KMT2D

Overview

KMT2D (MLL2) is a histone H3K4 methyltransferase frequently mutated in B-cell lymphomas.

Alterations observed in the corpus

  • Epigenetic regulator enriched in M-CLL via SNV, showing pathway convergence with KMT2C loss PMID:35927489.
  • Truncating and missense KMT2D mutations in 11% of RT-ANGS (vs 1% sporadic AS) and 21% of RT-MFH (UPS; vs 4% sporadic UPS), making it significantly enriched in both RT-sarcoma histotypes in the MSK 82-patient RT-sarcoma cohort PMID:37350195.
  • KMT2D altered in 9% of cervical cancers (n=177 MSK patients); enriched in squamous (14%) vs gastric-type adenocarcinoma (0%) PMID:37643132.
  • KMT2D mutation detected in one prostate cancer PDX model (PDX 316-1) in the MDA PCa PDX series (44 PDXs from 38 patients) PMID:38488813.
  • KMT2D is a frequent co-mutation in BRAF fusion-positive colorectal cancers alongside RNF43, INPPL1, MSH3, and ARID1A in a tumor-agnostic analysis of 212 patients with BRAF fusions PMID:38922339.
  • KMT2D is a chromatin-modifying gene with high prevalence of non-silent variants in metastatic UC (UC-GENOME cohort), consistent with TCGA-BLCA PMID:36333289
  • KMT2D was among the most frequently mutated genes in DLBCL and FL, establishing its role as a major epigenetic tumor suppressor in B-cell lymphomas PMID:21796119
  • Identified as a significantly mutated gene in HNSCC whole-exome sequencing of 74 tumor-normal pairs (Broad cohort) PMID:21798893
  • KMT2D is among the significantly mutated genes in DLBCL identified by whole-exome sequencing of 55 tumors (MutSig, Broad Institute) PMID:22343534
  • Second most frequent HBV integration target in HCC (11.8%); intronic and exonic insertions cause epigenomic modification and downregulate the p53 pathway with >20-fold expression increase PMID:22634756
  • KMT2D (MLL2/MLL4) found as one of the most frequently mutated genes in medulloblastoma WGS cohort (PCGP, 37 tumors), establishing H3K4 methyltransferase loss as a key event in pediatric brain tumors PMID:22722829
  • KMT2D alterations identified in prostate cancer WES cohort (Michigan, 112 tumors); KMT2D loss co-occurs with ETS fusions and EZH2 alterations, suggesting convergent epigenetic dysregulation PMID:22722839
  • Somatic mutations detected in medulloblastoma WES cohort (Broad, 92 tumors) PMID:22820256
  • Somatic mutations identified in medulloblastoma WGS/WES cohort (ICGC, 76 tumors) PMID:22832583
  • Significantly mutated (FDR q < 0.1) in lung squamous cell carcinoma (178 tumors, TCGA); one of 10 top-tier significantly mutated genes PMID:22960745
  • Truncating and FYRN/FYRC-domain missense mutations in 4/29 (14%) primary MCL WES cases and 2/6 MCL cell lines; no biallelic loss detected; restricted to SOX11-positive/IGHV-unmutated MCL; classified as an early/clonal event by allelic-frequency analysis in paired subclone samples PMID:24145436
  • KMT2D (MLL2, H3K4 methyltransferase) mutated in 27% of muscle-invasive bladder cancers with truncating enrichment; identified as a novel significantly mutated gene (SMG) in bladder cancer; mutually exclusive with KDM6A PMID:24476821
  • KMT2D (histone methyltransferase) is significantly mutated in ESCC, contributing to epigenetic dysregulation PMID:24686850
  • Included as one of four chromatin-modifier genes (CMGs) validated by orthogonal sequencing in muscle-invasive bladder cancer (MSKCC cohort); concordance rate 99.3% between discovery and validation platforms PMID:25092538
  • Chromatin-modifier mutation identified in MSK prostate cancer cell lines, consistent with Grasso 2012 CRPC findings PMID:25201530
  • Novel somatic mutation in chromatin/methyltransferase regulators in Ewing sarcoma WGS cohort (MLL2) PMID:25223734
  • Splice-site alteration in 1/22 gynaecologic carcinosarcomas (MLL2), co-occurring with a KMT2C mutation in the same tumor PMID:25233892
  • Mutated in 69.2% of 39 aggressive cSCC tumors; another histone-methylation regulator significant by inactivation-bias methods; shared with HNSC mutation landscape PMID:25303977
  • KMT2D chromatin-remodeling defect detected in hypermutated gastric adenocarcinoma (Pt1); co-occurs with MSH6, KDM5A, and TGFBR2 in the hypermutated subclone PMID:25583476
  • KMT2D (MLL2) nonsense mutations observed in 5/29 (17%) metastatic cSCC cases as part of a 48% chromatin-remodeling inactivation rate; chromatin-remodeling mutations independently associated with shorter PFS and worst outcome in combination with RAS/RTK/PI3K activation. PMID:25589618
  • KMT2D (MLL2) significantly mutated in 18% of 279 HNSC (MutSigCV q<0.1); contributes to defective immunosurveillance. PMID:25631445
