The observation and analysis of intra-tumour heterogeneity (ITH), particularly in genomic studies, has advanced our understanding of the evolutionary forces that shape cancer growth and development. However, only a subset of the variation observed in a single tumour will have an impact on cancer evolution, highlighting the need to distinguish between functional and non-functional ITH. Emerging studies highlight a role for the cancer epigenome, transcriptome and immune microenvironment in functional ITH. Here, we consider the importance of both genetic and non-genetic ITH and their role in tumour evolution, and present the rationale for a broad research focus beyond the cancer genome. Systems-biology analytical approaches will be necessary to outline the scale and importance of functional ITH. By allowing a deeper understanding of tumour evolution this will, in time, encourage development of novel therapies and improve outcomes for patients.
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The authors thank C. Bailey, A. Frankell, E. Colliver, C.-M. Ruiz and J. Demeulemeester for their thoughtful review of the manuscript. N.M is a Sir Henry Dale Fellow, jointly funded by the Wellcome Trust and the Royal Society (Grant Number 211179/Z/18/Z), and also receives funding from Cancer Research UK Lung Cancer Centre of Excellence, Rosetrees, and the NIHR BRC at University College London Hospitals.
The authors declare no competing interests. N.M. has received consultancy fees and has stock options in Achilles Therapeutics. N.M. holds European patents relating to targeting neoantigens (PCT/EP2016/ 059401), identifying patient response to immune checkpoint blockade (PCT/ EP2016/071471), determining HLA LOH (PCT/GB2018/052004), predicting survival rates of patients with cancer (PCT/GB2020/050221). J.R.M.B. declares no competing interests.
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- Intra-tumour heterogeneity
(ITH). Variation within the same tumour; this can be non-functional, a result of neutral evolution, or functional, leading to selection that shapes ongoing tumour evolution.
- Chromosomal instability
(CIN). A defect in which cells can gain, lose or rearrange parts of chromosomes or whole chromosomes during cell division; this is a source of variation in cancer.
A mutational process in which large numbers of clustered structural rearrangements occur in single or multiple chromosomes.
- Molecular time
An estimate of the timing of an event, from the first cell division following fertilization to a cell division that occurred only recently before sampling.
A short genomic region that influences the expression of another gene in cis.
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Black, J.R.M., McGranahan, N. Genetic and non-genetic clonal diversity in cancer evolution. Nat Rev Cancer 21, 379–392 (2021). https://doi.org/10.1038/s41568-021-00336-2