EGLN1

Overview

EGLN1 (Egl-9 family hypoxia inducible factor 1), also known as PHD2 (prolyl hydroxylase domain protein 2), is the primary oxygen sensor that targets HIF-alpha subunits for VHL-mediated proteasomal degradation. Germline loss-of-function mutations in EGLN1 stabilize HIF and cause pseudohypoxia — a hallmark of a distinct pheochromocytoma/paraganglioma (PCC/PGL) molecular subtype. EGLN1 is one of eight known germline susceptibility genes in PCC/PGL.

Alterations observed in the corpus

  • Rare germline mutations identified in PCC/PGL (≤2% of patients) in the TCGA PCPG multi-platform study (n=173); grouped in the hypoxia signaling pathway axis alongside VHL, ARNT, and EPAS1 — these four are mutually exclusive PMID:28162975.
  • EGLN1 germline mutations are completely specific to the pseudohypoxia mRNA subtype in PCC/PGL PMID:28162975.

Cancer types (linked)

  • PHC / PGNG — rare germline EGLN1 mutations define a subset of pseudohypoxia-subtype PCC/PGL; mutually exclusive with VHL, ARNT, and EPAS1 alterations PMID:28162975.

Co-occurrence and mutual exclusivity

Therapeutic relevance

  • No EGLN1-directed therapeutic agents described in the corpus. The authors note FDA-approved targeted therapies exist for tumors carrying EGLN1 pathway alterations (VHL, EPAS1) PMID:28162975.

Open questions

  • The specific prevalence and spectrum of EGLN1 germline mutations in PCC/PGL are not detailed in the TCGA PCPG report; cited as one of eight known susceptibility genes at ≤2% frequency PMID:28162975.

Sources

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