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egfr突变肺癌的发育嵌合体表现为多发原发肿瘤

原文发布日期：2024-10-15

英文摘要：

摘要翻译：

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文章：

egfr突变肺癌的发育嵌合体表现为多发原发肿瘤

Developmental mosaicism underlying EGFR-mutant lung cancer presenting with multiple primary tumors

原文发布日期：2024-10-15

英文摘要：

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.

摘要翻译：

尽管吸烟者肺癌出现多个原发肿瘤通常与致癌物诱导的场域癌变有关，但在EGFR突变性肺癌患者中缺乏已知环境暴露而出现多发性肿瘤的现象仍未得到解释。本研究中，我们识别了十例早期可切除、非小细胞肺癌患者，他们均出现了多个、解剖学位置不同的EGFR突变性肿瘤。对每位患者的多个肿瘤，我们通过全基因组测序（WES）和超 mutable poly(G)重复区段基因otyping等正交方法进行了系谱关系分析。在四例患者中，发育性异质性分析表明存在共同的非同源细胞起始。另外两例患者中的系谱分析发现携带了突变的同源染色体。通过体外模型构建发现，携带突变的原发肿瘤呈现出显著增强的信号传导效果。基于这些观察结果，在EGFR突变性原发肿瘤多发性方面，不仅存在基因突变因素，还存在发育性异质性这一不同的遗传易位机制，这对阐明其病因和临床管理具有重要意义。