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The epigenetic progenitor origin of human cancer

Key Points

  • Cancer is fundamentally a disease of stem cells; we argue that the epigenome is a logical target for early events in carcinogenesis, given that stem cells are defined epigenetically and that epigenetic alterations in cancer modify stem/progenitor cell properties.

  • An epigenetic disruption of progenitor cells might be a common early event in human cancer.

  • Epigenetic alterations include global hypomethylation, site-specific hypomethylation and hypermethylation, and chromatin modification that is linked to tumour-suppressor-gene silencing and oncogene activation.

  • Epigenetic changes also promote chromosomal instability.

  • Cancer is proposed to involve three steps: an epigenetic alteration of stem cells, a gatekeeper mutation, and genetic instability during tumour progression.

  • Epigenetic changes, including loss of imprinting, are found in normal cells of patients with cancer and are associated with cancer risk.

  • We propose that cancer stem cells arise from misregulation of 'tumour-progenitor genes', which can include stem cell regulatory genes, imprinted genes, DNA deaminases and chromatin modifying genes.

  • The epigenetic progenitor model can help to explain tumour latency, progression, heterogeneity and environmental effects in cancer.

  • The model suggests that greater attention be paid to the apparently normal cells of patients with cancer or who are at risk of cancer, as they might be crucial targets for epigenetic alteration, and might be an important target for chemoprevention and screening.

Abstract

Cancer is widely perceived as a heterogeneous group of disorders with markedly different biological properties, which are caused by a series of clonally selected genetic changes in key tumour-suppressor genes and oncogenes. However, recent data suggest that cancer has a fundamentally common basis that is grounded in a polyclonal epigenetic disruption of stem/progenitor cells, mediated by 'tumour-progenitor genes'. Furthermore, tumour cell heterogeneity is due in part to epigenetic variation in progenitor cells, and epigenetic plasticity together with genetic lesions drives tumour progression. This crucial early role for epigenetic alterations in cancer is in addition to epigenetic alterations that can substitute for genetic variation later in tumour progression. Therefore, non-neoplastic but epigenetically disrupted stem/progenitor cells might be a crucial target for cancer risk assessment and chemoprevention.

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Figure 1: The clonal genetic model of cancer.
Figure 2: The epigenetic progenitor model of cancer.
Figure 3: The epigenetic progenitor model in the context of a stem cell niche.

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Acknowledgements

We thank A. Gondor, P. Onyango, S. Petersen-Mahrt, B. Vogelstein, H. Bjornsson and C. Iacobuzio-Donahue for helpful comments. This article is largely focused on the idea of early epigenetic events in stem cells before tumours are apparent. For this reason we have referred the reader to several excellent reviews for detailed discussions of later events in tumorigenesis, and apologize to authors whose work we were unable to discuss owing to space limitations. Work discussed here was supported by a US National Institutes of Health grant to A.F.

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DATABASES

OMIM

colorectal cancer

Wilms tumour

Glossary

Adenoma

A benign epithelial tumour.

Microsatellite

A class of repetitive DNA that is made up of repeats that are 2–8 nucleotides in length. They can be highly polymorphic and are frequently used as molecular markers in population genetics studies.

Hypomorph

A mutant allele that has reduced function, or an organism that carries such a mutation.

Lymphoma

A tumour of the lymphoid system.

Genomic imprinting

The parent-of-origin-specific silencing of a specific allele of a gene; loss of imprinting of IGF2 increases cancer risk and shifts the balance of normal intestinal epithelium to a less differentiated state.

Polyclonal

Arising from multiple cells.

SCID

Severe combined immunodeficiency disorder. Mice that have this disorder are used as hosts for tumour xenografts.

Astrocytoma

An early stage brain tumour.

Stem/progenitor cells

Stem cells are pluripotent cells that have an unlimited capacity for self-renewal, but limited replication frequency, that live within a tissue-specific compartment or niche. Tissue-specific progenitor cells are derived from stem cells and have a limited capacity for self-renewal.

Palindrome

A DNA sequence that is followed by its inverted repeat.

Chaperone

A protein that assists in protein folding.

Monoclonal

Arising from a single cell.

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Feinberg, A., Ohlsson, R. & Henikoff, S. The epigenetic progenitor origin of human cancer. Nat Rev Genet 7, 21–33 (2006). https://doi.org/10.1038/nrg1748

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