# Epigenetic reprogramming

Source: https://onco.cc/pathways/epigenetic-reprogramming/  
OnCo record `epigenetic-reprogramming` (Pathway). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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 Approved: azacitidine/decitabine (MDS/AML), HDAC inhibitors (T-cell lymphoma), EZH2 (tazemetostat, withdrawn 2026), IDH inhibitors, menin inhibitors (KMT2A/NPM1 leukaemia).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.

## Fields

- Kind: Pathway
- Last checked: 2026-09-08
- Tags: mechanism
- 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.
- 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

## Notes

- Leading programmes: Baylin (Johns Hopkins, DNA methylation); Pfister (DKFZ, methylation classification); Armstrong (Dana-Farber, menin/KMT2A); Allis legacy (Rockefeller, histone code).

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Cancer_epigenetics
- Hanahan, Hallmarks of Cancer: New Dimensions (Cancer Discovery 2022): https://doi.org/10.1158/2159-8290.CD-21-1059
- Baylin & Jones, Epigenetic determinants of cancer (Cold Spring Harbor Perspectives 2016): https://doi.org/10.1101/cshperspect.a019505

## Connected records

- terms: [Epigenetic progenitor theory: cancer without a first mutation](https://onco.cc/terms/epigenetic-progenitor-theory/), [H3 K27M (diffuse midline glioma)](https://onco.cc/terms/h3k27m/), [Hallmark (2022): non-mutational epigenetic reprogramming](https://onco.cc/terms/nonmutational-epigenetic-reprogramming/), [Hallmark (2022): unlocking phenotypic plasticity](https://onco.cc/terms/unlocking-phenotypic-plasticity/), [MGMT promoter methylation](https://onco.cc/terms/mgmt/), [The germinal centre: why lymphoma starts where antibodies are made](https://onco.cc/terms/lymphoma-bio-germinal-centre/)
- cancers: [Atypical teratoid/rhabdoid tumour (ATRT)](https://onco.cc/cancers/atrt/), [Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms](https://onco.cc/cancers/cmml/), [Colorectal cancer](https://onco.cc/cancers/colorectal/), [Diffuse large B-cell lymphoma](https://onco.cc/cancers/dlbcl/), [Diffuse midline glioma, H3 K27-altered (including DIPG)](https://onco.cc/cancers/dipg-dmg/), [Ependymoma](https://onco.cc/cancers/ependymoma/), [Epithelioid sarcoma](https://onco.cc/cancers/epithelioid-sarcoma/), [Follicular lymphoma](https://onco.cc/cancers/follicular-lymphoma/), [Nodal T-follicular helper cell lymphoma, angioimmunoblastic type (angioimmunoblastic T-cell lymphoma)](https://onco.cc/cancers/angioimmunoblastic-t-cell-lymphoma/), [Non-Hodgkin lymphoma (all types)](https://onco.cc/cancers/non-hodgkin-lymphoma/), [NUT carcinoma (midline carcinoma with NUTM1 rearrangement)](https://onco.cc/cancers/nut-carcinoma/), [Pancreatic ductal adenocarcinoma](https://onco.cc/cancers/pancreatic/), [Peripheral T-cell lymphomas (including cutaneous T-cell lymphoma)](https://onco.cc/cancers/peripheral-t-cell-lymphoma/), [Prostate cancer](https://onco.cc/cancers/prostate/)
- technologies: [DNA methylation profiling](https://onco.cc/technologies/methylation-profiling/), [Epigenetic drugs (HDAC, DNMT, EZH2, IDH, menin, BET)](https://onco.cc/technologies/epigenetic-drugs/), [Multi-cancer early detection (MCED)](https://onco.cc/technologies/mced/)
- targets: [B2M](https://onco.cc/targets/b2m/), [BCL6](https://onco.cc/targets/bcl6/), [BRD4](https://onco.cc/targets/brd4/), [CD58](https://onco.cc/targets/cd58/), [CREBBP](https://onco.cc/targets/crebbp/), [DNA methyltransferase 3A (DNMT3A)](https://onco.cc/targets/dnmt3a/), [EP300](https://onco.cc/targets/ep300/), [EZH2](https://onco.cc/targets/ezh2/), [FYN](https://onco.cc/targets/fyn/), [HOXA9](https://onco.cc/targets/hoxa9/), [IDH1 / IDH2](https://onco.cc/targets/idh/), [KMT2A (MLL) rearrangement](https://onco.cc/targets/kmt2a/), [KMT2D](https://onco.cc/targets/kmt2d/), [Menin](https://onco.cc/targets/menin/), [MLH1](https://onco.cc/targets/mlh1/), [NPM1 mutation](https://onco.cc/targets/npm1/), [RHOA](https://onco.cc/targets/rhoa/), [TET2](https://onco.cc/targets/tet2/)
- drugs: [Azacitidine](https://onco.cc/drugs/azacitidine/), [Revumenib](https://onco.cc/drugs/revumenib/), [Vorasidenib](https://onco.cc/drugs/vorasidenib/), [Ziftomenib](https://onco.cc/drugs/ziftomenib/)
- institutions: [Dana-Farber Brigham Cancer Center](https://onco.cc/institutions/dana-farber/), [German Cancer Research Center (DKFZ)](https://onco.cc/institutions/dkfz/), [Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center](https://onco.cc/institutions/johns-hopkins/), [Memorial Sloan Kettering Cancer Center](https://onco.cc/institutions/mskcc/)
