Abstract
Renal tumor heterogeneity studies have utilized the von Hippel-Lindau VHL gene to classify disease into molecularly defined subtypes to examine associations with etiologic risk factors and prognosis. The aim of this study was to provide a comprehensive analysis of VHL inactivation in clear cell renal tumors (ccRCC) and to evaluate relationships between VHL inactivation subgroups with renal cancer risk factors and VHL germline single nucleotide polymorphisms (SNPs). VHL genetic and epigenetic inactivation was examined among 507 sporadic RCC/470 ccRCC cases using endonuclease scanning and using bisulfite treatment and Sanger sequencing across 11 CpG sites within the VHL promoter. Case-only multivariate analyses were conducted to identify associations between alteration subtypes and risk factors. VHL inactivation, either through sequence alterations or promoter methylation in tumor DNA, was observed among 86.6% of ccRCC cases. Germline VHL SNPs and a haplotype were associated with promoter hypermethylation in tumor tissue (OR = 6.10; 95% CI: 2.28–16.35, p = 3.76E-4, p-global = 8E-5). Risk of having genetic VHL inactivation was inversely associated with smoking due to a higher proportion of wild-type ccRCC tumors [former: OR = 0.70 (0.20–1.31) and current: OR = 0.56 (0.32–0.99); P-trend = 0.04]. Alteration prevalence did not differ by histopathologic characteristics or occupational exposure to trichloroethylene. ccRCC cases with particular VHL germline polymorphisms were more likely to have VHL inactivation through promoter hypermethylation than through sequence alterations in tumor DNA, suggesting that the presence of these SNPs may represent an example of facilitated epigenetic variation (an inherited propensity towards epigenetic variation) in renal tissue. A proportion of tumors from current smokers lacked VHL alterations and may represent a biologically distinct clinical entity from inactivated cases.
Highlights
Von Hippel-Lindau (VHL) alteration leading to protein inactivation is considered a frequent, early event in renal carcinogenesis that can be used as a biomarker of tumor heterogeneity, to strengthen etiologic relationships with risk factors, and study mechanistic pathways of disease [1,2,3,4]
European Case-Control study (CEERCC) that were included in this analysis are compared to cases not included in this analysis by their personal/clinical characteristics, and risk factors that have been previously associated with the prevalence of renal cell cancer (RCC) or VHL alterations in tumor tissue
The higher percentage observed in clear cell renal cancer (ccRCC) compared to all RCC cases was due to a greater proportion of cases with VHL inactivating alterations and a lower proportion of wild type ccRCC cases [i.e. cases without inactivating VHL gene alterations], that were primarily observed among non-ccRCC cases
Summary
Von Hippel-Lindau (VHL) alteration leading to protein inactivation is considered a frequent, early event in renal carcinogenesis that can be used as a biomarker of tumor heterogeneity, to strengthen etiologic relationships with risk factors, and study mechanistic pathways of disease [1,2,3,4]. In a large case-series of 470 sporadic clear cell renal cancer (ccRCC) cases, we examined von Hippel-Lindau (VHL) inactivation as a biomarker of tumor heterogeneity. A high-risk haplotype associated with promoter hypermethylation in tumor DNA was identified These findings suggest that the presence of these polymorphisms and VHL promoter hypermethylation may represent an example of an inherited propensity toward epigenetic variation and potential silencing of the VHL gene in tumor tissue. This result could have translational implications, as individuals with the high-risk haplotype could be targeted for increased surveillance. Such tumors may be biologically distinct and have demonstrated a poorer prognosis compared to VHL inactivated cases
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