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Science. 2018 Sep 7;361(6406):1033-1037. doi: 10.1126/science.aat7171.

Minimal functional driver gene heterogeneity among untreated metastases.

Author information

1
Canary Center for Cancer Early Detection, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA 94305, USA. johannes.reiter@stanford.edu martin_nowak@harvard.edu.
2
Program for Evolutionary Dynamics, Harvard University, Cambridge, MA 02138, USA.
3
The David M. Rubenstein Center for Pancreatic Cancer Research, Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
4
Department of Radiation Oncology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
5
Department of Biomedical Engineering, Institute for Computational Medicine, Johns Hopkins University, Baltimore, MD 21218, USA.
6
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
7
The Ludwig Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
8
The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
9
Sidney Kimmel Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
10
Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.
11
Howard Hughes Medical Institute, The Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
12
Program for Evolutionary Dynamics, Harvard University, Cambridge, MA 02138, USA. johannes.reiter@stanford.edu martin_nowak@harvard.edu.
13
Department of Organismic and Evolutionary Biology and Department of Mathematics, Harvard University, Cambridge, MA 02138, USA.

Abstract

Metastases are responsible for the majority of cancer-related deaths. Although genomic heterogeneity within primary tumors is associated with relapse, heterogeneity among treatment-naïve metastases has not been comprehensively assessed. We analyzed sequencing data for 76 untreated metastases from 20 patients and inferred cancer phylogenies for breast, colorectal, endometrial, gastric, lung, melanoma, pancreatic, and prostate cancers. We found that within individual patients, a large majority of driver gene mutations are common to all metastases. Further analysis revealed that the driver gene mutations that were not shared by all metastases are unlikely to have functional consequences. A mathematical model of tumor evolution and metastasis formation provides an explanation for the observed driver gene homogeneity. Thus, single biopsies capture most of the functionally important mutations in metastases and therefore provide essential information for therapeutic decision-making.

PMID:
30190408
PMCID:
PMC6329287
[Available on 2019-03-07]
DOI:
10.1126/science.aat7171
[Indexed for MEDLINE]

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