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Clonal selection confers distinct evolutionary trajectories in BRAF-driven cancers

Author

Listed:
  • Priyanka Gopal

    (Cleveland Clinic
    Case Western Reserve University)

  • Elif Irem Sarihan

    (Cleveland Clinic)

  • Eui Kyu Chie

    (Seoul National University College of Medicine)

  • Gwendolyn Kuzmishin

    (Cleveland Clinic)

  • Semihcan Doken

    (Cleveland Clinic)

  • Nathan A. Pennell

    (Cleveland Clinic)

  • Daniel P. Raymond

    (Cleveland Clinic)

  • Sudish C. Murthy

    (Cleveland Clinic)

  • Usman Ahmad

    (Cleveland Clinic)

  • Siva Raja

    (Cleveland Clinic)

  • Francisco Almeida

    (Cleveland Clinic)

  • Sonali Sethi

    (Cleveland Clinic)

  • Thomas R. Gildea

    (Cleveland Clinic)

  • Craig D. Peacock

    (Cleveland Clinic)

  • Drew J. Adams

    (Case Western Reserve University, Department of Genetics)

  • Mohamed E. Abazeed

    (Cleveland Clinic
    Cleveland Clinic)

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.

Suggested Citation

  • 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 & Sona, 2019. "Clonal selection confers distinct evolutionary trajectories in BRAF-driven cancers," Nature Communications, Nature, vol. 10(1), pages 1-14, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-13161-x
    DOI: 10.1038/s41467-019-13161-x
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