Our understanding of genomic heterogeneity in lung cancer is largely based on the analysis of early-stage surgical specimens. Here we used endoscopic sampling of paired primary and intrathoracic metastatic tumors from 11 lung cancer patients to map genomic heterogeneity inoperable lung cancer with deep whole-genome sequencing. Intra-patient heterogeneity in driver or targetable mutations was predominantly in the form of copy number gain. Private mutation signatures, including patterns consistent with defects in homologous recombination, were highly variable both within and between patients. Irrespective of histotype, we observed a smaller than expected number of private mutations, suggesting that ancestral clones accumulated large mutation burdens immediately prior to metastasis. Single-region whole-genome sequencing of from 20 patients showed that tumors in ever-smokers with the strongest tobacco signatures were associated with germline variants in genes implicated in the repair of cigarette-induced DNA damage. Our results suggest that lung cancer precursors in ever-smokers accumulate large numbers of mutations prior to the formation of frank malignancy followed by rapid metastatic spread. In advanced lung cancer, germline variants in DNA repair genes may interact with the airway environment to influence the pattern of founder mutations, whereas similar interactions with the tumor microenvironment may play a role in the acquisition of mutations following metastasis.

中文翻译：

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深度多区域全基因组测序揭示了未经治疗的转移性肺癌的异质性和基因与环境的相互作用。


我们对肺癌基因组异质性的理解很大程度上基于对早期手术标本的分析。在这里，我们使用来自 11 名肺癌患者的配对原发性肿瘤和胸内转移性肿瘤的内窥镜取样，通过深度全基因组测序来绘制无法手术肺癌的基因组异质性。驱动突变或靶向突变的患者内异质性主要表现为拷贝数增加的形式。私人突变特征，包括与同源重组缺陷一致的模式，在患者内部和患者之间都存在很大差异。无论组织型如何，我们观察到的私人突变数量少于预期，这表明祖先克隆在转移前立即积累了巨大的突变负担。对 20 名患者进行的单区域全基因组测序表明，具有最强烟草特征的吸烟者的肿瘤与参与修复香烟引起的 DNA 损伤的基因的种系变异有关。我们的研究结果表明，经常吸烟者的肺癌前兆在形成明显的恶性肿瘤之前积累了大量突变，随后迅速转移扩散。在晚期肺癌中，DNA修复基因中的种系变异可能与气道环境相互作用，从而影响始祖突变的模式，而与肿瘤微环境的类似相互作用可能在转移后突变的获得中发挥作用。