{"entity":{"id":"epigenetic-reprogramming","kind":"pathway","name":"Epigenetic reprogramming","aka":[],"tldr":"Cancer changes not just its genes but how they are read: chemical tags on DNA and histones silence guardians and awaken growth programmes. Unlike mutations, these changes are reversible, which is the hope behind epigenetic drugs.","summary":"DNA methylation (DNMT1/3A, TET2, IDH-driven hypermethylation), histone marks (EZH2/H3K27me3, KMT2 family, H3K27M in glioma, NSD2 in myeloma), chromatin readers (BET proteins), and remodelling (SWI/SNF) are all mutated or hijacked. 'Non-mutational epigenetic reprogramming' is a 2022 hallmark: drug-tolerant persister states arise without new mutations. Approved: azacitidine/decitabine (MDS/AML), HDAC inhibitors (T-cell lymphoma), EZH2 (tazemetostat, withdrawn 2026), IDH inhibitors, menin inhibitors (KMT2A/NPM1 leukaemia). Solid tumour activity remains modest; combinations to re-express antigens or hormone receptors are the current bet. Methylation classifiers diagnose brain tumours and underlie cfDNA cancer detection.","asOf":"2026-09-08","wikipedia":"https://en.wikipedia.org/wiki/Cancer_epigenetics","links":[{"label":"Hanahan, Hallmarks of Cancer: New Dimensions (Cancer Discovery 2022)","url":"https://doi.org/10.1158/2159-8290.CD-21-1059"},{"label":"Baylin & Jones, Epigenetic determinants of cancer (Cold Spring Harbor Perspectives 2016)","url":"https://doi.org/10.1101/cshperspect.a019505"}],"tags":["mechanism"],"related":["epigenetic-progenitor-theory"],"cancers":["colorectal","non-hodgkin-lymphoma"],"sections":[],"technologies":["epigenetic-drugs","methylation-profiling","mced"],"targets":["idh","ezh2","menin","kmt2a","npm1","tet2","brd4"],"drugs":["azacitidine","revumenib","ziftomenib","vorasidenib"],"companies":[],"institutions":["johns-hopkins","dkfz","dana-farber","mskcc"],"pathways":["swi-snf-chromatin","cancer-stem-cells-plasticity","er-signaling"],"terms":["nonmutational-epigenetic-reprogramming","mgmt","h3k27m"],"trials":[],"people":[],"bottlenecks":[],"keyPapers":["paper-baylin-cold-spring-harb-perspect-biol"],"journals":[],"dependsOn":[],"notes":["Leading programmes: Baylin (Johns Hopkins, DNA methylation); Pfister (DKFZ, methylation classification); Armstrong (Dana-Farber, menin/KMT2A); Allis legacy (Rockefeller, histone code)."],"analogy":"The genome is the book; epigenetics is the highlighting and the pages stapled shut. Cancer staples shut the safety chapters and highlights the growth chapters. Epigenetic drugs pull staples.","nodes":[{"id":"dnmt","label":"DNA methylation (DNMT, TET2, IDH/2-HG)","x":15,"y":25,"targetId":"idh"},{"id":"hist","label":"Histone marks (EZH2, KMT2A, H3K27M)","x":15,"y":55,"targetId":"ezh2"},{"id":"reader","label":"Readers (BET) & remodellers (SWI/SNF)","x":15,"y":85},{"id":"chrom","label":"Chromatin state","x":50,"y":55},{"id":"sil","label":"Silenced tumour suppressors, antigens","x":82,"y":30},{"id":"act","label":"Active oncogenic programmes, persister states","x":82,"y":75},{"id":"menin","label":"Menin-KMT2A scaffold","x":50,"y":20,"targetId":"menin"}],"edges":[{"from":"dnmt","to":"chrom","type":"activates"},{"from":"hist","to":"chrom","type":"activates"},{"from":"reader","to":"chrom","type":"activates"},{"from":"chrom","to":"sil","type":"activates"},{"from":"chrom","to":"act","type":"activates"},{"from":"menin","to":"hist","type":"activates"}],"interventions":["Hypomethylating agents (azacitidine, decitabine) with venetoclax in AML","Menin inhibitors (revumenib, ziftomenib) in KMT2A/NPM1 leukaemia","IDH inhibitors reverse 2-HG hypermethylation","HDAC, BET, LSD1 inhibitors mostly in trials; epigenetic priming for