Clonal selection confers distinct evolutionary trajectories in BRAF-driven cancers
Clonal selection confers distinct evolutionary trajectories in BRAF-driven cancers
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DOI：
10.1038/s41467-019-13161-x
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发表时间：
2019-11-13
影响因子：
16.6
通讯作者：
Abazeed, Mohamed E.
中科院分区：
文献类型：
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作者：
Gopal, Priyanka;Sarihan, Elif Irem;Abazeed, Mohamed E.
控制肿瘤亚克隆向系统发生分支或固定进化的分子决定因素仍然未知。使用测序数据，我们模拟表达不同类别BRAF突变的克隆的繁殖和选择，以估计它们的进化轨迹。我们发现，强烈激活BRAF突变表现出硬扫描动力学，而BRAF信号通路激活不太明显的突变赋予软扫描或亚克隆。我们使用克隆重建来估计个体肿瘤中“驱动”选择的强度。使用肿瘤细胞和人源性小鼠异种移植物，我们表明肿瘤扫描动力学可以显着影响对BRAF/MEK或DNA损伤剂的靶向抑制剂的反应。我们的研究揭示了不同的BRAF克隆进化动力学模式，并根据BRAF突变及其克隆组成的身份提出了治疗策略。
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.