Minimal functional driver gene heterogeneity among untreated metastases

Johannes G Reiter; Alvin P Makohon-Moore; Jeffrey M Gerold; Alexander Heyde; Marc A Attiyeh; Zachary A Kohutek; Collin J Tokheim; Alexia Brown; Rayne M DeBlasio; Juliana Niyazov; Amanda Zucker; Rachel Karchin; Kenneth W Kinzler; Christine A Iacobuzio-Donahue; Bert Vogelstein; Martin A Nowak

doi:10.1126/science.aat7171

Minimal functional driver gene heterogeneity among untreated metastases

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

Authors

Johannes G Reiter^{1

2}, Alvin P Makohon-Moore³, Jeffrey M Gerold², Alexander Heyde², Marc A Attiyeh³, Zachary A Kohutek⁴, Collin J Tokheim⁵, Alexia Brown³, Rayne M DeBlasio³, Juliana Niyazov³, Amanda Zucker³, Rachel Karchin^{5

6}, Kenneth W Kinzler^{7

8

9}, Christine A Iacobuzio-Donahue^{3

10}, Bert Vogelstein^{7

8

9

11}, Martin A Nowak^{12

13}

Affiliations

¹ Canary Center for Cancer Early Detection, Department of Radiology, Stanford University School of Medicine, Palo Alto, CA 94305, USA. [email protected] [email protected].
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. [email protected] [email protected].
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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Genetic Heterogeneity*
Humans
Models, Theoretical
Mutation
Neoplasm Metastasis / drug therapy*
Neoplasm Metastasis / genetics*
Neoplasm Metastasis / pathology
Neoplasms / drug therapy*
Neoplasms / genetics*
Neoplasms / pathology

Abstract

Publication types

MeSH terms

Grants and funding