Von Hippel-Lindau (VHL) Inactivation in Sporadic Clear Cell Renal Cancer: Associations with Germline VHL Polymorphisms and Etiologic Risk Factors

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.

The epigenetic landscape of renal cancer

“…Somatic inactivation of VHL, which was originally identified in the hereditary cancer syndrome von HippelLindau (VHL) disease 19 , is very common in ccRCC (~52% of patients) 4 . The majority of the inactivating events are point mutations 4,15,20,21 . The VHL disease tumour suppressor protein (pVHL) has multiple functions 22 , and is best known as a regulator of oxygen and energy sensing via the targeted degradation of the hypoxia-inducible factors (HIF) 1 and HIF2 [Au: Refs OK?].…”

Hypoxia inducible factor‐1α suppresses Peroxiredoxin 3 expression to promote proliferation of CCRCC cells

“…Because of VHL is mutated or silenced in >50% of CCRCC [17], we asked whether the decreased Prx3 is related to VHL. RCC4 which is a VHL defective cell line derived from CCRCC and RCC4 with stable re-expression of VHL (RCC4/VHL) were tested by quantitative real-time PCR and western blot, respectively.…”

Hypertension and Circulating Cytokines and Angiogenic Factors in Patients With Advanced Non-Clear Cell Renal Cell Carcinoma Treated With Sunitinib: Results From a Phase II Trial

“…Although the ccRCC-defining loss of function of the von Hippel-Lindau gene (VHL) was thought uncommon in nccRCC, a recent study reported an incidence of ∼16% in sporadic cases [5]. Moreover, amplification or activating mutations in MET (encoding the hepatocyte growth factor [HGF] receptor), found in a subset of patients with sporadic papillary RCC (the most common nccRCC type), often result in tumor hypoxia, leading to overexpression of angiogenic mediators.…”