The most common type of kidney cancers are renal cell carcinomas, which emerge as a complex set of diseases of different histology and genetic makeup, with the most frequent subtype being clear cell renal cell carcinoma (ccRCC). Loss of function of the umor suppressor gene VHL by mutations, loss of heterozygosity or promoter methylation is the most common genetic alteration in inherited as well as sporadic forms of RCC. VHL is part of an E3 ubiquitin ligase complex that functions as an important oxygen-sensing complex and mediates degradation of the hypoxia-inducible factors (HIFs) under normoxic conditions. Loss of VHL leads to accumulation of HIFs, which in turn promote proliferation, cell survival, motility, angiogenesis, extracellular matrix re-organization, and metabolic reprogramming. Underscoring the importance of hypoxia signaling in RCC biology, another member of the HIF-targeting E3 ligase complex, TCEB1, is inactivated by genetic alterations in a subset of VHL-wildtype tumors. Given the prominence of HIF signaling in RCC, drugs that target HIF downstream effectors such as sunitinib, sorafenib, temsirolimus, everolimus, axitinib and bevacizumab, have proven beneficial in treating RCC.
Besides VHL, additional genetic driver events have been identified in RCC. Interestingly, in contrast to most epithelial cancers these do not include mutations in classical oncogenic pathways, instead they encode tumor suppressor genes that regulate chromatin or histone modification, including PBRM1, SETD2, BAP1 and KDM5C. Therefore, the thorough evaluation of the epigenetic landscape of RCC holds promise to reveal new predictive measures and novel therapeutic approaches.
TICC Faculty who are involved in Kidney cancer research: