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

  1. Author:
    Moore, L. E.
    Nickerson, M. L.
    Brennan, P.
    Toro, J. R.
    Jaeger, E.
    Rinsky, J.
    Han, S. S.
    Zaridze, D.
    Matveev, V.
    Janout, V.
    Kollarova, H.
    Bencko, V.
    Navratilova, M.
    Szeszenia-Dabrowska, N.
    Mates, D.
    Schmidt, L. S.
    Lenz, P.
    Karami, S.
    Linehan, W. M.
    Merino, M.
    Chanock, S.
    Boffetta, P.
    Chow, W. H.
    Waldman, F. M.
    Rothman, N.

  2. Author Address

    [Moore, LE; Toro, JR; Rinsky, J; Han, SS; Karami, S; Chanock, S; Chow, WH; Rothman, N] NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA. [Nickerson, ML; Boffetta, P] NCI, Canc & Inflammat Program, Frederick, MD 21701 USA. [Brennan, P] Int Agcy Res Canc, F-69372 Lyon, France. [Jaeger, E; Waldman, FM] Univ Calif San Francisco, San Francisco, CA 94143 USA. [Zaridze, D; Matveev, V] Russian Acad Med Sci, Canc Res Ctr, Inst Carcinogenesis, Moscow, Russia. [Janout, V; Kollarova, H] Palacky Univ, Fac Med, Dept Prevent Med, CR-77147 Olomouc, Czech Republic. [Bencko, V] Charles Univ Prague, Inst Hyg & Epidemiol, Prague, Czech Republic. [Navratilova, M] Masaryk Mem Canc Inst, Dept Canc Epidemiol & Genet, Brno, Czech Republic. [Szeszenia-Dabrowska, N] Inst Occupat Med, Dept Epidemiol, Lodz, Poland. [Mates, D] Inst Publ Hlth, Bucharest, Romania. [Schmidt, LS] NCI, Basic Sci Program, SAIC Frederick, Frederick, MD 21701 USA. [Schmidt, LS; Linehan, WM] NCI, Urol Oncol Branch, NIH, Bethesda, MD 20892 USA. [Lenz, P; Merino, M] NCI, Div Canc Epidemiol & Genet, SAIC Frederick, Frederick, MD 21701 USA. [Chanock, S] NCI, Core Genotyping Facil, Adv Technol Ctr, NIH,Dept Hlth & Human Serv, Bethesda, MD 20892 USA. [Boffetta, P] Mt Sinai Sch Med, Tisch Canc Inst, New York, NY USA. [Boffetta, P] Int Canc Prevent Res Inst, Lyon, France.;Moore, LE (reprint author), NCI, Div Canc Epidemiol & Genet, NIH, Bethesda, MD 20892 USA;moorele@mail.nih.gov
    1. Year: 2011
    2. Date: Oct
  2. Journal: Plos Genetics
    1. 7
    2. 10
    3. Pages: 13
  4. Type of Article: Article
  5. Article Number: e1002312
  6. ISSN: 1553-7390
  1. 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.

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  2. DOI: 10.1371/journal.pgen.1002312
  3. View record in Web of Science®
  4. WOS: 000296665400013

Library Notes

  1. Fiscal Year: FY2011-2012
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