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BMC Med. 2017 Jul 18;15(1):133. doi: 10.1186/s12916-017-0900-y.

The role of tumour heterogeneity and clonal cooperativity in metastasis, immune evasion and clinical outcome.

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Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.
Translational Cancer Therapeutics Laboratory, The Francis Crick Institute, 1 Midland Rd, London, NW1 1AT, UK.
Cancer Research UK Lung Cancer Centre of Excellence, University College London Cancer Institute, Paul O'Gorman Building, 72 Huntley Street, London, WC1E 6BT, UK.



The advent of rapid and inexpensive sequencing technology allows scientists to decipher heterogeneity within primary tumours, between primary and metastatic sites, and between metastases. Charting the evolutionary history of individual tumours has revealed drivers of tumour heterogeneity and highlighted its impact on therapeutic outcomes.


Scientists are using improved sequencing technologies to characterise and address the challenge of tumour heterogeneity, which is a major cause of resistance to therapy and relapse. Heterogeneity may fuel metastasis through the selection of rare, aggressive, somatically altered cells. However, extreme levels of chromosomal instability, which contribute to intratumour heterogeneity, are associated with improved patient outcomes, suggesting a delicate balance between high and low levels of genome instability.


We review evidence that intratumour heterogeneity influences tumour evolution, including metastasis, drug resistance, and the immune response. We discuss the prevalence of tumour heterogeneity, and how it can be initiated and sustained by external and internal forces. Understanding tumour evolution and metastasis could yield novel therapies that leverage the immune system to control emerging tumour neo-antigens.


Aneuploidy tolerance; Branched evolution; Competitive evolution; Cooperative evolution; Immunotherapy; Intratumour heterogeneity; Linear evolution; Metastasis; Mutation burden; Tumour progression

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