Abstract
We investigated the relationship between germline single nucleotide polymorphisms (SNPs) in Von Hippel-Lindau (VHL) and Hypoxia-inducible factor 1-alpha (HIF1A), and their gene-environment and gene-gene interactions, and clear-cell RCC (ccRCC) risk. Furthermore, we assessed the relationship between VHL SNPs and VHL promoter methylation. Three VHL polymorphisms and one HIF1A polymorphism were genotyped in the Netherlands Cohort Study. In 1986, 120,852 participants aged 55–69 completed a self-administered questionnaire on diet and lifestyle and toenail clippings were collected. Toenail DNA was genotyped using the Sequenom MassARRAY platform. After 20.3 years, 3004 subcohort members and 406 RCC cases, of which 263 ccRCC cases, were eligible for multivariate case-cohort analyses. VHL_rs779805 was associated with RCC (Hazard Ratio (HR) 1.53; 95% Confidence Interval (CI) 1.07–2.17) and ccRCC risk (HR 1.88; 95% CI 1.25–2.81). No associations were found for other SNPs. Potential gene-environment interactions were found between alcohol consumption and selected SNPs. However, none remained statistically significant after multiple comparison correction. No gene-gene interactions were observed between VHL and HIF1A. VHL promoter methylation was not associated with VHL SNPs. VHL SNPs may increase (cc)RCC susceptibility. No associations were found between gene-environment and gene-gene interactions and (cc)RCC risk and between VHL promoter methylation and VHL SNPs.
Highlights
Genetic and epigenetic alterations in the Von Hippel-Lindau (VHL) gene are important drivers of carcinogenesis in clear-cell renal cell carcinoma[1]
Genotype and allele frequencies for the four selected Single Nucleotide Polymorphisms (SNPs) in subcohort members of the Netherlands Cohort Study on diet and cancer (NLCS) are presented in Supplementary Table 1
A statistically significantly increased RCC risk was found for individuals that carry genotypes with at least one variant allele for the VHL_rs779805 SNP
Summary
Genetic and epigenetic alterations in the Von Hippel-Lindau (VHL) gene are important drivers of carcinogenesis in clear-cell renal cell carcinoma (ccRCC)[1]. Previous studies have estimated that 50–82% of patients with sporadic ccRCC have a mutation in the VHL gene[4,5,6,7,8]. Genetic or epigenetic alterations in VHL and HIF1A may lead to enhanced cell survival and carcinogenesis. Previous studies have indicated the importance of assessing the interplay between genetic, epigenetic and environmental triggers when assessing ccRCC risk. The relationship between established environmental risk factors associated with RCC risk, namely smoking, hypertension, obesity and alcohol consumption[29], and VHL and HIF1A SNPs remains unstudied. We investigated the relationship between three selected germline VHL SNPs and one HIF1A SNP and (cc)RCC risk in the Netherlands Cohort Study on diet and cancer (NLCS). We investigated the association between VHL promoter methylation and VHL SNPs
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