The evolution of the unstable cancer genome

doi:10.1016/j.gde.2013.11.011

Current Opinion in Genetics & Development

Volume 24, February 2014, Pages 61-67

https://doi.org/10.1016/j.gde.2013.11.011 Get rights and content

Cancer next-generation sequencing and genomics studies published over the last five years have provided unprecedented insights into the forces shaping cancer genome evolution. In particular, these studies have revealed a high level of heterogeneity not only between different tumours, but also within individual tumours; the ‘cancer genome’ may evolve along several independent trajectories within a single tumour. There is an increasing appreciation of the importance of intratumour genetic heterogeneity in determining disease progression and clinical outcome in cancer medicine, and thus an increasing awareness of the need to understand the processes that both generate genetic diversity and shape genome evolution in human tumours.

Introduction

Over the last five years it has become increasingly apparent that there is extensive genetic variation not only between different tumours but also within individual tumours [1]. Excavating the genetic diversity within tumours can yield insights into the patterns and dynamics of cancer evolution, from initiation [2, 3] through to metastasis [4, 5] and relapse after surgery or therapy [6••, 7••, 8, 9, 10••, 11, 12].

The majority of tumours display some level of genomic instability [13], and hence there may be millions of different genomic configurations or ‘cancer genomes’ within a single tumour. Only a small proportion of this genetic diversity will yield phenotypes that are beneficial within a given context, such as growth in low oxygen concentrations (hypoxia) or during treatment, leading to clonal expansion of cells with a given genotype and thereby contributing to tumour progression and cancer genome evolution. It should be noted that selective outgrowth of cells with a given genotype may occur not only as a direct consequence of environmental selection pressures acting on a given genotype, but also upon non-genetic factors; epigenetically regulated phenotypes, influenced by the microenvironment, or other stochastic influences, such as cellular dormancy, may also shape the evolutionary dynamics of tumour cell populations [12, 14, 15, 16•].

In this review, we focus primarily on cancer genome evolution during disease progression, rather than the evolution of the cancer genome during the acquisition of the genomic changes required for transformation and the initiation of carcinogenesis. We review the insights into patterns of cancer evolution that have been provided by next generation sequencing studies in recent years, with a particular focus on the effect of genomic instability in shaping cancer genome evolution, drawing insights from experimental studies of evolution.

Section snippets

Linear versus branched evolution

A common finding of recent studies is that the majority of tumours are genetically heterogeneous, harbouring subclonal populations of cells [4, 5, 6••, 7••, 10••, 17••, 18, 19••, 20]. Examination of this subclonal tumour architecture over space and time can provide insights into patterns of cancer genome evolution. Classically, cancer has been thought to evolve in a linear fashion, whereby beneficial mutations are sequentially acquired, followed by a wave of clonal expansion and clonal

Genomic instability and cancer genome evolution

Various forms of genomic instability are observed in human malignancies, from increased rates of point mutation to chromosomal rearrangements, whole and partial chromosome gains and losses and whole genome duplications [1, 13]. Genomic instability may occur through mutations that affect cellular capacity to accurately replicate and divide the genome, such as mutations in genes involved in DNA mismatch repair and homologous recombination, as well as mutations in common oncogenes and tumour

Recurrent aberrations in the cancer genome

As described above, genomic instability refers to cell-to-cell variation in mutations and/or karyotype. However, the shaping influence of genomic instability upon cancer genome evolution can be observed in the ‘footprints’ or ‘mutational signatures’ of instability left in the genome, which can be identified through genomic and cytogenetic methods [7••, 17••, 38, 42••]. The footprints of some forms of instability, such as chromosomal instability and mismatch repair deficits, or those with

Punctuated versus gradual genome evolution

Another insight gained from the wealth of genomics data now available to cancer researchers, is that genomic rearrangements may occur in transient bursts [43, 60•, 61, 62•], as well as (and potentially instead of) the gradual accumulation of genomic rearrangements over time. While there is significant evidence for ongoing instability, which is likely to contribute to gradual genomic evolution [17••, 54], ‘punctuated’ episodes of genome evolution may drastically alter cellular genotype (and

Conclusions

The wealth of genomics data that has become available over the last four to five years has provided invaluable insight into the complexities of cancer genome evolution. The identification of novel mutational processes that mould the cancer genome will enhance our understanding of how cancer develops and progresses, and may reveal novel therapeutic opportunities, since targeting genomic instability has already yielded some success in cancer medicine. Integrative approaches have also revealed how

References and recommended reading

Papers of particular interest, published within the period of review, have been highlighted as:

• of special interest
•• of outstanding interest

References (65)

D.A. Landau et al.
Evolution and impact of subclonal mutations in chronic lymphocytic leukemia
Cell
(2013)
L. Ding et al.
Clonal evolution in relapsed acute myeloid leukaemia revealed by whole-genome sequencing
Nature
(2012)
P.J. Campbell et al.
The patterns and dynamics of genomic instability in metastatic pancreatic cancer
Nature
(2010)
G.I. Lang et al.
Pervasive genetic hitchhiking and clonal interference in forty evolving yeast populations
Nature
(2013)
R. Govindan et al.
Genomic landscape of non-small cell lung cancer in smokers and never-smokers
Cell
(2012)
E. Hodis et al.
A landscape of driver mutations in melanoma
Cell
(2012)
S.L. Poon et al.
Genome-wide mutational signatures of aristolochic acid and its application as a screening tool
Sci Transl Med
(2013)
L.B. Alexandrov et al.
Signatures of mutational processes in human cancer
Nature
(2013)
S.A. Roberts et al.
An APOBEC, cytidine deaminase mutagenesis pattern is widespread in human cancers
Nat Genet
(2013)
Comprehensive molecular characterization of human colon and rectal cancer
Nature
(2012)

S.P. Shah et al.

The clonal and mutational evolution spectrum of primary triple-negative breast cancers

Nature

(2012)

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The evolution of the unstable cancer genome

Introduction

Section snippets

Linear versus branched evolution

Genomic instability and cancer genome evolution

Recurrent aberrations in the cancer genome

Punctuated versus gradual genome evolution

Conclusions

References and recommended reading

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Genetic variegation of clonal architecture and propagating cells in leukaemia

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Clonal competition with alternating dominance in multiple myeloma

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Clonal evolution in cancer

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Evolutionary dynamics of carcinogenesis and why targeted therapy does not work

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KDM4A lysine demethylase induces site-specific copy gain and rereplication of regions amplified in tumors

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Mutational evolution in a lobular breast tumour profiled at single nucleotide resolution

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