VHL tumor suppressor gene alterations associated with good prognosis in sporadic clear-cell renal carcinoma

J Natl Cancer Inst. 2002 Oct 16;94(20):1569-75. doi: 10.1093/jnci/94.20.1569.


Background: Somatic alteration of the von Hippel-Lindau disease tumor suppressor gene (VHL) is one of the most common genetic changes observed in the sporadic, clear-cell subtype of renal cell carcinoma (RCC). However, the prognostic utility of VHL mutations has not been examined. The purpose of this study was to explore the association between VHL mutations and the risk of death from sporadic clear-cell RCC.

Methods: A total of 187 Japanese patients with clear-cell RCC who underwent nephrectomy from October 1986 through December 1995 were examined for somatic VHL gene alteration. Clinicopathologic and survival data were also collected. Kaplan-Meier analyses and Cox proportional hazards models were used to explore associations. All statistical tests were two-sided.

Results: A VHL alteration (mutation or hypermethylation) was detected in 108 RCC tumor samples: intragenic mutations in 98 (52%) and hypermethylation in 10 (5.3%). VHL alterations were strongly associated with better cancer-free survival and cancer-specific survival for the 134 patients with stage I-III clear-cell RCC treated by radical nephrectomy (log-rank P =.024 and.023, respectively). These associations were more statistically significant among patients with relatively advanced disease (stage III [P =.014 and.010, respectively] or stage II + III [P =.002 and.009]) or higher grade tumors (G3 or higher [P =.013 and.032] or G2 or higher [P =.013 and.018]) and among patients who presented with symptoms (P =.005 and.012). VHL alterations remained an independent prognostic factor for patients with stage I-III tumors after adjustment for sex, age, stage, grading, and symptomatic presentation. VHL alterations were not associated with cancer-specific survival for the 53 patients with stage IV tumors treated with palliative or adjunctive nephrectomy (log-rank P =.760).

Conclusion: The VHL alteration status may provide useful prognostic information, as a biomolecular marker, for patients with stage I-III clear-cell RCC who have undergone nephrectomy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma, Clear Cell / diagnosis
  • Adenocarcinoma, Clear Cell / genetics*
  • Adenocarcinoma, Clear Cell / mortality*
  • Adenocarcinoma, Clear Cell / surgery
  • Analysis of Variance
  • Female
  • Follow-Up Studies
  • Genes, Tumor Suppressor*
  • Humans
  • Japan
  • Kidney Neoplasms / diagnosis
  • Kidney Neoplasms / genetics*
  • Kidney Neoplasms / mortality*
  • Kidney Neoplasms / surgery
  • Ligases / genetics*
  • Male
  • Middle Aged
  • Mutation*
  • Nephrectomy
  • Prognosis
  • Risk Assessment
  • Survival Analysis
  • Tumor Suppressor Proteins*
  • Ubiquitin-Protein Ligases*
  • Von Hippel-Lindau Tumor Suppressor Protein


  • Tumor Suppressor Proteins
  • Ubiquitin-Protein Ligases
  • Von Hippel-Lindau Tumor Suppressor Protein
  • Ligases
  • VHL protein, human