VHL

Overview

VHL (Von Hippel-Lindau Tumor Suppressor) encodes an E3 ubiquitin ligase subunit that targets HIF-1alpha for proteasomal degradation under normoxic conditions. Inactivation of VHL leads to constitutive HIF activation and downstream angiogenic signaling. While VHL is the canonical driver of clear cell renal cell carcinoma (RCC), WES of pancreatic cystic neoplasms revealed that serous cystadenomas (SCAs) also carry VHL-inactivating mutations and chromosome 3p loss of heterozygosity, consistent with shared pathogenesis.

Alterations observed in the corpus

  • WES of 32 pancreatic cystic neoplasms identified VHL inactivating point mutations in 4/8 serous cystadenomas (SCAs), with LOH at chr3p in 8/8 SCAs; all detected mutations were previously described in renal cell carcinoma, supporting VHL as the defining driver of SCAs PMID:22158988
  • 9/18 SCA cyst fluid samples were also VHL-mutant, demonstrating feasibility of non-invasive molecular diagnosis from cyst fluid PMID:22158988
  • Top significantly mutated gene in TCGA CCRCC comprehensive molecular characterization; mutations mutually exclusive with promoter methylation (~7% epigenetically silenced); central role in HIF stabilization PMID:23792563
  • Biallelic conditional inactivation (Vhl-null mouse model) is the central perturbation mimicking the truncal event in human ccRCC; VHL loss stabilizes both HIF1A and HIF2A, with HIF1A driving anti-survival effects in renal papilla and HIF2A driving dedifferentiation/proliferation in cortical proximal tubule cells PMID:23797736
  • VHL somatic mutation was present in 9/10 ccRCC tumors; the remaining case was silenced by promoter methylation. VHL loss is truncal in all 10 tumors and confirmed as the founding driver event together with chromosome 3p loss PMID:24487277
  • VHL referenced as a known germline kidney-cancer predisposition gene; contrasted against somatic nccRCC mutation profiles in the UTSW comprehensive study PMID:25401301
  • Only 1/62 uRCC cases (T08) carried a VHL mutation; the near-absence of VHL alteration despite frequent 3p loss distinguishes unclassified high-grade RCC from clear-cell RCC (where VHL is altered in ~75%). PMID:27713405
  • V166G germline mutation diagnostic of Von Hippel-Lindau syndrome in a pediatric renal cell carcinoma patient; I180T germline mutation in an ependymoma patient flagged as Von Hippel-Lindau syndrome (ACMG secondary finding) PMID:28007021
  • Germline (4%) and somatic mutations specific to the pseudohypoxia subtype of PCC/PGL; germline VHL co-occurs with 3p chromosomal deletion; FDA-approved targeted therapies are available for VHL-mutant tumors PMID:28162975
  • Identified as a lineage-restricted driver gene in renal clear-cell carcinoma in a pan-cancer MSK-IMPACT analysis of 10,336 patients across 62 tumor types PMID:28481359
  • Most commonly mutated gene in ccRCC; VHL LOF status did NOT correlate with immune-related gene expression, indicating the PBRM1-associated immune-transcriptional signal is PBRM1-specific and not a general consequence of VHL loss. PMID:29301960
  • Confirmed as a KIRC SMG called by both MutSig2CV and MuSiC2 on the TCGA MC3 open-access MAF; VHL is one of the canonical KIRC drivers consistently recovered across callers PMID:29596782

Cancer types (linked)

  • KIRC (clear cell renal cell carcinoma): Known canonical driver; all mutations observed in pancreatic SCAs were previously described in RCC PMID:22158988
  • Pancreatic SCA: VHL mutations and chr3p LOH define this benign cystic neoplasm subtype (8/8 SCA cases); not classified as PAAD but relevant to pancreatic surgical decision-making PMID:22158988

Co-occurrence and mutual exclusivity

  • VHL mutations in pancreatic cystic neoplasms are mutually exclusive with RNF43, GNAS, CTNNB1 mutations; VHL alterations are specific to SCAs, while IPMNs harbor RNF43/GNAS/KRAS and MCNs harbor KRAS/RNF43 PMID:22158988

Therapeutic relevance

  • VHL mutation status can distinguish benign SCAs from IPMNs and MCNs in cyst fluid, potentially reducing unnecessary surgical resections; a five-gene diagnostic panel (VHL, RNF43, CTNNB1, GNAS, KRAS) is proposed for preoperative cyst classification PMID:22158988

Open questions

  • 4/8 SCAs lacked detectable VHL point mutations; inactivation by deletion, translocation, or epigenetic silencing not detectable by exome sequencing may account for these cases PMID:22158988

Sources

This page was processed by entity-page-writer on 2026-05-15. - PMID:23792563

This page was processed by entity-page-writer on 2026-05-15. - PMID:23797736

This page was processed by entity-page-writer on 2026-05-15. - PMID:24487277

This page was processed by entity-page-writer on 2026-05-15. - PMID:25401301

This page was processed by entity-page-writer on 2026-05-15. - PMID:27713405

This page was processed by entity-page-writer on 2026-05-15. - PMID:28007021 - PMID:28162975

This page was processed by entity-page-writer on 2026-05-15. - PMID:28481359

This page was processed by wiki-cli on 2026-05-15. - PMID:29301960

This page was processed by entity-page-writer on 2026-05-15. - PMID:29596782

This page was processed by wiki-cli on 2026-05-15.