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Nat Genet. 2017 Jul;49(7):1015-1024. doi: 10.1038/ng.3891. Epub 2017 Jun 5.

Between-region genetic divergence reflects the mode and tempo of tumor evolution.

Author information

1
Department of Medicine, Stanford University School of Medicine, Stanford, California, USA.
2
Department of Genetics, Stanford University School of Medicine, Stanford, California, USA.
3
Stanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA.
4
Centre for Evolution and Cancer, The Institute of Cancer Research, London, UK.
5
Evolution and Cancer Laboratory, Barts Cancer Institute, Queen Mary University of London, London, UK.
6
Department of Biology, Stanford University, Stanford, California, USA.
7
Department of Molecular and Medical Genetics, Oregon Health and Science University, Portland, Oregon, USA.
8
Department of Pathology, Keck School of Medicine of the University of Southern California, Los Angeles, California, USA.

Abstract

Given the implications of tumor dynamics for precision medicine, there is a need to systematically characterize the mode of evolution across diverse solid tumor types. In particular, methods to infer the role of natural selection within established human tumors are lacking. By simulating spatial tumor growth under different evolutionary modes and examining patterns of between-region subclonal genetic divergence from multiregion sequencing (MRS) data, we demonstrate that it is feasible to distinguish tumors driven by strong positive subclonal selection from those evolving neutrally or under weak selection, as the latter fail to dramatically alter subclonal composition. We developed a classifier based on measures of between-region subclonal genetic divergence and projected patient data into model space, finding different modes of evolution both within and between solid tumor types. Our findings have broad implications for how human tumors progress, how they accumulate intratumoral heterogeneity, and ultimately how they may be more effectively treated.

PMID:
28581503
PMCID:
PMC5643198
DOI:
10.1038/ng.3891
[Indexed for MEDLINE]
Free PMC Article

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