immunotherapy"]},"route":"/pathways/epigenetic-reprogramming/","neighbours":{"term":[{"id":"epigenetic-progenitor-theory","kind":"term","name":"Epigenetic progenitor theory: cancer without a first mutation","route":"/terms/epigenetic-progenitor-theory/"},{"id":"h3k27m","kind":"term","name":"H3 K27M (diffuse midline glioma)","route":"/terms/h3k27m/"},{"id":"nonmutational-epigenetic-reprogramming","kind":"term","name":"Hallmark (2022): non-mutational epigenetic reprogramming","route":"/terms/nonmutational-epigenetic-reprogramming/"},{"id":"unlocking-phenotypic-plasticity","kind":"term","name":"Hallmark (2022): unlocking phenotypic plasticity","route":"/terms/unlocking-phenotypic-plasticity/"},{"id":"mgmt","kind":"term","name":"MGMT promoter methylation","route":"/terms/mgmt/"},{"id":"lymphoma-bio-germinal-centre","kind":"term","name":"The germinal centre: why lymphoma starts where antibodies are made","route":"/terms/lymphoma-bio-germinal-centre/"}],"cancer":[{"id":"atrt","kind":"cancer","name":"Atypical teratoid/rhabdoid tumour (ATRT)","route":"/cancers/atrt/"},{"id":"cmml","kind":"cancer","name":"Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms","route":"/cancers/cmml/"},{"id":"colorectal","kind":"cancer","name":"Colorectal cancer","route":"/cancers/colorectal/"},{"id":"dlbcl","kind":"cancer","name":"Diffuse large B-cell lymphoma","route":"/cancers/dlbcl/"},{"id":"dipg-dmg","kind":"cancer","name":"Diffuse midline glioma, H3 K27-altered (including DIPG)","route":"/cancers/dipg-dmg/"},{"id":"ependymoma","kind":"cancer","name":"Ependymoma","route":"/cancers/ependymoma/"},{"id":"epithelioid-sarcoma","kind":"cancer","name":"Epithelioid sarcoma","route":"/cancers/epithelioid-sarcoma/"},{"id":"follicular-lymphoma","kind":"cancer","name":"Follicular lymphoma","route":"/cancers/follicular-lymphoma/"},{"id":"angioimmunoblastic-t-cell-lymphoma","kind":"cancer","name":"Nodal T-follicular helper cell lymphoma, angioimmunoblastic type (angioimmunoblastic T-cell lymphoma)","route":"/cancers/angioimmunoblastic-t-cell-lymphoma/"},{"id":"non-hodgkin-lymphoma","kind":"cancer","name":"Non-Hodgkin lymphoma (all types)","route":"/cancers/non-hodgkin-lymphoma/"},{"id":"nut-carcinoma","kind":"cancer","name":"NUT carcinoma (midline carcinoma with NUTM1 rearrangement)","route":"/cancers/nut-carcinoma/"},{"id":"pancreatic","kind":"cancer","name":"Pancreatic ductal adenocarcinoma","route":"/cancers/pancreatic/"},{"id":"peripheral-t-cell-lymphoma","kind":"cancer","name":"Peripheral T-cell lymphomas (including cutaneous T-cell lymphoma)","route":"/cancers/peripheral-t-cell-lymphoma/"},{"id":"prostate","kind":"cancer","name":"Prostate cancer","route":"/cancers/prostate/"}],"technology":[{"id":"methylation-profiling","kind":"technology","name":"DNA methylation profiling","route":"/technologies/methylation-profiling/"},{"id":"epigenetic-drugs","kind":"technology","name":"Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)","route":"/technologies/epigenetic-drugs/"},{"id":"mced","kind":"technology","name":"Multi-cancer early detection (MCED)","route":"/technologies/mced/"}],"target":[{"id":"b2m","kind":"target","name":"B2M","route":"/targets/b2m/"},{"id":"bcl6","kind":"target","name":"BCL6","route":"/targets/bcl6/"},{"id":"brd4","kind":"target","name":"BRD4","route":"/targets/brd4/"},{"id":"cd58","kind":"target","name":"CD58","route":"/targets/cd58/"},{"id":"crebbp","kind":"target","name":"CREBBP","route":"/targets/crebbp/"},{"id":"dnmt3a","kind":"target","name":"DNA methyltransferase 3A (DNMT3A)","route":"/targets/dnmt3a/"},{"id":"ep300","kind":"target","name":"EP300","route":"/targets/ep300/"},{"id":"ezh2","kind":"target","name":"EZH2","route":"/targets/ezh2/"},{"id":"fyn","kind":"target","name":"FYN","route":"/targets/fyn/"},{"id":"hoxa9","kind":"target","name":"HOXA9","route":"/targets/hoxa9/"},{"id":"idh","kind":"target","name":"IDH1 / IDH2","route":"/targets/idh/"},{"id":"kmt2a","kind":"target","name":"KMT2A (MLL) rearrangement","route":"/targets/kmt2a/"},{"id":"kmt2d","kind":"target","name":"KMT2D","route":"/targets/kmt2d/"},{"id":"menin","kind":"target","name":"Menin","route":"/targets/menin/"},{"id":"mlh1","kind":"target","name":"MLH1","route":"/targets/mlh1/"},{"id":"npm1","kind":"target","name":"NPM1 mutation","route":"/targets/npm1/"},{"id":"rhoa","kind":"target","name":"RHOA","route":"/targets/rhoa/"},{"id":"tet2","kind":"target","name":"TET2","route":"/targets/tet2/"}],"drug":[{"id":"azacitidine","kind":"drug","name":"Azacitidine","route":"/drugs/azacitidine/"},{"id":"revumenib","kind":"drug","name":"Revumenib","route":"/drugs/revumenib/"},{"id":"vorasidenib","kind":"drug","name":"Vorasidenib","route":"/drugs/vorasidenib/"},{"id":"ziftomenib","kind":"drug","name":"Ziftomenib","route":"/drugs/ziftomenib/"}],"institution":[{"id":"dana-farber","kind":"institution","name":"Dana-Farber Brigham Cancer Center","route":"/institutions/dana-farber/"},{"id":"dkfz","kind":"institution","name":"German Cancer Research Center (DKFZ)","route":"/institutions/dkfz/"},{"id":"johns-hopkins","kind":"institution","name":"Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center","route":"/institutions/johns-hopkins/"},{"id":"mskcc","kind":"institution","name":"Memorial Sloan Kettering Cancer Center","route":"/institutions/mskcc/"}],"pathway":[{"id":"cancer-stem-cells-plasticity","kind":"pathway","name":"Cancer stem cells & phenotypic plasticity","route":"/pathways/cancer-stem-cells-plasticity/"},{"id":"clonal-haematopoiesis","kind":"pathway","name":"Clonal haematopoiesis (CHIP)","route":"/pathways/clonal-haematopoiesis/"},{"id":"drug-tolerant-persisters","kind":"pathway","name":"Drug-tolerant persister cells","route":"/pathways/drug-tolerant-persisters/"},{"id":"field-cancerisation","kind":"pathway","name":"Field cancerisation","route":"/pathways/field-cancerisation/"},{"id":"lineage-plasticity-neuroendocrine","kind":"pathway","name":"Lineage plasticity & neuroendocrine transformation","route":"/pathways/lineage-plasticity-neuroendocrine/"},{"id":"menin-kmt2a","kind":"pathway","name":"Menin / KMT2A (HOXA9-MEIS1 axis)","route":"/pathways/menin-kmt2a/"},{"id":"idh-2hg","kind":"pathway","name":"Mutant IDH / 2-hydroxyglutarate","route":"/pathways/idh-2hg/"},{"id":"er-signaling","kind":"pathway","name":"Oestrogen receptor signalling","route":"/pathways/er-signaling/"},{"id":"swi-snf-chromatin","kind":"pathway","name":"SWI/SNF chromatin remodelling","route":"/pathways/swi-snf-chromatin/"},{"id":"t-cell-exhaustion","kind":"pathway","name":"T-cell exhaustion","route":"/pathways/t-cell-exhaustion/"},{"id":"germinal-centre-reaction","kind":"pathway","name":"The germinal centre reaction","route":"/pathways/germinal-centre-reaction/"},{"id":"theories-of-cancer","kind":"pathway","name":"Theories of cancer: how the ideas connect","route":"/pathways/theories-of-cancer/"},{"id":"transcription-addiction","kind":"pathway","name":"Transcriptional machinery & addiction","route":"/pathways/transcription-addiction/"}],"paper":[{"id":"paper-weisenberger-cimp-braf-mlh1-colorectal-nat-genet-2006","kind":"paper","name":"CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly 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it)","route":"/biomarkers/nepc-transformation/"}],"roadmap":[{"id":"epigenetics-roadmap","kind":"roadmap","name":"Epigenetic therapy roadmap: loosening silenced genes → mutation-specific enzymes → editing the epigenome","route":"/roadmaps/epigenetics-roadmap/"}]}}