A patient with von Hippel-Lindau disease develops a clear cell renal cell carcinoma and a cerebellar haemangioblastoma, along with an elevated haemoglobin level. The biochemical consequence of VHL loss that explains both tumorigenesis and the polycythaemia is:

• A Constitutive activation of JAK2 tyrosine kinase in erythroid precursors
• B Failure to ubiquitinate HIF-1alpha, causing accumulation of HIF and transcription of VEGF and erythropoietin ✓
• C Loss of pVHL-mediated sequestration of beta-catenin in the nucleus
• D Impaired hydroxylation of proline residues in collagen, destabilising basement membranes

Explanation

Under normoxia, HIF-1alpha is prolyl-hydroxylated, recognised by pVHL, and destroyed by ubiquitin-mediated proteolysis. When VHL is lost, HIF-1alpha accumulates even in normoxia and drives transcription of VEGF (angiogenesis, haemangioblastomas) and erythropoietin (secondary polycythaemia). JAK2 V617F causes primary polycythaemia vera without VHL involvement, and beta-catenin destruction requires APC, not pVHL.

Reference: Robbins and Cotran Pathologic Basis of Disease, 10th ed.

High-yield for: NEET PGINI-CETNExTFMGEUSMLEPLABMRCP

Written and medically reviewed by the StethoPrep medical team.