Gene Mutations Associated with Renal Cell Carcinoma (RCC)
VHL gene mutation is the most frequent genetic alteration in clear cell renal cell carcinoma (ccRCC), occurring as an early truncal oncogenic driving event through genetic or epigenetic mechanisms. 1
Primary Gene Mutations in RCC by Subtype
Clear Cell RCC (70-85% of cases)
- VHL gene mutations or inactivation is present in the vast majority of sporadic ccRCC cases, with complete loss through genetic mechanisms (point mutations, indels, and 3p25 loss) and/or epigenetic mechanisms (promoter methylation) 1
- Loss of VHL leads to aberrant accumulation of hypoxia-inducible factors (HIFs), resulting in uncontrolled activation of genes regulating angiogenesis, glycolysis, and apoptosis 1
- 3p loss of heterozygosity is nearly universal in ccRCC and constitutes an early genetic event 1
- Other prevalent mutations in ccRCC include:
Papillary RCC (7-15% of cases)
- Type 1 papillary RCC is associated with c-MET mutations 2, 1
- Type 2 papillary RCC is linked to SETD2 mutations, CDKN2A mutations, or TFE3 fusions 2, 1
- Activation of the NRF2-ARE pathway is associated with type 2 papillary RCC 1
Chromophobe RCC (5-10% of cases)
- Characterized by chromosomal losses in chromosomes 1,2,6,10,13,17, and 21 2
- TP53 is the most frequently mutated gene (32%) 2
- VHL mutations are not found in chromophobe RCCs 3
Clinical Significance of Gene Mutations
Prognostic Implications
- VHL mutation status alone has no effect on clinical outcome as it is the founding event of ccRCC 1
- Mutations involved in disease progression show correlation with clinical features:
- PBRM1 mutations are associated with stage III pathological features 1
- BAP1 mutations correlate with larger tumor sizes, higher nuclear grade, and worse cancer-specific survival 1
- SETD2 mutations are associated with reduced relapse-free survival 1
- KDM5C mutations are predominantly detected in male patients and correlate with long-term therapeutic benefit from sunitinib 1
Tumor Heterogeneity and Evolution
- VHL mutation and 3p loss of heterozygosity are ubiquitous events across all regions of ccRCC tumors 1
- Common driver mutations (SETD2, PBRM1, MTOR, etc.) are present heterogeneously within primary tumors and metastatic sites 1
- This genetic heterogeneity contributes to tumor evolution and adaptation to new microenvironmental pressures 1
Therapeutic Implications
- Understanding the VHL-HIF pathway has led to the development of targeted therapies for metastatic RCC 1
- Agents that inhibit VEGF and its receptor VEGFR are effective treatments for metastatic ccRCC due to the highly vascular nature of these tumors resulting from VHL loss 1
- MTOR mutations in ccRCC are generally missense and functionally activating, explaining why mTOR pathway inhibitors like everolimus and temsirolimus are effective 1
Important Considerations
- VHL loss alone is insufficient to induce ccRCC, as evidenced by the long latency (>30 years) in individuals with VHL germline mutations to develop ccRCC 1
- Multiple mutations in VHL are associated with higher tumor grade, suggesting a relationship between VHL mutation and extent of nuclear atypia 3
- Mutations in BAP1 and PBRM1 or KDM5C tend to occur mutually exclusively in ccRCC, offering a potential molecular subclassification 1