Clonal selection confers distinct evolutionary trajectories in BRAF-driven cancers

Priyanka Gopal; Elif Irem Sarihan; Eui Kyu Chie; Gwendolyn Kuzmishin; Semihcan Doken; Nathan A. Pennell; Daniel P. Raymond; Sudish C. Murthy; Usman Ahmad; Siva Raja; Francisco Almeida; Sonali Sethi; Thomas R. Gildea; Craig D. Peacock; Drew J. Adams; Mohamed E. Abazeed

doi:10.1038/s41467-019-13161-x

Clonal selection confers distinct evolutionary trajectories in BRAF-driven cancers

Priyanka Gopal, Elif Irem Sarihan, Eui Kyu Chie, Gwendolyn Kuzmishin, Semihcan Doken, Nathan A. Pennell, Daniel P. Raymond, Sudish C. Murthy, Usman Ahmad, Siva Raja, Francisco Almeida, Sonali Sethi, Thomas R. Gildea, Craig D. Peacock, Drew J. Adams, Mohamed E. Abazeed^*

^*Corresponding author for this work

Radiation Oncology

Research output: Contribution to journal › Article › peer-review

10 Scopus citations

Abstract

Molecular determinants governing the evolution of tumor subclones toward phylogenetic branches or fixation remain unknown. Using sequencing data, we model the propagation and selection of clones expressing distinct categories of BRAF mutations to estimate their evolutionary trajectories. We show that strongly activating BRAF mutations demonstrate hard sweep dynamics, whereas mutations with less pronounced activation of the BRAF signaling pathway confer soft sweeps or are subclonal. We use clonal reconstructions to estimate the strength of “driver” selection in individual tumors. Using tumors cells and human-derived murine xenografts, we show that tumor sweep dynamics can significantly affect responses to targeted inhibitors of BRAF/MEK or DNA damaging agents. Our study uncovers patterns of distinct BRAF clonal evolutionary dynamics and nominates therapeutic strategies based on the identity of the BRAF mutation and its clonal composition.

Original language	English (US)
Article number	5143
Journal	Nature communications
Volume	10
Issue number	1
DOIs	https://doi.org/10.1038/s41467-019-13161-x
State	Published - Dec 1 2019

ASJC Scopus subject areas

Physics and Astronomy(all)
Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-019-13161-x

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Gopal, P., Sarihan, E. I., Chie, E. K., Kuzmishin, G., Doken, S., Pennell, N. A., Raymond, D. P., Murthy, S. C., Ahmad, U., Raja, S., Almeida, F., Sethi, S., Gildea, T. R., Peacock, C. D., Adams, D. J., & Abazeed, M. E. (2019). Clonal selection confers distinct evolutionary trajectories in BRAF-driven cancers. Nature communications, 10(1), [5143]. https://doi.org/10.1038/s41467-019-13161-x

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title = "Clonal selection confers distinct evolutionary trajectories in BRAF-driven cancers",

abstract = "Molecular determinants governing the evolution of tumor subclones toward phylogenetic branches or fixation remain unknown. Using sequencing data, we model the propagation and selection of clones expressing distinct categories of BRAF mutations to estimate their evolutionary trajectories. We show that strongly activating BRAF mutations demonstrate hard sweep dynamics, whereas mutations with less pronounced activation of the BRAF signaling pathway confer soft sweeps or are subclonal. We use clonal reconstructions to estimate the strength of “driver” selection in individual tumors. Using tumors cells and human-derived murine xenografts, we show that tumor sweep dynamics can significantly affect responses to targeted inhibitors of BRAF/MEK or DNA damaging agents. Our study uncovers patterns of distinct BRAF clonal evolutionary dynamics and nominates therapeutic strategies based on the identity of the BRAF mutation and its clonal composition.",

