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Evolution of the cancer genome

Nature Reviews Genetics volume 13, pages 795–806 (2012)Cite this article

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Key Points

  • Each tumour represents an independent evolutionary experiment, starting from almost the same point: namely, the fertilized egg. As tools for genome-wide analysis become more widely applied, commonalities and variations in the patterns of cancer evolution are emerging, and this has important implications for our understanding of cancer biology and the management of patients with tumours.

  • Evolution may be investigated within an individual cancer through various sampling approaches, ranging from a single sample to multiple samples taken over space and/or time or even from multiple single cells.

  • Massively parallel sequencing data from bulk tumour sampling lend themselves to mathematical approaches that permit the reconstruction of the underlying genomic architecture.

  • Genomic technologies have identified extreme genomic heterogeneity between and even within tumour types. This suggests that evolutionary pathways underlying cancers are diverse and highlights one of the challenges for the design of cancer therapies.

  • Intratumoural heterogeneity reflects the branching and dynamic nature of cancer evolution.

  • When a new mutation arises in a cancer cell, the subsequent evolutionary trajectory of the cell will be influenced by the cellular ground state and any pre-existing mutations. Understanding epistatic interactions that operate within a cancer cell will contribute to our comprehension of carcinogenesis and is important for designing targeted therapeutic approaches.

  • Emerging observations suggest that cancers do not necessarily arise gradually through multiple steps but that sudden 'crisis' events can accelerate carcinogenesis.

  • Many of the aggressive clinical characteristics of cancer depend on the continued generation of variation. There is evidence for the existence of genomic instability in many cancer types, but it remains unclear whether it is a pre-requisite for cancer development or whether cancers can evolve in the presence of a normal mutation rate.

Abstract

The advent of massively parallel sequencing technologies has allowed the characterization of cancer genomes at an unprecedented resolution. Investigation of the mutational landscape of tumours is providing new insights into cancer genome evolution, laying bare the interplay of somatic mutation, adaptation of clones to their environment and natural selection. These studies have demonstrated the extent of the heterogeneity of cancer genomes, have allowed inferences to be made about the forces that act on nascent cancer clones as they evolve and have shown insight into the mutational processes that generate genetic variation. Here we review our emerging understanding of the dynamic evolution of the cancer genome and of the implications for basic cancer biology and the development of antitumour therapy.

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Figure 1: The evolution of clonal populations.
Figure 2: The role of the environment in evolutionary adaptation.
Figure 3: Stepwise versus crisis-driven mutation accumulation.
Figure 4: 'Mutator mutations' drive genomic instability in cancers.

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Acknowledgements

We would like to thank the Wellcome Trust for funding.

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Authors and Affiliations

  1. Cancer Genome Project, Wellcome Trust Sanger Institute, Hinxton, CB10 1SA, UK

    Lucy R. Yates & Peter J. Campbell

  2. Department of Haematology, University of Cambridge, Cambridge, CB2 2XY, UK

    Peter J. Campbell

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Glossary

Mutational signatures

Patterns of mutations that are characteristic of a type of cancer or that are indicative of a specific process.

Chromothripsis

A single event that causes genome shattering and reassembly, resulting in a characteristic pattern of oscillating copy number and up to several hundred genomic rearrangements localized to one or a few chromosomes.

Driver mutations

Somatic mutations within cancer genes that confer a clonal advantage, that are causally implicated in oncogenesis and that are positively selected for during cancer evolution.

Synthetic lethality

Two genes are synthetically lethal if mutation of either in isolation is compatible with viability, but mutation of both leads to cell death.

Kataegis

A localized hypermutation that often colocalizes with somatic rearrangements.

Microsatellite instability

(MSI). Microsatellites are repeating sequences within DNA of 2–6 base pairs in length; defects in mismatch repair can give rise to genomic instability within these regions.

Chromosomal instability

(CIN). A form of genomic instability that is common in cancers and is characterized by large chromosomal losses by as of yet undefined mechanisms.

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Yates, L., Campbell, P. Evolution of the cancer genome. Nat Rev Genet 13, 795–806 (2012). https://doi.org/10.1038/nrg3317

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