Minimal functional driver gene heterogeneity among untreated metastases

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...

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Bibliographic Details
Published in:	Science (American Association for the Advancement of Science) Vol. 361; no. 6406; pp. 1033 - 1037
Main Authors:	Reiter, Johannes G, Makohon-Moore, Alvin P, Gerold, Jeffrey M, Heyde, Alexander, Attiyeh, Marc A, Kohutek, Zachary A, Tokheim, Collin J, Brown, Alexia, DeBlasio, Rayne M, Niyazov, Juliana, Zucker, Amanda, Karchin, Rachel, Kinzler, Kenneth W, Iacobuzio-Donahue, Christine A, Vogelstein, Bert, Nowak, Martin A
Format:	Journal Article
Language:	English
Published:	United States The American Association for the Advancement of Science 07-09-2018
Subjects:	Biopsy Breast cancer Cancer Data processing Decision analysis Decision making Endometrium Fatalities Genetic Heterogeneity Heterogeneity Homogeneity Humans Lesions Lungs Mathematical models Melanoma Metastases Metastasis Models, Theoretical Mutation Neoplasm Metastasis - drug therapy Neoplasm Metastasis - genetics Neoplasm Metastasis - pathology Neoplasms - drug therapy Neoplasms - genetics Neoplasms - pathology Pancreas Patients Prostate Prostate cancer Sequences Tumors
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Summary:	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.
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 Author contributions: J.G.R., A.P.M.-M., C.A.I.-D., B.V., and M.A.N. conceived and designed the study. A.P.M.-M., M.A., Z.A.K., A.B., R.D., J.N., A.Z., and C.A.I.-D. performed autopsies. A.P.M.-M., M.A., Z.A.K., K.W.K., C.A.I.-D., and B.V. generated sequencing data. J.G.R. performed computational analysis. J.G.R., J.M.G., A.H., and M.A.N. performed mathematical modeling. C.J.T. and R.K. performed CHASMplus analysis. C.A.I.-D., B.V., and M.A.N. supervised the study. J.G.R., A.P.M.-M., J.M.G., A.H., C.A.I.-D., B.V., and M.A.N. wrote the manuscript. All authors read and approved the manuscript.
ISSN:	0036-8075 1095-9203
DOI:	10.1126/science.aat7171