Clonal selection confers distinct evolutionary trajectories in BRAF-driven cancers

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

doi:10.1038/s41467-019-13161-x

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.

Highlights

Molecular determinants governing the evolution of tumor subclones toward phylogenetic branches or fixation remain unknown
Several other residues had modest variant frequencies including G464, G466, G469, N581, D594, and L597 (Fig. 1b). These residues comprise the activation loop (A-loop) near V600 (L597), the phosphate binding loop (P-loop) (464–469), and residues critical for chelation of the divalent Mg+2 associated with ATP to help orient the molecule for optimal substitution (D594 and N581) (Fig. 1c)
We found that the cancer cell fraction (CCF) of the BRAF variants varied significantly on the basis of cancer type, with ~9% of analyzed lung adenocarcinoma (LUAD) containing BRAF variants that were clonal compared to >80% of SKCM

Summary

Introduction

Molecular determinants governing the evolution of tumor subclones toward phylogenetic branches or fixation remain unknown. Estimates of effect size across a population using the substitution rate of a variant can provide some indication of selection intensity, or the average selective effect[13] This and other similar approaches do not quantify the strength of selection in individual tumors[14]. Despite the confirmed activation of the mitogenactivated extracellular-signal-regulated kinase (MEK/ERK) pathway in some of these tumors, it is not clear whether mutations in these putative BRAF-driven tumors confer upfront sensitivity to inhibitors of BRAF (BRAFi) and/or MEK (MEKi) or alter the tumor genetic composition[21,22,23]. Due to its multitude of variants, its significant alteration frequency in several cancer types and the variable clinical efficacy of drugs that target it, BRAF is a model oncogene to study molecular classification-based heterogeneity

Methods

Results

Conclusion