Recent advances in etiology and treatment of von Hippel-Lindau Disease (VHLD).

Von Hippel-Lindau disease (VHLD) is a rare autosomal dominant disease, occuring in ~ 1 in 35,000 individuals. Overall, individuals with inherited mutations in the VHL tumor suppressor gene are predisposed to a variety of cancer, including high frequencies of clear cell renal cell carcinoma (ccRCC), pancreatic neuroendocrine tumors, and hemangioblastomas, as well as benign cystic conditions and other cancers. The degree of risk for each of these pathological conditions depends on the location and severity of the inherited germline mutation, and the specific VHL protein interactions and functions disrupted. A core VHL protein function is as the targeting subunit of an E3 ligase complex, with protein degradation activity based on interactions with elongins (ELOB, ELOC), Cullin 2 (CUL2), and RBX1. For ccRCC and some other cancers, loss of VHL-dependent degradation of key substrates-the transcription factors hypoxia-inducible factor alpha (HIF-1α and HIF-2α)-and upregulation of HIF-dependent transcripts are critical to promote tumor formation. For this reason, drugs such as the HIF signaling inhibitor belzutifan have emerged as promising clinical agents for treatment of VHLD patients prone to ccRCC. However, other biological consequences of VHL loss are independent of HIFα degradation, and in some cases independent of the VHL ubiquitin ligase activity. Non-canonical activities of VHL include regulation of microtubule stability, mitotic progression, and ciliation, as well as formation of the extracellular matrix (ECM); the degree to which disruption of these activities contributes to VHLD is currently not well understood. This review provides a concise update of the current literature on VHLD pathogenesis, the relationship of VHL structure and protein interactions to the spectrum of phenotypes associated with VHLD, and current and proposed treatment, prevention, and interception of cancer formation for VHLD patients.