KEAP1

Overview

KEAP1 is a substrate adaptor for NRF2 ubiquitination; loss of function drives NRF2 pathway activation. In LUAD it is a recognized poor-prognosis co-mutation partner.

Alterations observed in the corpus

  • One of ten genes differentially altered between ever- and never-metastatic LUAD primary tumors PMID:37084736.
  • Mutually exclusive with EGFR alterations PMID:37084736.
  • KEAP1 mutations were detected in CSF ctDNA from lung cancer patients with CNS involvement in the csf_msk_2024 cohort (1,007 CSF samples, 711 patients) PMID:39289779.
  • KEAP1 mutations detected in plasma ctDNA are associated with the strongest gene-specific VTE risk (adjusted HR = 2.50, 95% CI: 1.62-3.85; n=76 patients with KEAP1 alteration) in a multi-cancer liquid biopsy analysis of 5,765 MSK patients PMID:39147831.
  • Loss-of-function mutation in lung squamous cell carcinoma (TCGA, 178 tumors); one of 10 significantly mutated genes (FDR q < 0.1); mutually exclusive with NFE2L2 mutations; NFE2L2/KEAP1/CUL3 pathway altered in 34% of LUSC tumors PMID:22960745
  • Inactivating mutations in 12% of 183 LUAD cases; anti-correlated with never/light smoking status PMID:22980975
  • KEAP1 is identified as a driver linked to oxidative-stress signaling in HCC by integrated genomic analysis PMID:24735922
  • KEAP1 loss-of-function mutations occur in ~3% of HCCs (co-listed with NFE2L2 at 4%) as part of the oxidative stress/NRF2 pathway alterations in the HCC mutational landscape. PMID:24798001
  • Loss-of-function mutations in 17% of LUAD (TCGA, n=230); enriched in oncogene-negative tumours (P < 0.01); co-occurs with STK11 as a defining feature of the PP transcriptional subtype PMID:25079552
  • KEAP1 alterations co-occur with NFE2L2 and CUL3 in the classical mRNA subtype of HNSC (TCGA, n=279), associated with heavy smoking and laryngeal sub-site, paralleling the oxidative-stress axis in LUSC. PMID:25631445
  • KEAP1 harbored deleterious mutations in ≥4 DCB patients and 0 NDB patients in a 34-patient NSCLC pembrolizumab cohort (association not corrected for mutation burden). PMID:25765070
  • KEAP1 significantly mutated by MutSigCV in HCC (243-case European WES cohort); part of oxidative-stress pathway altered in 12% of HCC; KEAP1-mutant cell lines show elevated NQO1 and candidate sensitivity to HSP90 inhibitors 17-AAG/17-DMAG, modulated by NQO1 P187S genotype PMID:25822088
  • Significantly mutated exclusively in lung ADC vs other TCGA tumor types (q < 0.1) in the TCGA pan-lung cancer cohort PMID:27158780
  • KEAP1 altered in esophageal squamous cell carcinoma (ESCC1) alongside NFE2L2 and CUL3, disrupting the NRF2-degradation complex and activating the NRF2 pathway associated with chemoradiotherapy resistance PMID:28052061.
  • Significantly enriched in UMD (unmatched molecular driver) cohort vs level 1–4 patients (p<0.05) in prospective LUAD study (860 patients, MSK-IMPACT); missense variants cluster in the Kelch domain interacting with NFE2L2/Nrf2; authors propose Nrf2 inhibitors (luteolin, brusatol) as chemosensitizers in future trials PMID:28336552

Cancer types (linked)

  • LUAD — enriched in ever-metastatic primaries (MSK cohort, n=2,532) PMID:37084736.

Co-occurrence and mutual exclusivity

  • TP53/EGFR co-alteration with KEAP1 (q<0.001) was significant only in ever-metastatic primaries PMID:37084736.
  • Mutually exclusive with EGFR alterations PMID:37084736.
  • KEAP1 was included in LUAD pathway/metastasis analyses in MSK-CHORD (n=24,950) PMID:39506116.

Therapeutic relevance

  • Co-alteration patterns including KEAP1 may inform site-specific metastatic risk stratification in LUAD PMID:37084736.

Open questions

  • None noted in the corpus.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:22960745

This page was processed by crosslinker on 2026-05-14. - PMID:22980975

This page was processed by crosslinker on 2026-05-14. - PMID:24735922

This page was processed by crosslinker on 2026-05-14. - PMID:24798001

This page was processed by crosslinker on 2026-05-14. - PMID:25079552

This page was processed by crosslinker on 2026-05-14. - PMID:25631445

This page was processed by crosslinker on 2026-05-14. - PMID:25765070

This page was processed by crosslinker on 2026-05-14. - PMID:25822088

This page was processed by crosslinker on 2026-05-14. - PMID:27158780

This page was processed by entity-page-writer on 2026-05-15. - PMID:28052061

This page was processed by entity-page-writer on 2026-05-15. - PMID:28336552

This page was processed by wiki-cli on 2026-05-14.