FOXA2

Overview

FOXA2 (forkhead box A2, also known as HNF3B) is a pioneer transcription factor with established roles in proximal tubule and renal development. In the context of ccRCC initiation, FOXA2 is identified as a mediator of HIF2A-specific transcriptional output following VHL loss in proximal tubule cells.

Alterations observed in the corpus

  • Identified by LISA and ChEA3 (top 50 in both analyses) as a transcription factor whose binding sites are enriched at HIF2A-specific (but not HIF1A-specific) Vhl-dependent gene loci in a murine ccRCC precursor model; proposed to mediate HIF2A’s tissue-restricted, dedifferentiation-linked transcriptional output PMID:23797736
  • Recurrent FOXA2 mutations were enriched in mCRPC tumors with neuroendocrine features (small-cell histology) across 63 men profiled at rapid autopsy PMID:26928463

Cancer types (linked)

  • CCRCC — FOXA2 binding-site enrichment at EPAS1/HIF2A-specific targets after VHL loss links this developmental TF to the dedifferentiation program in ccRCC precursor cells PMID:23797736

Co-occurrence and mutual exclusivity

Therapeutic relevance

  • FOXA2 mediates the HIF2A-driven dedifferentiation program that is therapeutically targeted by belzutifan in VHL disease PMID:23797736

Open questions

  • Whether FOXA2 is directly required for ccRCC tumor initiation or is a cooperative factor has not been tested by genetic perturbation in this model PMID:23797736

Sources

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