In order to identify the VHL gene, investigators conducted genetic linkage analysis in VHL families. The VHL gene was identified on the short arm of chromosome 3 (7). The VHL gene was found to be mutated in the germline of patients affected by VHL (8). This provided a clinical test to make the diagnosis of VHL in at-risk individuals in VHL kindreds.

When tumor tissue from patients with sporadic (noninherited) kidney cancer was evaluated for alteration of the VHL gene, mutation of this gene was found in a high percentage of tumors from patients with clear cell renal carcinoma (9,10). VHL gene mutations were not found in tumors from patients with papillary renal carcinoma, chromophobe renal carcinoma, or oncocytoma. The VHL gene is the gene for the common form of sporadic clear cell renal carcinoma (Fig. 41.4).

Understanding the genetic basis of cancer of the kidney provides a method for molecular classification of the cancer and could provide enhanced methods for diagnosis of this disease. Yao et al. have shown that there is an improved survival rate in patients with sporadic clear cell renal carcinoma with VHL mutation (11). VHL mutations have been detected in circulating cells, lymph nodes, and urine of patients with clear cell renal carcinoma, providing possible approaches for early diagnosis of this disease. Most importantly, understanding the VHL gene pathway has provided the foundation for the development of targeted therapeutic approaches to patients with advanced, clear cell kidney cancer.

The VHL protein forms a multiprotein complex with elongins c and b, and Cul2 to target the alpha subunits of the hypoxia-inducible factors (HIFs), HIF1α and HIF2α for ubiquitin-mediated degradation (12,13,14,15,16). This is an oxygendependent process. In normoxia, the VHL complex targets HIF and promotes its degradation. During hypoxia, the complex cannot degrade HIF α subunits and HIF overaccumulates in the cell. HIF is a transcription factor that regulates the transcription of a number of genes important in cancer, such as vascular endothelial growth factor (VEGF), transforming growth factor alpha (TGFα), platelet-derived growth factor (PDGF), and epidermal growth factor receptor (EGFR) (17,18) (Fig. 41.5).

One approach to the development of effective forms of therapy for patients with advanced clear cell renal carcinoma is to develop agents which target the VHL pathway. To date, the Food and Drug Administration (FDA) has approved six therapeutic agents that target the VHL pathway in patients with advanced clear cell kidney cancer. The first agent used to target the VHL pathway in patients with advanced clear cell kidney cancer was bevacizumab, a monoclonal antibody which targets VEGF (19). Sorafenib and sunitinib target the vascular endothelial growth factor receptor (VEGFR) and the platelet-derived growth factor receptor (PDGFR), everolimus and temsirolimus target the mammalian target of rapamycin (mTOR) and are thought to affect HIF translation, and pazopanib targets the VEGFR1/R2/R3 receptors (20,21,22,23,24). In a randomized phase III study in previously untreated patients with metastatic clear cell RCC, sunitinib has been reported to induce RECIST partial responses in 31% of patients with an improvement in both progression-free survival and overall survival compared to interferon α (21); however, there are few complete responses and most patients eventually progress. Further studies are in progress to identify more effective forms of therapy targeting the VHL kidney cancer gene pathway for the treatment of patients with advanced clear cell kidney cancer (Fig. 41.6).