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. ( The incidence of renal cancer is increasing and currently accounts for ∼2% to 3% of cancers worldwide, with around 210,000 new cases diagnosed annually (GLOBOCAN 2002). 6 Patients often present late with advanced or unresectable disease, and up to 30% of patients relapse after potentially curative surgery. Metastatic renal cancer is associated with a 5-year survival rate of ∼10% (1, 2). Traditional treatments, such as interferon and interleukin, only have response rates of 15% to 20% but more recently, therapies such as the tyrosine kinase inhibitors sunitinib and sorafenib (3) have shown response rates and survival benefits.The von Hippel Lindau (VHL) tumor suppressor gene on chromosome 3p plays a central role in the development of the conventional (clear cell) histologic subtype of renal cell carcinoma. Identified in patients with familial VHL disease, an autosomal dominant cancer syndrome associated with the development of a number of tumors including conventional renal cell carcinoma (4), VHL has also been shown to be important in sporadic conventional renal cell carcinomas, with a large number of studies reporting potential loss of VHL function as a result of allele loss, mutation, and promoter methylation (5-47). In one of the most comprehensive studie...

Multilocular cystic renal cell carcinoma is a subtype of clear cell renal cell carcinoma

“…Only 3% of the cases showed wild type VHL. 30 In this study we performed FISH analysis for 3p deletion on samples from multilocular cystic renal cell carcinomas and compared the findings with those from a population of similarly low grade conventional clear cell renal cell carcinomas. Deletion in 3p was observed in 74% of the multilocular cystic renal cell carcinomas and in 89% of the clear cell renal cell carcinomas with no statistically significant difference in the incidence of 3p deletion, between the groups.…”

The epigenetic landscape of renal cancer

“…3a), and unregulated β-catenin activation increases the tumourgenicity of renal cells 74 . In addition, VHL is inactivated in ~11-30% of ccRCC and pRCC by promoter methylation [75][76][77] or by loss of chromosome 3. In the absence of pVHL, β-catenin can be targeted for degradation by the E3 ligase F-box/WD repeat-containing protein 1A (β-TrCP, also called β-transducin repeat containing protein) 72,73,78 .…”

JunB promotes cell invasion and angiogenesis in VHL-defective renal cell carcinoma

“…von Hippel-Lindau (VHL) disease is caused by inactivating germline mutations of the VHL tumor-suppressor gene and is associated with an increased risk of ccRCC and other tumors, including pheochromocytoma, and hemangioblastoma of the retina, cerebellum and spinal cord (Woodward and Maher, 2006). In addition, it has been reported that biallelic inactivation of the VHL gene also occurs in the majority of sporadic ccRCCs (Young et al, 2009). These observations have motivated studies aimed at determining how the VHL protein (pVHL) suppresses tumor growth.…”