author = "Priyanka Gopal and Sarihan, {Elif Irem} and Chie, {Eui Kyu} and Gwendolyn Kuzmishin and Semihcan Doken and Pennell, {Nathan A.} and Raymond, {Daniel P.} and Murthy, {Sudish C.} and Usman Ahmad and Siva Raja and Francisco Almeida and Sonali Sethi and Gildea, {Thomas R.} and Peacock, {Craig D.} and Adams, {Drew J.} and Abazeed, {Mohamed E.}",

note = "Funding Information: M.E.A. was supported by NIH KL2 TR0002547, NIH R37 CA222294, the American Lung Association and VeloSano. E.K.C. was supported by SNUH Research Fund 0420160010. Funding Information: M.E.A. receives grant support, travel support, and honoraria from Bayer AG and receives grant support from Siemens Medical Solutions, USA in subject matter or material not directly related to this work. The other authors disclose no potential conflicts of interest. Publisher Copyright: {\textcopyright} 2019, The Author(s).",

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doi = "10.1038/s41467-019-13161-x",

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AU - Gopal, Priyanka

AU - Sarihan, Elif Irem

AU - Chie, Eui Kyu

AU - Kuzmishin, Gwendolyn

AU - Doken, Semihcan

AU - Pennell, Nathan A.

AU - Raymond, Daniel P.

AU - Murthy, Sudish C.

AU - Ahmad, Usman

AU - Raja, Siva

AU - Almeida, Francisco

AU - Sethi, Sonali

AU - Gildea, Thomas R.

AU - Peacock, Craig D.

AU - Adams, Drew J.

AU - Abazeed, Mohamed E.

N1 - Funding Information: M.E.A. was supported by NIH KL2 TR0002547, NIH R37 CA222294, the American Lung Association and VeloSano. E.K.C. was supported by SNUH Research Fund 0420160010. Funding Information: M.E.A. receives grant support, travel support, and honoraria from Bayer AG and receives grant support from Siemens Medical Solutions, USA in subject matter or material not directly related to this work. The other authors disclose no potential conflicts of interest. Publisher Copyright: © 2019, The Author(s).

PY - 2019/12/1

Y1 - 2019/12/1

N2 - Molecular determinants governing the evolution of tumor subclones toward phylogenetic branches or fixation remain unknown. Using sequencing data, we model the propagation and selection of clones expressing distinct categories of BRAF mutations to estimate their evolutionary trajectories. We show that strongly activating BRAF mutations demonstrate hard sweep dynamics, whereas mutations with less pronounced activation of the BRAF signaling pathway confer soft sweeps or are subclonal. We use clonal reconstructions to estimate the strength of “driver” selection in individual tumors. Using tumors cells and human-derived murine xenografts, we show that tumor sweep dynamics can significantly affect responses to targeted inhibitors of BRAF/MEK or DNA damaging agents. Our study uncovers patterns of distinct BRAF clonal evolutionary dynamics and nominates therapeutic strategies based on the identity of the BRAF mutation and its clonal composition.

AB - Molecular determinants governing the evolution of tumor subclones toward phylogenetic branches or fixation remain unknown. Using sequencing data, we model the propagation and selection of clones expressing distinct categories of BRAF mutations to estimate their evolutionary trajectories. We show that strongly activating BRAF mutations demonstrate hard sweep dynamics, whereas mutations with less pronounced activation of the BRAF signaling pathway confer soft sweeps or are subclonal. We use clonal reconstructions to estimate the strength of “driver” selection in individual tumors. Using tumors cells and human-derived murine xenografts, we show that tumor sweep dynamics can significantly affect responses to targeted inhibitors of BRAF/MEK or DNA damaging agents. Our study uncovers patterns of distinct BRAF clonal evolutionary dynamics and nominates therapeutic strategies based on the identity of the BRAF mutation and its clonal composition.

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Clonal selection confers distinct evolutionary trajectories in BRAF-driven cancers

Abstract

ASJC Scopus subject areas

UN SDGs

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