Cancer Epigenetics

Cancer epigenetics studies the heritable changes in gene expression that accompany and contribute to malignant transformation without altering the DNA sequence. It describes how cancer cells rewrite their DNA-methylation, histone-modification, and chromatin landscape so that tumour-suppressor genes fall silent and the genome becomes destabilised, and how these reversible changes cooperate with genetic mutations.

Definition

Cancer epigenetics is the study of epigenetic alterations — principally aberrant DNA methylation and histone modification — that occur in cancer cells and contribute to tumour initiation and progression by changing gene expression rather than gene sequence.

Scope

The entry covers the defining epigenetic alterations of the cancer cell — global DNA hypomethylation, focal promoter hypermethylation, disturbed histone marks, and chromatin-remodeller mutations — and the concept of the cancer epigenome as a complement to the cancer genome. It is an educational reference on mechanism and evidence, not clinical oncology guidance.

Core questions

• Why do cancer genomes show simultaneous global hypomethylation and local hypermethylation?
• How do epigenetic and genetic alterations cooperate in tumourigenesis?
• Which epigenetic changes are drivers and which are passengers?
• How can the cancer epigenome be mapped and exploited clinically?

Key concepts

• Cancer epigenome
• Global DNA hypomethylation
• Promoter CpG-island hypermethylation
• Tumour-suppressor gene silencing
• Epigenetic-genetic cooperation
• Aberrant histone modification
• Chromatin-remodeller mutations

Mechanisms

Cancer cells characteristically lose DNA methylation across the bulk of the genome while gaining dense methylation at CpG islands in the promoters of specific genes. The genome-wide hypomethylation is associated with chromosomal instability and reactivation of normally repressed sequences, whereas the focal hypermethylation silences tumour-suppressor genes, providing a non-mutational route to the same loss of function that a deletion or point mutation would cause. These DNA-methylation changes are accompanied by altered histone modifications and by mutations in chromatin-remodelling and histone-modifying enzymes, together reshaping the cancer epigenome. Because writing and erasing of these marks is enzyme-mediated, the alterations are potentially reversible, which distinguishes them from genetic lesions.

Clinical relevance

The cancer epigenome yields biomarkers used in research for detection, classification, and prognosis, and it is the target of an emerging class of therapies. This entry summarises mechanism and evidence for orientation only and does not provide diagnostic or treatment recommendations for any patient.

Epidemiology

Aberrant DNA methylation and other epigenetic alterations have been documented across essentially all human cancer types studied, making epigenetic dysregulation a near-universal feature of malignancy; the specific genes affected and their frequencies vary by tumour type.

History

Cancer epigenetics emerged in the 1980s with the observation that tumour genomes were globally hypomethylated, followed by the discovery that tumour-suppressor promoters could be silenced by hypermethylation. Jones and Baylin's 2002 review crystallised the role of epigenetic events in cancer, their 2007 synthesis framed the cancer epigenome, and their 2011 retrospective traced a decade of translational progress, establishing the field as a parallel to cancer genetics.

Debates

Are epigenetic alterations causes or consequences of malignancy?

Distinguishing driver epigenetic changes that promote tumourigenesis from passenger changes that merely accompany the malignant state remains difficult, because epigenetic marks are dynamic and respond to the altered cellular environment of the tumour.

Key figures

• Peter A. Jones
• Stephen Baylin
• Manel Esteller
• Andrew P. Feinberg

Seminal works

• jones-baylin-2002
• jones-baylin-2007
• esteller-2008
• baylin-jones-2011

Frequently asked questions

Can cancer be caused by epigenetic changes alone?

Epigenetic alterations can silence tumour-suppressor genes and contribute to malignancy, but in most cancers they act together with genetic mutations rather than entirely on their own.

Why are epigenetic changes in cancer considered reversible?

Unlike DNA mutations, methylation and histone marks are added and removed by enzymes, so in principle they can be reset — which is why they are attractive therapeutic targets.