Journal Article

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

Toro, Jorge R., Schmidt, Laura S., Szeszenia-Dabrowska, Neonilia, Kollarova, Hellena, Bencko, Vladimir, Chow, Wong-Ho, Matveev, Vsevolod, Janout, Vladimir, Rothman, Nathaniel, Waldman, Frederic M., Han, Summer S., Moore, Lee E., Mates, Dana, Merino, Maria, Zaridze, David, Jaeger, Erich, Rinsky, Jessica, Brennan, Paul, Lenz, Petra, Karami, Sara, Nickerson, Michael L., Boffetta, Paolo, Chanock, Stephen, Linehan, W. Marston, Navratilova, Marie

2011

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adult / Aged / Biology / Cancer / Carcinoma, Renal cell / Carcinoma, Renal Cell - genetics / Carcinoma, Renal Cell - pathology / Care and treatment / Case-Control Studies / Confidence intervals / CpG Islands - genetics / Deoxyribonucleic acid / Diagnosis / DNA / DNA Methylation / Epigenesis, Genetic / Epigenetics / Female / Gene expression / Gene Silencing / Generalized linear models / Genetic aspects / Genetic Association Studies / Genetic polymorphisms / Germ-Line Mutation / Haplotypes / Humans / Kidney Neoplasms - genetics / Kidney Neoplasms - pathology / Male / Medical research / Medicine / Middle Aged / Neoplasm Staging / Polymorphism, Single Nucleotide / Promoter Regions, Genetic / Risk Factors / Tumors / Von Hippel-Lindau Tumor Suppressor Protein - genetics / Von Hippel-Lindau Tumor Suppressor Protein - metabolism