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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.
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 Approved: azacitidine/decitabine (MDS/AML), HDAC inhibitors (T-cell lymphoma), EZH2 (tazemetostat, withdrawn 2026), IDH inhibitors, menin inhibitors (KMT2A/NPM1 leukaemia).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.
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.
It is the right shape of answer for a transition that is epigenetic rather than genetic, and it could in principle spare the biopsy that is currently the only way to make this diagnosis.
Cancer is now understood to change its identity and behaviour without new mutations, to be shaped by bacteria inside and around it, and to be helped along by ageing cells. This explains why some tumours escape targeted drugs by changing cell type and why gut bacteria affect immunotherapy response.
It gives the PD-L1-negative mesenchymal subtype, the group immunotherapy leaves behind, a mechanistic route back to immune visibility, and explains why immune infiltration and subtype are coupled.
It is the number behind 'basal-like is chemoresistant' and the validation of the GATA6 stain that lets a pathology laboratory call the subtype without RNA sequencing.
It links the molecular route to the practical failure mode: interval cancers after a clear colonoscopy are disproportionately serrated, so detection quality is a molecular problem as much as a technical one.
It gives the 3 to 4% of KDM6A-mutant, squamous-programme tumours a mechanism and a candidate drug class.
It is the quantitative answer to why prostate cancer has so few targeted therapies. The common events are not druggable, the druggable ones are individually rare, and no trial can be powered on a driver present in 2% of men without an international basket.
It turned neuroendocrine transformation from a pathological curiosity into a mechanism with a genotype and a candidate intervention, and it is the reason EZH2 inhibitors are in prostate cancer trials at all.
Shares Loss of KDM6A activates super-enhancers to induce gender-specific squamous-like pancreatic cancer and confers sensitivity to BET inhibitors, BRD4, The germinal centre reaction, NUT carcinoma (midline carcinoma with NUTM1 rearrangement) and the tag mechanism.
Shares Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer, The mutational landscape of lethal castration-resistant prostate cancer, Cancer stem cells & phenotypic plasticity, Drug-tolerant persister cells and the tag mechanism.
Shares Multi-omics analysis identifies therapeutic vulnerabilities in triple-negative breast cancer subtypes, B2M, T-cell exhaustion, Johns Hopkins Hospital / Sidney Kimmel Comprehensive Cancer Center and the tag mechanism.
Shares The long tail of oncogenic drivers in prostate cancer, Chronic myelomonocytic leukaemia and MDS/MPN overlap neoplasms, Dana-Farber Brigham Cancer Center, Memorial Sloan Kettering Cancer Center and the tag mechanism.
Shares Ependymoma, German Cancer Research Center (DKFZ), Clonal haematopoiesis (CHIP), Memorial Sloan Kettering Cancer Center and the tag mechanism.
Shares Genomic analyses identify molecular subtypes of pancreatic cancer, Cancer stem cells & phenotypic plasticity, Lineage plasticity & neuroendocrine transformation, Dana-Farber Brigham Cancer Center and the tag mechanism.
Shares Vorasidenib, Theories of cancer: how the ideas connect, IDH1 / IDH2, Memorial Sloan Kettering Cancer Center and the tag mechanism.
Shares Cancer stem cells & phenotypic plasticity, Atypical teratoid/rhabdoid tumour (ATRT), Dana-Farber Brigham Cancer Center, Pancreatic ductal adenocarcinoma and the tag mechanism.