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Improved Identification of von Hippel-Lindau Gene Alterations in Clear Cell Renal Tumors

Authors' Affiliations: ¹ Transgenomic, Gaithersburg, Maryland; ² Comprehensive Cancer Center, University of California at San Francisco, San Francisco, California; ³ Institute of Carcinogenesis, Cancer Research Centre, Moscow, Russia; ⁴ Department of Preventive Medicine, Faculty of Medicine, Palacky University, Olomouc, Czech Republic; ⁵ Institute of Hygiene and Epidemiology, Charles University, Prague, Czech Republic; ⁶ Department of Cancer Epidemiology and Genetics, Masaryk Memorial Cancer Institute, Brno, Czech Republic; ⁷ Department of Epidemiology, Institute of Occupational Medicine, Lodz, Poland; ⁸ Institue of Public Health, Bucharest, Romania; ⁹ Basic Research Program, Science Applications International Corporation, National Cancer Institute-Frederick; ¹⁰ Laboratory of Immunobiology, National Cancer Institute-Frederick, NIH, Frederick, Maryland; ¹¹ Division of Cancer Epidemiology and Genetics, National Cancer Institute; ¹² Urologic Oncology Branch, National Cancer Institute, and ¹³ National Cancer Institute, NIH, Bethesda, Maryland; ¹⁴ University of Toronto, Ontario; and ¹⁵ International Agency for Research on Cancer (IARC), Lyon, France

Requests for reprints: Lee E. Moore, Division of Cancer Epidemiology and Genetics, National Cancer Institute, NIH, 6120 Executive Boulevard, EPS Room 8102, Bethesda, MD 20852. Phone: 301-496-6427; Fax: 301-402-1819; E-mail: moorele{at}mail.nih.gov or Michael L. Nickerson, 626 Stonehouse Lane, Shepherdstown, WV 25443. Phone: 304-995-6975; Fax: 304-876-0740; E-mail: mrnick{at}frontiernet.net.

Purpose: To provide a comprehensive, thorough analysis of somatic mutation and promoter hypermethylation of the von Hippel-Lindau (VHL) gene in the cancer genome, unique to clear cell renal cancer (ccRCC). Identify relationships between the prevalence of VHL gene alterations and alteration subtypes with patient and tumor characteristics.

Experimental Design: As part of a large kidney cancer case-control study conducted in Central Europe, we analyzed VHL mutations and promoter methylation in 205 well-characterized, histologically confirmed patient tumor biopsies using a combination of sensitive, high-throughput methods (endonuclease scanning and Sanger sequencing) and analysis of 11 CpG sites in the VHL promoter.

Results: We identified mutations in 82.4% of cases, the highest VHL gene mutation prevalence reported to date. Analysis of 11 VHL promoter CpG sites revealed that 8.3% of tumors were hypermethylated and all were mutation negative. In total, 91% of ccRCCs exhibited alteration of the gene through genetic or epigenetic mechanisms. Analysis of patient and tumor characteristics revealed that certain mutation subtypes were significantly associated with Fuhrman nuclear grade, metastasis, node positivity, and self-reported family history of RCC.

Conclusion: Detection of VHL gene alterations using these accurate, sensitive, and practical methods provides evidence that the vast majority of histologically confirmed ccRCC tumors possess genetic or epigenetic alteration of the VHL gene and support the hypothesis that VHL alteration is an early event in ccRCC carcinogenesis. These findings also indicate that VHL molecular subtypes can provide a sensitive marker of tumor heterogeneity among histologically similar ccRCC cases for etiologic, prognostic, and translational studies.