EZH2

Overview

EZH2 encodes the catalytic subunit of the Polycomb Repressive Complex 2 (PRC2), responsible for trimethylating histone H3 at lysine 27 (H3K27me3). In cancer, gain-of-function mutations at Y641 and nearby residues enhance H3K27 trimethylation, silencing tumor suppressor genes and promoting proliferation. EZH2 is a key oncogenic driver in germinal center B-cell (GCB) subtypes of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL).

Alterations observed in the corpus

  • EZH2 was recurrently mutated in DLBCL and FL, with gain-of-function mutations at Y641 (including Y641F, Y641N, Y641S, Y641H, Y641C), A682G, and A692V, leading to enhanced H3K27 trimethylation; mutations enriched in GCB subtype PMID:21796119
  • Identified as a significantly mutated gene in HNSCC whole-exome sequencing of 74 tumor-normal pairs (Broad cohort) PMID:21798893
  • EZH2 is among the significantly mutated genes in DLBCL identified by whole-exome sequencing of 55 tumors (MutSig, Broad Institute) PMID:22343534
  • Mutated in medulloblastoma WGS cohort (PCGP, 37 tumors); EZH2 alterations implicate Polycomb-mediated epigenetic silencing in pediatric brain cancer PMID:22722829
  • EZH2 alterations detected in prostate cancer WES cohort (Michigan, 112 tumors); EZH2 overexpression and mutation co-occur with ETS fusions in aggressive prostate cancer PMID:22722839
  • Somatic mutations detected in melanoma WES cohort (Broad, 121 tumors) PMID:22817889
  • Somatic mutations detected in pediatric ALL (St. Jude WGS/WES, 44 tumors); loss-of-function mutations implicated in epigenetic dysregulation PMID:23334668
  • Member of the chromatin-modifying gene category (with KDM6A, KMT2A, KMT2C) recurrently mutated in AML; contributes to the epigenetic regulation landscape of the disease PMID:23634996
  • Somatic variants identified in 4 patients in whole-exome sequencing of myeloproliferative neoplasms (ET, PV, MF) as part of the CALR discovery cohort PMID:24325359
  • Identified as an established EWS::FLI1 transcriptional target induced upon oncogene expression in heMSCs; validated by RT-qPCR as part of the Ewing sarcoma transcriptional program PMID:25186949
  • Recurrent SET-domain missense mutations Y646F, Y646H, A682G (3/112 cases) in Ewing sarcoma; known gain-of-function alleles in B-cell lymphoma; one of three significantly mutated genes by MuSiC SMG test PMID:25223734
  • Not altered in any MPNST discovery or validation cohort; explicit negative finding — PRC2 loss in MPNST occurs exclusively via EED or SUZ12 inactivation, not EZH2 PMID:25240281
  • Y641S gain-of-function lymphoma allele found in cSCC (cutaneous squamous cell carcinoma) PMID:25589618
  • Y641 hotspot mutation in Triple-WT cutaneous melanoma subtype (n=1) PMID:26091043
  • Y641S hotspot in 1 desmoplastic melanoma tumor PMID:26343386
  • Mentioned in study PMID:26855148
  • EZH2 identified as a chromatin regulator within the chromatin-spliceosome AML subgroup in a genomic classification of 1,540 patients; SMARCB1 deletion in a related context nominated EZH2 inhibitors as a therapeutic strategy PMID:27276561
  • Mutated in 3 HR+/HER2− metastatic breast cancer (BRCA) cases including hotspot COSM220530; enriched in HR+ mBC at FDR<0.1 vs early breast cancer PMID:28027327.
  • EZH2 mutations and/or altered expression were reported in the context of epigenetic dysregulation and cancer progression PMID:28196596
  • Upregulated EZH2 expression in Cluster 1 CCA alongside downregulated TET1, suggesting gain-of-repressive-methylation as the epigenetic mechanism driving CpG-shore hypermethylation in this cholangiocarcinoma subtype PMID:28667006.
  • Preferentially mutated in GCB-DLBCL; EZH2 mutations associated with better survival in GCB-DLBCL in the comprehensive genetic and functional driver analysis (n=1,001 patients) PMID:28985567
  • Identified via cited preclinical work (Ler et al. 2017; Wu et al. 2016) as part of the BRD4–EZH2 chromatin-modification growth pathway whose inhibition is therapeutically tractable in KDM6A-loss bladder cancer; EZH2 inhibitors proposed alongside JQ1 for KDM6A-deficient MIBC PMID:28988769

Cancer types (linked)

  • DLBCL (GCB subtype): Y641 hotspot mutations confer enhanced PRC2 activity, silencing target genes and driving GCB B-cell differentiation block PMID:21796119
  • FL: Y641 mutations also recurrent, supporting a shared epigenetic mechanism with DLBCL PMID:21796119

Co-occurrence and mutual exclusivity

  • EZH2 mutations co-occur with CREBBP and EP300 mutations within the GCB DLBCL landscape, suggesting convergent disruption of histone modification balance PMID:21796119

Therapeutic relevance

  • EZH2 inhibitors (e.g., tazemetostat) have been developed targeting Y641 gain-of-function mutations; clinical relevance supported by the high recurrence frequency in GCB DLBCL and FL.

Open questions

  • Whether EZH2 mutations are drivers or passengers in FL progression to DLBCL remains under investigation.

Sources

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

This page was processed by entity-page-writer on 2026-05-15. - PMID:26855148

This page was processed by entity-page-writer on 2026-05-15. - PMID:27276561

This page was processed by entity-page-writer on 2026-05-15. - PMID:28027327

This page was processed by wiki-cli on 2026-05-14. - PMID:28196596

This page was processed by wiki-cli on 2026-05-14. - PMID:28667006

This page was processed by wiki-cli on 2026-05-15. - PMID:28985567

This page was processed by wiki-cli on 2026-05-15. - PMID:28988769

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