A 28-year-old Indian male presents with progressive headache, ataxia, and diplopia. Imaging reveals a cerebellar hemangioblastoma. Genetic testing confirms a germline mutation in the region marked **A** in the diagram. Which of the following best explains the molecular mechanism by which loss of function at this locus leads to hypervascular tumor formation?

Question

Accepted Answer

D. Loss of VHL protein function → constitutive HIF-α stabilization → VEGF and PDGF overexpression → angiogenesis. ## Why option 1 is correct

The structure marked **A** represents VHL deletion at chromosome 3p25.3. The VHL tumor suppressor protein (pVHL) normally targets hypoxia-inducible factor alpha (HIF-α) for proteasomal degradation under normoxic conditions. Loss of functional pVHL due to germline VHL mutations leads to constitutive stabilization and accumulation of HIF-α, which drives transcription of pro-angiogenic factors including VEGF (vascular endothelial growth factor) and PDGF (platelet-derived growth factor). This results in the characteristic hypervascular tumors seen in VHL disease, including cerebellar hemangioblastomas. This mechanism is the pathophysiologic cornerstone of VHL-associated tumorigenesis (Harrison's Principles of Internal Medicine 21e).

## Why each distractor is wrong

- **Option 2 (NF2 deletion)**: NF2 (chromosome 22q12) encodes merlin and is associated with neurofibromatosis type 2, not VHL disease. Loss of NF2 leads to Hippo pathway dysregulation, not HIF-α-mediated angiogenesis.
- **Option 3 (RET deletion)**: RET (chromosome 10q11) is the gene mutated in multiple endocrine neoplasia type 2 (MEN2) and familial medullary thyroid carcinoma. RET is a proto-oncogene (gain-of-function mutations), not a tumor suppressor, and does not regulate HIF-α.
- **Option 4 (MEN1 deletion)**: MEN1 (chromosome 11q13) encodes menin and is mutated in MEN1 syndrome. While MEN1 is a tumor suppressor, its mechanism involves transcriptional regulation and cell cycle control, not HIF-α stabilization or VEGF-mediated angiogenesis.

**High-Yield:** VHL loss → HIF-α accumulation → VEGF/PDGF overexpression → hypervascular tumors (hemangioblastomas, clear-cell RCC, pheochromocytomas).

[cite: Harrison's Principles of Internal Medicine 21e; VHL Alliance Guidelines]

Answer

A. Loss of NF2 protein function → increased Wnt signaling → enhanced cell proliferation

Answer

B. Loss of MEN1 protein function → menin-mediated transcriptional dysregulation → tumor growth

Answer

C. Loss of RET protein function → impaired tyrosine kinase signaling → reduced apoptosis

Explanation

Why option 1 is correct

Why each distractor is wrong

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