VHL and EPAS1 (HIF-2α)

  • VHL (von Hippel-Lindau tumor suppressor) encodes a component of a ubiquitin ligase complex that targets hypoxia-inducible factor (HIF) alpha subunits for degradation.1
  • EPAS1 (endothelial PAS domain protein 1) encodes hypoxia-inducible factor 2-alpha (HIF-2α).2,3
  • Gene Location: Chromosome 3 (3p25.3) for VHL; chromosome 2 (2p21) for EPAS1.1,3

Biology

  • Under normal oxygen levels, VHL protein targets HIF-2α for ubiquitin-proteasomal degradation. Loss of functional VHL stabilizes HIF-2α, which pairs with HIF-1β to induce genes for proliferation, angiogenesis, and tumor growth.4
  • HIF-2α targets in clear cell RCC (ccRCC) include VEGF-A, cyclin D1, GLUT-1, TGF-α, and PDGF-B, linking VHL loss to the angiogenic and proliferative phenotype of ccRCC.5,6

Etiology and Epidemiology

  • Sporadic ccRCC: loss of chromosome 3p, which carries VHL, occurs in 91% of tumors; somatic VHL mutations are found in 30% to 60%, and VHL promoter methylation in about 7% (mutually exclusive with mutation).7,8
  • von Hippel-Lindau (VHL) disease: autosomal dominant, about 1 in 36,000 births (about 20% de novo). About 70% of carriers develop ccRCC by age 60, often bilateral and multifocal. Other tumors include CNS and retinal hemangioblastomas, pancreatic neuroendocrine tumors (5% to 17%), pheochromocytoma, and endolymphatic sac tumors.9

Testing

When to Test:

  • Germline testing should be considered for patients with suspected hereditary RCC, including early-onset RCC, bilateral or multifocal tumors, or a family history of RCC or a known familial variant. RCC at age 40 or younger, retinal or CNS hemangioblastoma, pheochromocytoma, or multiple renal and pancreatic cysts should prompt evaluation for VHL disease.9,10
  • Somatic testing: not required for belzutifan in sporadic ccRCC; trial eligibility for LITESPARK-005, LITESPARK-011, and LITESPARK-022 did not depend on VHL status.4

Testing Methodologies:

  • Germline multigene panel NGS on blood or saliva, including VHL, with deletion/duplication analysis; genetic counseling before and after testing.9,10

Guideline Recommendations

  • Clinical consensus (2021): genetic risk assessment for hereditary RCC based on family history, bilateral or multifocal disease, specific histologies, and use of multigene panels.10
  • NCCN (Kidney Cancer): belzutifan is a preferred subsequent therapy for ccRCC after prior immunotherapy (category 2A).11

Targeted Therapy

Approved Agents

Belzutifan (Welireg)

FDA-Approved Indication:

  • VHL disease-associated RCC, CNS hemangioblastomas, or pancreatic neuroendocrine tumors not requiring immediate surgery (2021).4
  • Advanced ccRCC after a PD-1/PD-L1 inhibitor and a VEGF-TKI, as monotherapy (2023); with lenvatinib after a PD-1/PD-L1 inhibitor (September 2026).4
  • With pembrolizumab, adjuvant treatment of ccRCC at intermediate-high or high risk of recurrence after nephrectomy (June 12, 2026).4
  • Locally advanced, unresectable, or metastatic pheochromocytoma or paraganglioma in patients 12 years and older (2025).4

Mechanism of Action:

  • Oral HIF-2α inhibitor that blocks the HIF-2α/HIF-1β interaction, reducing transcription of HIF-2α target genes.4

Drug Information: Learn more about Belzutifan ›

Patient Resources: https://www.welireg.com/

References

  1. NCBI Gene. VHL von Hippel-Lindau tumor suppressor [Homo sapiens]. Gene ID 7428. Accessed October 2026.
  2. MedlinePlus Genetics. EPAS1 gene. National Library of Medicine. Accessed October 2026.
  3. Atlas of Genetics and Cytogenetics in Oncology and Haematology. EPAS1 (endothelial PAS domain protein 1). Accessed October 2026.
  4. Welireg (belzutifan) tablets. Prescribing information. Merck Sharp & Dohme LLC; revised 09/2026. Accessed October 2026.
  5. Meléndez-Rodríguez F, Roche O, Sanchez-Prieto R, et al. Hypoxia-inducible factor 2-dependent pathways driving von Hippel-Lindau-deficient renal cancer. Front Oncol. 2018;8:214. doi:10.3389/fonc.2018.00214
  6. Kim H, Shim BY, Lee SJ, et al. Loss of von Hippel-Lindau (VHL) tumor suppressor gene function: VHL-HIF pathway and advances in treatments for metastatic renal cell carcinoma (RCC). Int J Mol Sci. 2021;22(18):9795. doi:10.3390/ijms22189795
  7. Cancer Genome Atlas Research Network. Comprehensive molecular characterization of clear cell renal cell carcinoma. Nature. 2013;499(7456):43-49. doi:10.1038/nature12222
  8. Kim HS, Kim JH, Jang HJ, et al. Clinicopathologic significance of VHL gene alteration in clear-cell renal cell carcinoma: an updated meta-analysis and review. Int J Mol Sci. 2018;19(9):2529. doi:10.3390/ijms19092529
  9. van Leeuwaarde RS, Ahmad S, van Nesselrooij B, Zandee W, Giles RH. Von Hippel-Lindau syndrome. In: GeneReviews. University of Washington, Seattle; last revised May 1, 2025.
  10. Bratslavsky G, Mendhiratta N, Daneshvar M, et al. Genetic risk assessment for hereditary renal cell carcinoma: clinical consensus statement. Cancer. 2021;127(21):3957-3966. doi:10.1002/cncr.33679
  11. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines®) for Kidney Cancer V.1.2026. © National Comprehensive Cancer Network, Inc. 2026. All rights reserved. Accessed October 2026. To view the most recent and complete version of the guideline, go online to NCCN.org.