BAP1

Overview

BAP1 (BRCA1-Associated Protein 1) is a nuclear deubiquitinase that functions as a tumor suppressor in a broad range of malignancies. It is a canonical driver in diffuse pleural mesothelioma (DPM) and has been identified in rhabdomyosarcoma relapse specimens via liquid biopsy. BAP1 is not enriched in the genomic near-haploidization (GNH) subset of DPM.

Alterations observed in the corpus

  • BAP1 is a classical DPM driver; in a study of genomic near-haploidization (GNH) in DPM, BAP1 was altered in non-GNH DPM but not enriched in the GNH subset (n=10 GNH, n=44 non-GNH) PMID:38630790.
  • BAP1 deletions detected in 2/17 FN-RMS (fusion-negative rhabdomyosarcoma) patients exclusively at relapse, identified by ctDNA liquid biopsy in a multi-sample genomic analysis (n=35 tumor pairs) PMID:37730754.
  • One BRCA1/2 wild-type, MAPK-WT PAAD tumor harboring a BAP1 loss-of-function fusion received durable PARPi benefit in the MSK PDAC genomic cohort (n=2,336 tumors); BAP1 loss may confer HRD-like sensitivity to PARP inhibitors PMID:39753968.
  • BAP1 assessed in gallbladder carcinoma (GBC) genomic landscape study PMID:36228155
  • BAP1 loss-of-function mutations identified as a molecular subtype-defining event in clear cell renal cell carcinoma (ccRCC) with implications for immunotherapy response prediction PMID:22138691
  • BAP1 mutations identified in breast cancer WES of 100 tumors, implicating deubiquitinase-mediated chromatin regulation in breast cancer PMID:22722201
  • BAP1 is recurrently mutated in the Yale melanoma WES cohort of 147 tumors, suggesting a role for this ubiquitin carboxyl-terminal hydrolase and tumor suppressor in cutaneous melanoma PMID:22842228
  • Significantly mutated gene in CCRCC (TCGA, n=446); only SMG independently correlated with worse overall survival; enriched in mRNA subtype m4 (17% vs 7%, p=0.002) PMID:23792563
  • Inactivating mutations (nonsense, frameshift, splice-site) in 13/64 (20%) intrahepatic cholangiocarcinoma; first report in a gastrointestinal cancer; encodes a nuclear deubiquitinase implicated in chromatin remodeling PMID:24185509
  • Somatic mutation in 1/23 (4%) pancreatic acinar carcinomas; flagged as candidate for DNA cross-linking agents and PARP inhibition PMID:24293293
  • Subclonal/branch driver in ccRCC; RMH008 harbored three independent BAP1 hits (p.Gln277*, p.Asn411fs, p.Pro519fs); BAP1 mutation is a marker of poor prognosis and was heterogeneous in all cases detected across 10 ccRCC tumors PMID:24487277
  • Somatic mutation reported in the HCC molecular landscape (WES, n=1,289) as a non-actionable driver PMID:24798001
  • Recurrent somatic mutations in thymic carcinomas (cohort-level observation) PMID:24974848
  • Referenced as a known germline kidney-cancer predisposition gene; somatic profiles of nccRCC are contrasted against its germline role PMID:25401301
  • Loss enriched in non-fluke-related cholangiocarcinoma and small-duct intrahepatic CCA; small-duct iCCA arising on chronic liver disease backgrounds enriched for BAP1 and IDH1/IDH2 hotspot mutations and FGFR2 fusions PMID:25526346
  • Co-occurs with SF3B1 R625H and GNAQ/GNA11 hot-spots in Triple-WT cutaneous melanoma (typically uveal-melanoma drivers); BAP1 and SF3B1 mutations are mutually exclusive PMID:26091043
  • 11 truncating/splice/missense mutations in uveal melanoma (28/28 samples); all 6 BAP1-mutant WGS samples were chromosome-3 hemizygous, consistent with two-hit tumor-suppressor inactivation; one intronic 154 bp deletion identified via SV calling PMID:26683228
  • Essentially absent in extrahepatic cholangiocarcinoma (CAC) in this periampullary tumour cohort (single IDH1 hotspot only); contrasts with intrahepatic CAC where BAP1 alterations are common, confirming molecular distinctness of extra- vs intra-hepatic subtypes PMID:26804919
  • Inactivating mutation identified as a Mut-driver in breast cancer (METABRIC 2,433-sample cohort); flagged as a cross-cancer driver where therapies developed in other cancer types may be applicable PMID:27161491
  • BAP1: recurrent germline pathogenic/likely pathogenic variant in Indian familial NSCLC cohort enriched in young lung cancer PMID:27346245
  • BAP1 mutated in 13% of uRCC cases (62-patient MSK-IMPACT cohort); no significant outcome stratification on its own in this sample PMID:27713405
  • BAP1 enriched in IDH-WT Cluster 4 of cholangiocarcinoma (q < 0.001 for inactivating point mutations, q < 0.05 for regional deletions); BAP1-mutant CCAs show increased CpG hypermethylation; more frequent in intrahepatic CCAs (q < 0.1) PMID:28667006
  • BAP1 is an SMG identified by both MutSig2CV and MuSiC2 in KIRC using the TCGA MC3 open-access MAF. PMID:29596782

Cancer types (linked)

  • PLMESO (Diffuse Pleural Mesothelioma) — BAP1 is a canonical driver; its absence from the GNH subset suggests a distinct molecular path to aggressive DPM PMID:38630790.
  • RMS (Rhabdomyosarcoma) — BAP1 deletions arise exclusively at relapse in FN-RMS, detectable in ctDNA, suggesting a role in progression rather than initiation PMID:37730754.

Co-occurrence and mutual exclusivity

  • In DPM, BAP1 alterations are characteristic of the non-GNH majority; GNH DPM is instead defined by SETDB1 loss-of-function mutations and genome-wide LOH PMID:38630790.

Therapeutic relevance

  • BAP1 loss in DPM has been associated with potential immune checkpoint inhibitor sensitivity (ipilimumab/nivolumab); the GNH subset without BAP1 loss showed 67% response rate to ICB vs. 2% in non-GNH patients PMID:38630790.

Open questions

  • The mechanistic basis for BAP1 depletion being restricted to non-GNH DPM and absent from the GNH subset is not understood PMID:38630790.
  • Whether BAP1 deletion at RMS relapse is a driver of acquired resistance or a passenger alteration in clonal evolution is unresolved PMID:37730754.

Sources

This page was processed by crosslinker on 2026-05-14. - PMID:36228155

This page was processed by crosslinker on 2026-05-14. - PMID:22138691

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

This page was processed by crosslinker on 2026-05-14. - PMID:22842228

This page was processed by crosslinker on 2026-05-14. - PMID:23792563

This page was processed by crosslinker on 2026-05-14. - PMID:24185509

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

This page was processed by crosslinker on 2026-05-14. - PMID:24487277

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

This page was processed by crosslinker on 2026-05-14. - PMID:24974848

This page was processed by crosslinker on 2026-05-14. - PMID:25401301

This page was processed by crosslinker on 2026-05-14. - PMID:25526346

This page was processed by crosslinker on 2026-05-14. - PMID:26091043

This page was processed by crosslinker on 2026-05-14. - PMID:26683228

This page was processed by entity-page-writer on 2026-05-15. - PMID:26804919

This page was processed by entity-page-writer on 2026-05-15. - PMID:27161491

This page was processed by entity-page-writer on 2026-05-15. - PMID:27346245

This page was processed by entity-page-writer on 2026-05-15. - PMID:28667006

This page was processed by wiki-cli on 2026-05-15. - PMID:29596782

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