MEGF8
Overview
MEGF8 (Multiple Epidermal Growth Factor-Like Domains 8) functions as a negative regulator of Hedgehog signaling. Hedgehog pathway activation can promote an immunosuppressive tumor microenvironment. Somatic mutations in MEGF8 have been identified as candidate genomic biomarkers for response to PD-1 blockade in dMMR gynecologic cancers.
Alterations observed in the corpus
- Mutated in 18% of dMMR/MSI-H gynecologic cancers overall; enriched in responders to nivolumab (32% in responders vs. 0% in non-responders, P=0.027); functions as a negative regulator of Hedgehog signaling, which can promote immunosuppressive tumor microenvironment PMID:38653864.
Cancer types (linked)
- Gynecologic cancers (dMMR/MSI-H) — MEGF8 mutations associated with response to nivolumab (anti-PD-1); candidate biomarker warranting validation in larger cohorts PMID:38653864.
Co-occurrence and mutual exclusivity
- Co-mutated with other MMR pathway and Hedgehog pathway genes (PTCH1 mutated in 18% of the same cohort) PMID:38653864.
Therapeutic relevance
- MEGF8 mutations are candidate genomic predictors of response to nivolumab in dMMR gynecologic cancers; proposed mechanism is reduced Hedgehog-driven immunosuppression PMID:38653864.
Open questions
- The association between MEGF8 mutations and nivolumab response is based on a small cohort (n=35); independent validation is required.
- Whether MEGF8 loss relieves Hedgehog-mediated immunosuppression functionally, improving immune recognition, has not been experimentally confirmed.
Sources
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