尽管肺癌吸烟者中多发性原发肿瘤的发生可归因于致癌物诱导的局部癌化，但缺乏已知环境暴露的 EGFR 突变型肺癌患者出现多发性肿瘤的原因仍无法解释。在本研究中，我们确定了 10 名早期可切除非小细胞肺癌患者，他们患有多个解剖学上不同的 EGFR 突变肿瘤。我们使用全外显子组测序 (WES) 和高可变聚鸟嘌呤 (poly(G)) 重复基因分型作为谱系追踪的正交方法，分析了每位患者的多个肿瘤之间的系统发育关系。在四名患者中，通过 WES 和 Poly(G) 谱系追踪评估，发育嵌合体表明存在共同的非生殖细胞来源。在另外两名患者中，我们发现了种系 EGFR 变异，在体外建模时，其信号传导适度增强。因此，除了种系变异之外，发育嵌合现象定义了多种 EGFR 突变原发性肿瘤的遗传易感性的独特机制，对其病因学和临床管理具有影响。© 2024。作者。

Although the development of multiple primary tumors in smokers with lung cancer can be attributed to carcinogen-induced field cancerization, the occurrence of multiple tumors at presentation in individuals with EGFR-mutant lung cancer who lack known environmental exposures remains unexplained. In the present study, we identified ten patients with early stage, resectable, non-small cell lung cancer who presented with multiple, anatomically distinct, EGFR-mutant tumors. We analyzed the phylogenetic relationships among multiple tumors from each patient using whole-exome sequencing (WES) and hypermutable poly(guanine) (poly(G)) repeat genotyping as orthogonal methods for lineage tracing. In four patients, developmental mosaicism, assessed by WES and poly(G) lineage tracing, indicates a common non-germline cell of origin. In two other patients, we identified germline EGFR variants, which confer moderately enhanced signaling when modeled in vitro. Thus, in addition to germline variants, developmental mosaicism defines a distinct mechanism of genetic predisposition to multiple EGFR-mutant primary tumors, with implications for their etiology and clinical management.© 2024. The Author(s).