A widespread approach to modern cancer therapy is to identify a single oncogenic driver gene and target its mutant-protein product (for example, EGFR-inhibitor treatment in EGFR-mutant lung cancers). However, genetically driven resistance to targeted therapy limits patient survival. Through genomic analysis of 1,122 EGFR-mutant lung cancer cell-free DNA samples and whole-exome analysis of seven longitudinally collected tumor samples from a patient with EGFR-mutant lung cancer, we identified critical co-occurring oncogenic events present in most advanced-stage EGFR-mutant lung cancers. We defined new pathways limiting EGFR-inhibitor response, including WNT/β-catenin alterations and cell-cycle-gene (CDK4 and CDK6) mutations. Tumor genomic complexity increases with EGFR-inhibitor treatment, and co-occurring alterations in CTNNB1 and PIK3CA exhibit nonredundant functions that cooperatively promote tumor metastasis or limit EGFR-inhibitor response. This study calls for revisiting the prevailing single-gene driver-oncogene view and links clinical outcomes to co-occurring genetic alterations in patients with advanced-stage EGFR-mutant lung cancer.

中文翻译：

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EGFR突变晚期肺癌中同时发生的遗传变异的演变和临床影响。

现代癌症治疗的一种普遍方法是鉴定单个致癌驱动基因并靶向其突变蛋白产物（例如，EGFR突变型肺癌中的EGFR抑制剂治疗）。但是，基因驱动的针对靶向治疗的耐药性限制了患者的生存。通过对1,122个EGFR突变型肺癌无细胞DNA样本进行基因组分析以及对EGFR突变型肺癌患者的七个纵向收集的肿瘤样本进行全外显子组分析，我们确定了在大多数晚期阶段均存在的关键共同发生的致癌事件EGFR突变型肺癌。我们定义了限制EGFR抑制剂反应的新途径，包括WNT /β-catenin改变和细胞周期基因（CDK4和CDK6）突变。肿瘤基因组的复杂性随着EGFR抑制剂治疗的增加而增加，同时发生的CTNNB1和PIK3CA改变表现出非冗余功能，可协同促进肿瘤转移或限制EGFR抑制剂反应。这项研究呼吁重新审视流行的单基因驱动癌基因观点，并将临床结果与晚期EGFR突变型肺癌患者同时发生的基因改变联系起来。