Introduction: Data regarding the pre‐treatment intertumor heterogeneity of potential biomarkers in advanced‐stage lung cancers is limited. A finding of such heterogeneity between primary and metastatic lesions would prove valuable to determine if a metastatic lesion can be a surrogate for the primary tumor, as more biomarkers will likely be used in the future to inform treatment decisions. Methods: We performed RNA sequencing to analyze intertumor heterogeneity in 30 specimens (primary tumors, intrathoracic, and extrathoracic metastatic lesions) obtained from five treatment‐naïve lung cancer patients. Results: The global unsupervised clustering analysis showed that the lesions clustered at the individual patient level rather than on the metastatic sites, suggesting that the characteristics of specific tumor cells have a greater impact on the gene expression signature than the microenvironment in which the metastasis develops. The mutational and transcriptional data highlight the presence of intertumor heterogeneity showing that the primary tumors are usually distinct from metastatic lesions. Through a comparison between metastatic lesions and the primary tumors, we observed that pathways related to cell proliferation were upregulated, whereas immune‐related pathways were downregulated in metastatic lesions. Conclusion: These data not only provide insight into the evolution of lung cancers, but also imply possibilities and limitations of biomarker‐based treatment in lung cancers.

中文翻译：

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肺癌的先天遗传进化和空间异质性：治疗初治病变分析

简介：关于晚期肺癌潜在生物标志物治疗前肿瘤间异质性的数据有限。原发灶和转移灶之间的这种异质性的发现对于确定转移灶是否可以替代原发肿瘤是有价值的，因为未来可能会使用更多的生物标志物来为治疗决策提供信息。方法：我们进行了 RNA 测序，以分析来自 5 名初治肺癌患者的 30 个标本（原发肿瘤、胸腔内和胸腔外转移性病变）的肿瘤间异质性。结果：全局无监督聚类分析显示病变聚集在个体患者水平而不是转移部位，表明特定肿瘤细胞的特征对基因表达特征的影响比转移发生的微环境更大。突变和转录数据突出了肿瘤间异质性的存在，表明原发肿瘤通常与转移性病变不同。通过比较转移性病变和原发肿瘤，我们观察到与细胞增殖相关的通路被上调，而在转移性病变中免疫相关通路被下调。结论：这些数据不仅提供了对肺癌演变的洞察，而且暗示了基于生物标志物的肺癌治疗的可能性和局限性。突变和转录数据突出了肿瘤间异质性的存在，表明原发肿瘤通常与转移性病变不同。通过比较转移性病变和原发肿瘤，我们观察到与细胞增殖相关的通路被上调，而在转移性病变中免疫相关通路被下调。结论：这些数据不仅提供了对肺癌演变的洞察，而且暗示了基于生物标志物的肺癌治疗的可能性和局限性。突变和转录数据突出了肿瘤间异质性的存在，表明原发肿瘤通常与转移性病变不同。通过比较转移性病变和原发肿瘤，我们观察到与细胞增殖相关的通路被上调，而在转移性病变中免疫相关通路被下调。结论：这些数据不仅提供了对肺癌演变的洞察，而且暗示了基于生物标志物的肺癌治疗的可能性和局限性。而免疫相关通路在转移性病变中被下调。结论：这些数据不仅提供了对肺癌演变的洞察，而且暗示了基于生物标志物的肺癌治疗的可能性和局限性。而免疫相关通路在转移性病变中被下调。结论：这些数据不仅提供了对肺癌演变的洞察，而且暗示了基于生物标志物的肺癌治疗的可能性和局限性。