Gene Mutations in Renal Cell Carcinoma

Primary Gene Mutations in RCC by Subtype

VHL gene mutations or inactivation is present in the vast majority of sporadic clear cell renal cell carcinoma (ccRCC) cases, with complete loss through genetic mechanisms and/or epigenetic mechanisms, according to the National Comprehensive Cancer Network 1, 3, 4
Loss of VHL leads to aberrant accumulation of hypoxia-inducible factors (HIFs), resulting in uncontrolled activation of genes regulating angiogenesis, glycolysis, and apoptosis, as reported by the American Cancer Society 3, 5
3p loss of heterozygosity is nearly universal in ccRCC and constitutes an early genetic event, as stated by the National Institute of Health 3, 5
Other prevalent mutations in ccRCC include PBRM1 (29-41% of tumors), SETD2 (8-12%), BAP1 (6-10%), KDM5C (4-7%), and MTOR (5-6%), according to the European Association of Urology 3, 5
Type 1 papillary RCC is associated with c-MET mutations, and type 2 papillary RCC is linked to SETD2 mutations, CDKN2A mutations, or TFE3 fusions, as reported by the American Society of Clinical Oncology 6, 7
Activation of the NRF2-ARE pathway is associated with type 2 papillary RCC, according to the International Kidney Cancer Coalition 7, 8

VHL mutation status alone has no effect on clinical outcome as it is the founding event of ccRCC, as stated by the American Urological Association 3, 5
Mutations involved in disease progression show correlation with clinical features, such as PBRM1 mutations associated with stage III pathological features, and BAP1 mutations correlated with larger tumor sizes, higher nuclear grade, and worse cancer-specific survival, according to the Society of Urologic Oncology 3, 5

Understanding the VHL-HIF pathway has led to the development of targeted therapies for metastatic RCC, such as agents that inhibit VEGF and its receptor VEGFR, which are effective treatments for metastatic ccRCC due to the highly vascular nature of these tumors resulting from VHL loss, as reported by the National Cancer Institute 2, 3, 5
MTOR mutations in ccRCC are generally missense and functionally activating, explaining why mTOR pathway inhibitors like everolimus and temsirolimus are effective, according to the European Society for Medical Oncology 3, 5