Review Article | Published:

Genetic insights into the morass of metastatic heterogeneity

Nature Reviews Cancer volume 18, pages 211223 (2018) | Download Citation

Abstract

Tumour heterogeneity poses a substantial problem for the clinical management of cancer. Somatic evolution of the cancer genome results in genetically distinct subclones in the primary tumour with different biological properties and therapeutic sensitivities. The problem of heterogeneity is compounded in metastatic disease owing to the complexity of the metastatic process and the multiple biological hurdles that the tumour cell must overcome to establish a clinically overt metastatic lesion. New advances in sequencing technology and clinical sample acquisition are providing insights into the phylogenetic relationship of metastases and primary tumours at the level of somatic tumour genetics while also illuminating fundamental mechanisms of the metastatic process. In addition to somatically acquired genetic heterogeneity in the tumour cells, inherited population-based genetic heterogeneity can profoundly modify metastatic biology and further complicate the development of effective, broadly applicable antimetastatic therapies. Here, we examine how genetic heterogeneity impacts metastatic disease and the implications of current knowledge for future research endeavours and therapeutic interventions.

Key points

  • Metastasis heterogeneity within and between patients is a substantial problem for the clinical management of advanced cancer and has both genetic and nongenetic origins.

  • Recent advances in sequencing and acquisition of metastatic tissue are illuminating the phylogenetic relationship between primary tumours and metastases and the biology that underlies this evolutionary process.

  • Few recurrent metastasis-specific mutational driver events have been identified to date, highlighting the potential importance of other mechanisms, such as increased epigenetic plasticity, in metastatic progression.

  • Beyond heterogeneity in somatic tumour genetics, inherited germline polymorphisms may contribute substantially to differences in metastatic biology across populations.

  • Additional larger, well-controlled genomics studies using metastatic samples will be critical for a better understanding of the contribution of somatic heterogeneity to the clinical course of metastatic disease.

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Acknowledgements

The authors wish to apologize to the many colleagues whose work may have been inadvertently omitted or not included owing to space constraints. This research was supported by the Intramural Research Program of the US National Institutes of Health (NIH), National Cancer Institute (K.W.H., L.W.).

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    • Kent W. Hunter
    •  & Lalage Wakefield

    These authors contributed equally: Kent W. Hunter, Lalage Wakefield

Affiliations

  1. Laboratory of Cancer Biology and Genetics, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.

    • Kent W. Hunter
    • , Ruhul Amin
    • , Sarah Deasy
    • , Ngoc-Han Ha
    •  & Lalage Wakefield

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Contributions

K.W.H. and L.W. researched the data for the article. K.W.H., L.W., R.A., S.D. and N.-H.H. provided substantial contributions to the discussions of the content. K.W.H. and L.W. contributed equally to writing and reviewing the article. R.A., S.D. and N.-H.H. also reviewed and edited the article before submission. S.D. and N.-H.H. created the figures for the article.

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The authors declare no competing financial interests.

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Correspondence to Kent W. Hunter or Lalage Wakefield.

Glossary

Microcell-mediated chromosome transfer

A method of chromosomal transfer by fusion of membrane-encapsulated donor chromosomes with recipient cells.

Polymorphisms

Naturally occurring DNA variants that are passed down through different generations in populations.

Modifier genes

Genes that contribute to or affect the distribution of continuous traits, such as human height.

Quantitative trait locus mapping

Genetic mapping to identify genomic intervals that contain genes that contribute to continuously distributed traits, such as human height.

Genetic backcross mapping panels

A population of animals used for genetic mapping that are generated by breeding two strains to generate F1 progeny, which are then bred back to one of the parental strains.

Recombinant inbred backcross

A genetic mapping study that results from breeding a panel of recombinant inbred strains to a mouse strain of interest.

Haplotypes

Collections of specific DNA sequences of single nucleotide polymorphisms that are clustered and frequently inherited together.

Warm autopsy programmes

Autopsies and tissue collection that occur as soon as possible after patient demise (also known as rapid autopsy programmes).

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