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

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
PLoS Genetics (Impact Factor: 7.53). 10/2011; 7(10):e1002312. DOI: 10.1371/journal.pgen.1002312
Source: PubMed


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.

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    • "Mutations in VHL gene exons 1–3 were detected using SURVEYOR® and WAVE® analyses, which can detect mutations in extracted DNA down to the level of 5 % heterozygosity (mutated VHL: normal VHL), and characterized by Sanger sequencing. Rules for predicting inactivation status were based on previously published criteria [20]. Laboratory analyses were conducted at Transgenomic, Inc. (Omaha, NE, USA). "
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    • "Presence of VHL gene mutations in considerable numbers of CCRCC has also been reported by other studies. Moore et al.8 reports 88.3% of CCRCC with VHL mutations, while Brauch et al.9 reports 75% and Shuin et al.(1994)10 reports 56% of clear cell carcinoma with VHL mutations. On the other side of spectrum, Qing et al.11 reports a lower figure that is of 35% of CCRCC with VHL mutations. "
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    • "Alterations of the VHL gene are observed in up to 80% of sporadic ccRCC and involve either somatic mutations, loss of heterozygosity and promoter hypermethylation [19] [20] [21]. Among those, evidence of biallelic inactivation of VHL is found in 60–70% of ccRCC patients [20] [22] [23]. Still, 30–40% of sporadic ccRCCs have a functional VHL gene, suggesting that different gene(s) and alternative tumorigenesis pathway(s) are involved in the same histological cancer subtype. "
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