. Author manuscript; available in PMC: 2022 Jan 1.

Published in final edited form as: Nat Rev Genet. 2020 Aug 17;22(1):3–18. doi: 10.1038/s41576-020-0265-5

Table 1 |.

The role of epigenetics in tumour evolution

Epigenetic defects in cancer	Mechanism of tumour evolution	Examples
Disrupted epigenetic modifiers	Somatic mutations in epigenetic modifiers	DNMT3A, TET2 and AXL1 mutations in haematological malignancies¹⁰⁵; SWI/SNF (BAF) mutations in solid tumours¹⁰⁷
	Somatic mutations in epigenetic substrates	Histone H3F3A and HIST1H3B K27M mutations in paediatric high-grade gliomas^177,178
	Dysregulated expression of epigenetic modifiers	KDM5 overexpression linked with drug resistance in breast cancer¹⁰²
Epigenetic diversification and/or plasticity	Changes in epimutation rate	Increased epimutation in CLL versus normal B cells¹²¹; AML subsets defined by epimutation rates¹⁷⁹
	Suppression of differentiation	EZH2-activating mutations in DLBCL inhibit differentiation programmes^118,119
	Discoordination of epigenetic layers	Discoherence of DNA methylation and histone modifications in CLL¹¹⁵
	Global hypomethylation linked with genomic instability	MMR-positive CRC displays de novo methylating defect whereas MMR-deficient CRC does not, suggesting two modes of chromosomal instability¹⁸⁰
	Positive selection of epigenetic disruption	Hypermethylation of CTCF insulator protein binding motifs results in loss of insulation between enhancers and genes¹¹⁶

AML, acute myeloid leukaemia; CLL, chronic lymphocytic leukaemia; CRC, colorectal cancer; DLBCL, diffuse large B cell lymphoma; MMR, mismatch repair.