CGAS

Overview

CGAS (cyclic GMP-AMP synthase) encodes a DNA sensor that detects cytosolic double-stranded DNA and initiates innate immune signaling via production of the second messenger cGAMP, which activates STING1. The cGAS-STING pathway links DNA damage and chromosomal instability to innate immune activation and interferon signaling. In high-grade serous ovarian carcinoma (HGSOC) precursors, cGAS is recruited to ruptured micronuclei generated by chromosomal instability events, representing an early step in immune pathway activation during tumorigenesis.

Alterations observed in the corpus

  • cGAS-STING pathway activated by ruptured micronuclei in HGSOC precursors; cGAS recruited to BANF1+ micronuclei as early as the STIC.I (serous tubal intraepithelial carcinoma) stage; this activates interferon signaling and contributes to the interferon-related DNA damage resistance signature (IRDS) PMID:39386723.

Cancer types (linked)

  • HGSOC: cGAS activation by micronuclei from chromosomal instability (linked to CCNE1 amplification) is an early event in HGSOC precursor evolution; the resulting chronic interferon activation through cGAS-STING contributes to the IRDS signature and may drive chemoresistance in advanced HGSOC PMID:39386723.

Co-occurrence and mutual exclusivity

  • cGAS pathway activation co-occurs with STING1 signaling, CCNE1 amplification, and breakage-fusion-bridge cycles in HGSOC precursors; BANF1+ micronuclei serve as the cytosolic DNA substrate activating cGAS PMID:39386723.

Therapeutic relevance

  • Chronic cGAS-STING activation contributes to the IRDS signature, which may promote chemoresistance in >80% of stage III/IV HGSOC; modulating this pathway could represent a strategy to sensitize resistant tumors PMID:39386723.
  • cGAS pathway activity in STIC precursors could serve as a biomarker for risk stratification in high-risk patients undergoing risk-reducing salpingo-oophorectomy PMID:39386723.

Open questions

  • Whether cGAS-STING inhibition (to block IRDS-driven chemoresistance) vs. activation (to enhance anti-tumor immunity) represents the optimal therapeutic intervention in HGSOC remains unresolved.

Sources

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