Clonal selection confers distinct evolutionary trajectories in BRAF-driven cancers

Area of Science:

• Cancer Genomics
• Evolutionary Biology
• Molecular Oncology

Background:

• The evolutionary trajectories of tumor subclones, whether branching or fixing, are not fully understood.
• BRAF mutations are common drivers in various cancers, but their varying impact on clonal evolution requires elucidation.

Purpose of the Study:

• To model the propagation and selection of clones with different BRAF mutations.
• To estimate the evolutionary trajectories and selection strengths of tumor subclones.
• To investigate how BRAF clonal dynamics influence therapeutic responses.

Main Methods:

• Utilized sequencing data to model clonal propagation and selection.
• Developed computational models to estimate evolutionary trajectories.
• Employed clonal reconstructions to quantify driver selection strength.
• Used tumor cells and murine xenografts for experimental validation.

Main Results:

• Strongly activating BRAF mutations exhibit hard sweep dynamics.
• Less activating BRAF mutations result in soft sweeps or remain subclonal.
• Tumor sweep dynamics significantly impact responses to BRAF/MEK inhibitors and DNA damaging agents.

Conclusions:

• Distinct BRAF clonal evolutionary dynamics were uncovered.
• The identity of BRAF mutations and clonal composition dictate therapeutic strategies.
• This research nominates novel therapeutic approaches based on specific BRAF mutation profiles.