JAK1

Overview

JAK1 encodes a Janus kinase involved in cytokine receptor signaling through the JAK-STAT pathway. In cancer genomics, JAK1 is frequently mutated in MSI-H/dMMR tumors and has been implicated in resistance to immune checkpoint blockade.

Alterations observed in the corpus

  • JAK1 is mutated in 24% of dMMR/MSI-H gynecologic cancers (endometrial, cervical, ovarian) in a phase 2 trial of nivolumab (n=35); previously implicated in resistance to immunotherapy, but no significant association with nivolumab response or resistance was observed in this cohort PMID:38653864.
  • JAK1 mutation rate is higher in MSI-H/dMMR prostate cancer (56%) vs TMB-H/MSS (15%) and TMB-L/MSS (32%, p<0.001) prostate cancer; enrichment in MSI-H/dMMR is likely due to a microsatellite tract within JAK1 making it a passenger mutation in this hypermutated context PMID:38949888.
  • Somatic mutation in 4/23 (17%) pancreatic acinar cell carcinomas; flagged as a potentially targetable alteration given clinical-stage JAK1 inhibitors available at time of publication PMID:24293293
  • Mutations activating JAK-STAT3 signaling identified in ESCC (139 paired tumor/germline samples) PMID:24686850
  • JAK1 is listed among recurrently mutated genes in the HCC WES landscape (n=1,289), part of the JAK/STAT signaling axis implicated in hepatocellular carcinoma. PMID:24798001
  • JAK1 was identified as one of 20 significantly mutated genes in African American colorectal cancers (103 AA vs 129 Caucasian MSS CRC), part of the 15-gene subset preferentially mutated in AA CRCs (~41% of AA vs 15% of Caucasian CRCs). PMID:25583493
  • JAK1 identified as a low-frequency but FDA-druggable alteration in JAK/STAT pathway in HCC (<1% frequency); part of 28% of HCC with at least one FDA-targetable alteration in the 243-case European cohort PMID:25822088
  • HD-defined candidate newly identified as linked to immune evasion/immune modulation in breast cancer via combined homozygous deletion and inactivating-mutation evidence PMID:27161491
  • JAK1 K1026E activating mutation identified in pediatric T-cell lymphoblastic lymphoma/leukemia (T-BLL), co-occurring with STAT5B I704L and KRAS V14I as a JAK-inhibitor target PMID:28007021.
  • Mutations not associated with resistance to nivolumab in advanced melanoma (CA209-038, n=68), contrary to prior reports linking JAK pathway disruption to IFN-γ-blockade resistance. PMID:29033130
  • Low-frequency loss-of-function events noted alongside JAK2 in a 240-patient NSCLC immunotherapy cohort; one patient with homozygous loss-of-function JAK2 splice mutation had primary resistance (PD), consistent with interferon-gamma signaling defects described in melanoma PMID:29337640

Cancer types (linked)

  • UCEC and other dMMR gynecologic cancers — JAK1 mutated in 24% of MSI-H tumors; no differential association with nivolumab benefit vs non-benefit PMID:38653864.
  • PRAD — JAK1 enriched in MSI-H/dMMR (56%) vs MSS prostate cancer; attributed to microsatellite instability at a JAK1 intronic microsatellite tract PMID:38949888.

Co-occurrence and mutual exclusivity

  • JAK1 mutations are enriched in MSI-H/dMMR tumors across cancer types, likely as a passenger event due to microsatellite instability rather than a primary driver PMID:38949888.

Therapeutic relevance

  • JAK1 mutations have been proposed as a mechanism of resistance to IFN-gamma-mediated immune recognition and anti-PD-1 therapy; however, in the nivolumab gynecologic cancer trial (n=35), JAK1 mutation was not associated with response or resistance PMID:38653864.

Open questions

  • Whether JAK1 mutations in dMMR tumors represent true resistance drivers or are predominantly microsatellite instability-associated passenger events requires larger prospective studies PMID:38653864 PMID:38949888.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:24293293

This page was processed by crosslinker on 2026-05-14. - PMID:24686850

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

This page was processed by crosslinker on 2026-05-14. - PMID:25583493

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

This page was processed by crosslinker on 2026-05-14. - PMID:27161491

This page was processed by entity-page-writer on 2026-05-15. - PMID:28007021

This page was processed by entity-page-writer on 2026-05-15. - PMID:29033130

This page was processed by entity-page-writer on 2026-05-15. - PMID:29337640

This page was processed by wiki-cli on 2026-05-15.