- pathways: [Cancer stem cells & phenotypic plasticity](https://onco.cc/pathways/cancer-stem-cells-plasticity/), [Clonal haematopoiesis (CHIP)](https://onco.cc/pathways/clonal-haematopoiesis/), [Drug-tolerant persister cells](https://onco.cc/pathways/drug-tolerant-persisters/), [Field cancerisation](https://onco.cc/pathways/field-cancerisation/), [Lineage plasticity & neuroendocrine transformation](https://onco.cc/pathways/lineage-plasticity-neuroendocrine/), [Menin / KMT2A (HOXA9-MEIS1 axis)](https://onco.cc/pathways/menin-kmt2a/), [Mutant IDH / 2-hydroxyglutarate](https://onco.cc/pathways/idh-2hg/), [Oestrogen receptor signalling](https://onco.cc/pathways/er-signaling/), [SWI/SNF chromatin remodelling](https://onco.cc/pathways/swi-snf-chromatin/), [T-cell exhaustion](https://onco.cc/pathways/t-cell-exhaustion/), [The germinal centre reaction](https://onco.cc/pathways/germinal-centre-reaction/), [Theories of cancer: how the ideas connect](https://onco.cc/pathways/theories-of-cancer/), [Transcriptional machinery & addiction](https://onco.cc/pathways/transcription-addiction/)
- key papers: [CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer](https://onco.cc/key-papers/paper-weisenberger-cimp-braf-mlh1-colorectal-nat-genet-2006/), [Detecting neuroendocrine prostate cancer through tissue-informed cell-free DNA methylation analysis](https://onco.cc/key-papers/paper-berchuck-cfdna-methylation-nepc-detection-ccr-2022/), [Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer](https://onco.cc/key-papers/paper-beltran-nepc-divergent-evolution-nat-med-2016/), [Epigenetic Determinants of Cancer](https://onco.cc/key-papers/paper-baylin-cold-spring-harb-perspect-biol/), [GATA6 expression distinguishes classical and basal-like subtypes in advanced pancreatic cancer](https://onco.cc/key-papers/paper-okane-gata6-basal-like-compass-ccr-2020/), [Genomic analyses identify molecular subtypes of pancreatic cancer](https://onco.cc/key-papers/paper-bailey-molecular-subtypes-pancreatic-nature-2016/), [Hallmarks of Cancer 2022: adding phenotypic plasticity, epigenetic reprogramming, microbiomes and senescent cells](https://onco.cc/key-papers/paper-hallmarks-new-dimensions-cancer-discov-2022/), [Heritable somatic methylation and inactivation of MSH2 in families with Lynch syndrome due to deletion of the 3' exons of TACSTD1](https://onco.cc/key-papers/paper-ligtenberg-epcam-deletion-msh2-silencing-nat-genet-2009/), [Incidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma](https://onco.cc/key-papers/paper-herman-mlh1-promoter-hypermethylation-colorectal-pnas-1998/), [Loss of KDM6A activates super-enhancers to induce gender-specific squamous-like pancreatic cancer and confers sensitivity to BET inhibitors](https://onco.cc/key-papers/paper-andricovich-kdm6a-squamous-pancreatic-cancer-cell-2018/), [Multi-omics analysis identifies therapeutic vulnerabilities in triple-negative breast cancer subtypes](https://onco.cc/key-papers/paper-lehmann-tnbc-subtype-multiomics-nat-commun-2021/), [Rb1 and Trp53 cooperate to suppress prostate cancer lineage plasticity, metastasis and antiandrogen resistance](https://onco.cc/key-papers/paper-ku-rb1-trp53-lineage-plasticity-science-2017/), [SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer](https://onco.cc/key-papers/paper-mu-sox2-lineage-plasticity-science-2017/), [TCGA: the molecular taxonomy of primary prostate cancer](https://onco.cc/key-papers/paper-tcga-molecular-taxonomy-primary-prostate-cell-2015/), [Terminology, molecular features, epidemiology, and management of serrated colorectal neoplasia](https://onco.cc/key-papers/paper-crockett-nagtegaal-serrated-neoplasia-gastroenterology-2019/), [The long tail of oncogenic drivers in prostate cancer](https://onco.cc/key-papers/paper-armenia-long-tail-oncogenic-drivers-prostate-nat-genet-2018/), [The mutational landscape of lethal castration-resistant prostate cancer](https://onco.cc/key-papers/paper-grasso-mutational-landscape-lethal-crpc-nature-2012/), [The serrated pathway to colorectal carcinoma: current concepts and challenges](https://onco.cc/key-papers/paper-bettington-serrated-pathway-colorectal-histopathology-2013/)
- biomarkers: [EZH2 gain-of-function mutation (Tyr646, originally Tyr641)](https://onco.cc/biomarkers/ezh2-y646-mutation/), [RHOA G17V](https://onco.cc/biomarkers/rhoa-g17v/), [Treatment-emergent neuroendocrine transformation (recognising it)](https://onco.cc/biomarkers/nepc-transformation/)
- roadmaps: [Epigenetic therapy roadmap: loosening silenced genes → mutation-specific enzymes → editing the epigenome](https://onco.cc/roadmaps/epigenetics-roadmap/)

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