  • KMT2D selectively mutated in mCRPC vs. primary prostate cancer (q<0.1, Benjamini-Hochberg) in the SU2C–PCF 150-case prospective WES cohort PMID:26000489
  • Chromatin-modifying gene mutated in UTUC; mutations common in both low- and high-grade tumors and concordant across spatial tumor components, suggesting early/clonal events PMID:26278805
  • Subclonal chromatin remodeling mutation in breast adenoid cystic carcinoma (AdCC); may contribute to intra-tumor heterogeneity and therapeutic escape PMID:26095796
  • Truncating chromatin-modifier mutations in KMT2D enriched in the 26% ‘unclassified’ prostate cancer subset with high SCNA burden in the TCGA prostate cohort PMID:26544944
  • Truncating mutation p.Gln2418* in mycosis fungoides (CTCL); KMT2D chromatin-modifier mutations identified alongside KMT2C in the CTCL/Sézary syndrome exome cohort PMID:26551667
  • 3 mutations in 2 tumors (MLL2) in adenoid cystic carcinoma (ACC; n=25 WGS); significant enrichment of truncating mutations (p=0.008); part of a chromatin-regulator cluster with KMT2C, KDM6A, SMARCA2, and SMARCC1 PMID:26862087
  • KMT2D, together with KMT2A, KMT2C, and SETD2, are histone methyltransferases mutated collectively in 24% of ATC vs 7% of PDTC (P = 0.02) in a 341-gene panel sequencing study of thyroid cancers PMID:26878173
  • Recurrently mutated in unclassified renal cell carcinoma (uRCC, n=62 MSKCC cohort); among the most frequent chromatin-modulator alterations alongside KMT2C and KMT2A (combined KMT2 family 16%); clusters in the chromatin/DNA-damage regulator subgroup with intermediate clinical outcome. PMID:27713405
  • Among canonical urothelial carcinoma (UC) drivers (alongside PIK3CA and ATM) shown to be heterogeneously shared between matched pre/post-chemotherapy samples in a 32-patient cohort — mean ~28% mutation sharing — highlighting tumor evolutionary instability under platinum-based chemotherapy. PMID:27749842
  • Among the most frequently mutated epigenetic modifiers in DUX4/ERG B-ALL (epigenetic-modifier mutations in 56.3% of cases overall, with KMT2D, SETD2, ARID2 and NCOR1 as top hits) in a 1,913-patient B-ALL cohort. PMID:27776115
  • KMT2D (MLL2) homozygous frameshift M3881Cfs*9 established Kabuki syndrome in a 2-month-old hospitalized for fulminant hemophagocytic syndrome; familial HLH was ruled out and stem-cell transplant was averted PMID:28007021.
  • KMT2D (MLL2) histone-modifier alterations frequent in ESCC, especially in the ESCC2 subtype; mutated in 3/4 ESCC3 tumors; co-altered with KMT2C and KDM6A PMID:28052061.
  • Chromatin modifier enriched in UMD (unmatched molecular driver) subset, especially never/former-light smokers, in prospective LUAD cohort (860 patients, MSK-IMPACT) PMID:28336552
  • Recurrent histone-methylation-modifier mutations across medulloblastoma subgroups PMID:28726821
  • Identified as an epigenetic regulator with truncal/subclonal events in matched-tumor phylogenetic analysis of prostate cancer PMID:28825054
  • Recurrent driver in DLBCL (1001-patient cohort); mutually exclusive with MYC mutations; previously known as MLL2. PMID:28985567
  • Histone methyltransferase chromatin-modifier SMG in MIBC (n=412, TCGA BLCA 2017); predominantly inactivating mutations. PMID:28988769
  • Epigenetic-regulator SMG significantly enriched in metastatic vs primary PRAD tumors in the 1,013-sample WES meta-cohort (prad_p1000); part of the metastasis-enrichment genomic signature alongside TP53, AR, PTEN, RB1, FOXA1, APC, BRCA2, and KMT2C. PMID:29610475

Cancer types (linked)

  • CLLSLL — M-CLL-enriched driver in the integrated CLL map (n=1,148) PMID:35927489.
  • ANGS — KMT2D mutations enriched in RT-AS (11%) vs sporadic AS (1%); co-occurring with MYC amplification PMID:37350195.
  • MFH (UPS) — KMT2D mutations in 21% of RT-UPS vs 4% sporadic UPS PMID:37350195.
  • CESC — altered in 9% of cervical cancers; enriched in squamous histology (14%) PMID:37643132.
  • PRAD — somatic mutation in a prostate cancer PDX model PMID:38488813.

Co-occurrence and mutual exclusivity

Therapeutic relevance

  • None reported.

Open questions

  • None noted.

Sources

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This page was processed by crosslinker on 2026-05-14. - PMID:26000489

This page was processed by crosslinker on 2026-05-14. - PMID:26278805

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This page was processed by entity-page-writer on 2026-05-15. - PMID:27713405

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This page was processed by entity-page-writer on 2026-05-15. - PMID:27776115

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