Analysis of the VHL Tumor Suppressor Gene in Kidney Cancer

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Somatic alteration of the VHL tumor suppressor gene is one of the most common genetic changes observed in the sporadic, clear-cell subtype of renal cell carcinoma (RCC). A total of 187 Japanese patients with clear-cell RCC who underwent nephrectomy were examined for somatic VHL gene alteration and clinicopathologic and prognostic data were also collected. A VHL mutation was detected in 108 (57%) samples. VHL alterations were strongly associated with better prognosis for 134 patients with stage I-III clear-cell RCC treated by radical nephrectomy for cancer-free survival and cancer-specific survival (logrank P =.024 and.023, respectively). These associations with cancer-free survival and cancer-specific survival were more statistically significant among patients with relatively advanced-stage tumors (stage III[P =.014 and.010, respectively] or stage II+III [P =.002 and.009]) or higher-grade tumors (【greater than or equal】G3 [P =.013 and.032] or 【greater than or equal】G2 [P =.013 and.018] … More ) or patients who presented with symptoms (P =.005 and.012). The VHL alteration was determined to be an independent prognostic factor, after adjustment for sex, age, stage, grading, and symptomatic presentation. However, VHL alterations were not associated with cancer-specific survival for the 53 patients with stage IV tumors treated with palliative or adjunctive nephrectomy (logrank P =.760). We compared the gene expression profile between VHL-deflcient renal carcinoma 786-O cells and those infected with an adenovirus vector encoding VHL to identify the target gene of pVHL. We found cyclin D1 as a new target of pVHL at a high cell density. Consequently, the phosporylation level of the Rb protein remained high in these cells whereas there was no phosporylated Rb in VHL (+) cells under the contact inhibition. The abnormal expression of cyclin D1 at a high cell density was observed even in VHL (+) cells under the hypoxic state. Moreover, ectopic expression of a HIF mutant resistant to pVHL-mediated proteolysis causes the abnormal cyclin D1 expression in VHL (+) cells. Taken together, these observations indicate that VHL is required for the down-regulation of cyclin D1 at a high cell density through HIF. Less