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Pan-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases

View ORCID ProfileZheng Hu, Zan Li, Zhicheng Ma, View ORCID ProfileChristina Curtis
doi: https://doi.org/10.1101/825240
Zheng Hu
Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California, USADepartment of Genetics, Stanford University School of Medicine, Stanford, California, USAStanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA
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Zan Li
Life Science Research Center, Core Research Facilities, Southern University of Science and Technology, Shenzhen, Guangdong, China
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Zhicheng Ma
Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California, USADepartment of Genetics, Stanford University School of Medicine, Stanford, California, USAStanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA
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Christina Curtis
Department of Medicine, Division of Oncology, Stanford University School of Medicine, Stanford, California, USADepartment of Genetics, Stanford University School of Medicine, Stanford, California, USAStanford Cancer Institute, Stanford University School of Medicine, Stanford, California, USA
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  • For correspondence: cncurtis@stanford.edu
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Abstract

Metastasis is the primary cause of cancer-related deaths, but the natural history, clonal evolution and patterns of systemic spread are poorly understood. We analyzed exome sequencing data from 458 paired primary tumors (P) or metastasis (M) samples from 136 breast, colorectal and lung cancer patients, including both untreated (n=98) and treated (n=101) metastases. We find that treated metastases often harbored private driver gene mutations whereas untreated metastases did not, suggesting that treatment promotes clonal evolution. Polyclonal seeding was common in lymph node metastases (n=19/35, 54%; mostly untreated) and untreated distant metastases (n=20/70, 29%), but less frequent in treated metastases (n=9/90, 10%). The low number of metastasis-private clonal mutations is consistent with early metastatic seeding, which commonly occurred several years prior to diagnosis in breast (2.4 years, range 0−3.3), lung (3.6 years, range 2.8 − 3.7) and colorectal (4.1 years, range 3.1 − 4.6) cancers. Thus, this pan-cancer analysis reveals early systemic spread in three common cancer types. Further, these data suggest that the natural course of metastasis is selectively relaxed relative to early tumor development and that metastasis-private mutations are not drivers of cancer spread but are instead associated with drug resistance.

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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Posted October 31, 2019.
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Pan-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases
Zheng Hu, Zan Li, Zhicheng Ma, Christina Curtis
bioRxiv 825240; doi: https://doi.org/10.1101/825240
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Pan-cancer analysis of clonality and the timing of systemic spread in paired primary tumors and metastases
Zheng Hu, Zan Li, Zhicheng Ma, Christina Curtis
bioRxiv 825240; doi: https://doi.org/10.1101/825240

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