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 and Mohamed E. Abazeed ()
Additional contact information
Priyanka Gopal: Cleveland Clinic
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

Nature Communications, 2019, vol. 10, issue 1, 1-14

Abstract: 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.

Date: 2019
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DOI: 10.1038/s41467-019-13161-x

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