MAP3K1

Overview

MAP3K1 (Mitogen-Activated Protein Kinase Kinase Kinase 1, also MEKK1) is an upstream regulator of the MAPK and JNK signaling cascades. In cancer, MAP3K1 mutations have been reported in breast cancer and other solid tumors. In the sarcoma context, MAP3K1 was identified as a shared somatic SNV across synchronous metastatic lesions in a case of intra-tumoral heterogeneity.

Alterations observed in the corpus

  • MAP3K1 identified as one of three shared SNVs (alongside ARID2 and CRTC1) across four metastatic lesions resected synchronously from SARC0075 (epithelioid sarcoma with undifferentiated pleomorphic features) in the UCLA sarcoma PDTO biobank (n=194 specimens, 126 patients). The shared mutations confirm clonal relatedness despite extensive divergent CNV landscapes (including whole-genome duplications) among the four lesions. PMID:39305899
  • Truncating mutations in 6% of breast cancers (Sanger WES, 100 tumors), predominantly in ER+ tumors; inactivates JUN kinase signalling pathway; newly identified breast cancer driver gene PMID:22722201
  • Frameshift, nonsense, and missense mutations plus homozygous deletion in 3% of ER+ breast cancer (Broad WES, 103 tumors); pattern consistent with recessive inactivation PMID:22722202
  • Inactivating mutations in 14% of Luminal A breast cancer cases; acts in the p38/JNK1 pathway; mutually exclusive with MAP2K4 mutations PMID:23000897
  • Focal amplifications in 3 desmoplastic melanoma tumors; novel in melanoma; supported by analogy to a Sleeping Beauty mouse screen; functional validation in human desmoplastic melanoma not yet provided PMID:26343386
  • Recurrent focal deletion in prostate adenocarcinoma in the TCGA cohort (n=333); co-deletion of MAP3K7 with CHD1 marks aggressive ETS-negative disease PMID:26544944
  • MAP3K1 is the most common multi-hit gene (53/152 mutants with >1 functional mutation) in breast cancer, suggesting biallelic inactivation; classified as ER+ tumor-suppressor gene driver; mutations associated with improved BCSS (HR=0.56) PMID:27161491
  • Identified as a significantly mutated driver in metastatic breast cancer (mBC), also recurrent in early-stage breast cancer; enriched among HR+/HER2− mBC drivers PMID:28027327

Cancer types (linked)

  • Epithelioid sarcoma / undifferentiated pleomorphic sarcoma: MAP3K1 detected as a clonal (trunk) SNV shared across synchronous metastases in a single sarcoma case demonstrating substantial intra-patient spatial heterogeneity. PMID:39305899

Co-occurrence and mutual exclusivity

  • Co-mutated with ARID2 and CRTC1 as clonal trunk events in SARC0075 across all four synchronous metastatic lesions; CNV landscape was substantially divergent despite SNV sharing, indicating ongoing subclonal diversification. PMID:39305899

Therapeutic relevance

  • No direct therapeutic relevance reported. MAP3K1 mutation status was not used to guide drug selection in the PDTO screening; SARC0075 metastases showed Pearson correlations of 0.64–0.84 in drug-response profiles, suggesting shared biological vulnerabilities despite genomic heterogeneity. PMID:39305899

Open questions

  • Whether MAP3K1 mutation is a functional driver in epithelioid/undifferentiated pleomorphic sarcoma or a passenger event in a genomically complex tumor is unresolved based on single-case data. PMID:39305899

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:22722201

This page was processed by crosslinker on 2026-05-14. - PMID:22722202

This page was processed by crosslinker on 2026-05-14. - PMID:23000897

This page was processed by crosslinker on 2026-05-14. - PMID:26343386

This page was processed by crosslinker on 2026-05-14. - PMID:26544944

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

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