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In non-small cell lung cancer (NSCLC), the occurrence of multiple, independent tumours in the lungs of smokers is often attributed to field cancerization. In EGFR-mutant NSCLC, which occurs more frequently in non-smokers, the emergence of multiple primary tumours is more puzzling. In rare familial cases, heterozygous germline EGFR variants that lead to moderate (and thus germline-tolerable) EGFR activation, such as EGFRT790M, have been associated with NSCLC susceptibility.

在非小细胞肺癌（NSCLC）中，吸烟者肺部多发性独立肿瘤的发生通常归因于野外癌变。在非吸烟者中更常见的EGFR突变NSCLC中，多原发性肿瘤的出现更令人困惑。在罕见的家族病例中，导致中度（因此种系可耐受）EGFR激活的杂合种系EGFR变体（例如EGFRT790M）与NSCLC易感性有关。

In individuals carrying these mutations, multiple tumours arise when somatic ‘canonical’ EGFR mutations with strong activation (most commonly L858R and E746–A750del) co-occur with the germline allele in cis. In a recent study published in Nature Cancer, Burr, Leshchiner, Costantino et al. set out to test if other genetic mechanisms are at play.Four of these sporadic tumours displayed somatic mutations that were not shared with their matched normal tissues but had several shared mutations across lesions.

。在最近发表在《自然癌症》上的一项研究中，Burr、Leshchiner、Costantino等人着手测试是否还有其他遗传机制在起作用。这些散发性肿瘤中有四个显示出体细胞突变，这些突变与其匹配的正常组织不共享，但在病变中有几个共享突变。

Thus, these tumours arose neither completely independently, nor in the context of genetic predisposition, nor as clonally related metastasis. Instead, somatic mutation analysis suggested that the tumours derive from an ancestral clone that acquired somatic EGFR mutations during development. Progenitors of this clone were distributed throughout the adult body as part of normal development.

因此，这些肿瘤既不是完全独立产生的，也不是在遗传易感性的背景下产生的，也不是克隆相关的转移。相反，体细胞突变分析表明，肿瘤来源于祖先克隆，该克隆在发育过程中获得了体细胞EGFR突变。作为正常发育的一部分，该克隆的祖细胞分布在整个成年体内。

In the lung, this developmental mosaicism of EGFR mutations predisposes individuals to develop NSCLC. This hypothesis was further supported by poly(G) genotyping, which allows estimation of the number of cell divisions that separate somatic cell populations..

在肺中，EGFR突变的这种发育嵌合体使个体易于发展为NSCLC。poly（G）基因分型进一步支持了这一假设，该基因分型可以估计分离体细胞群的细胞分裂数量。。

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ReferencesOriginal articleBurr, R. et al. Developmental mosaicism underlying EGFR-mutant lung cancer presenting with multiple primary tumors. Nat. Cancer https://doi.org/10.1038/s43018-024-00840-y (2024)Article

参考文献Original articleBurr，R。等人。表现为多原发性肿瘤的EGFR突变型肺癌的发育嵌合体。自然癌症https://doi.org/10.1038/s43018-024-00840-y（2024）条

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Download referencesAuthor informationAuthors and AffiliationsNature Reviews Cancer http://www.nature.com/nrc/Daniela SenftAuthorsDaniela SenftView author publicationsYou can also search for this author in

下载参考文献作者信息作者和附属机构癌症评论http://www.nature.com/nrc/DanielaSenftAuthorsDaniela SenftView作者出版物您也可以在

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Daniela Senft.Rights and permissionsReprints and permissionsAbout this articleCite this articleSenft, D. Developing multiple EGFR-mutant lung cancers.

丹妮拉·森夫特。权利和许可打印和许可本文引用本文Senft，D。发展多种EGFR突变型肺癌。

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