Metastasis is the primary cause of cancer-related deaths, but the natural history, clonal evolution and impact of treatment are poorly understood. We analyzed whole-exome sequencing (WES) data from 457 paired primary tumor and metastatic samples from 136 patients with breast, colorectal and lung cancer, including untreated (n = 99) and treated (n = 100) metastases. Treated metastases often harbored private 'driver' mutations, whereas untreated metastases did not, suggesting that treatment promotes clonal evolution. Polyclonal seeding was common in untreated lymph node metastases (n = 17 out of 29, 59%) and distant metastases (n = 20 out of 70, 29%), but less frequent in treated distant metastases (n = 9 out of 94, 10%). The low number of metastasis-private clonal mutations is consistent with early metastatic seeding, which we estimated occurred 2-4 years before diagnosis across these cancers. Furthermore, these data suggest that the natural course of metastasis is selectively relaxed relative to early tumorigenesis and that metastasis-private mutations are not drivers of cancer spread but instead associated with drug resistance.

中文翻译：

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成对原发性肿瘤和转移瘤中克隆性和全身扩散时间的多癌症分析。

转移是癌症相关死亡的主要原因，但对其自然史、克隆进化和治疗影响知之甚少。我们分析了来自 136 名乳腺癌、结直肠癌和肺癌患者的 457 对原发肿瘤和转移样本的全外显子组测序 (WES) 数据，包括未治疗 (n = 99) 和治疗 (n = 100) 转移。经治疗的转移瘤通常含有私人“驱动”突变，而未经治疗的转移瘤则没有，这表明治疗促进了克隆进化。多克隆种植在未经治疗的淋巴结转移（29 例中有 17 例，59%）和远处转移（70 例中有 20 例，29%）中很常见，但在治疗后的远处转移中较少见（94 例中有 9 例， 10%)。低数量的转移-私有克隆突变与早期转移播种一致，我们估计这些癌症发生在诊断前 2-4 年。此外，这些数据表明，相对于早期肿瘤发生，转移的自然过程是选择性放松的，转移私有突变不是癌症扩散的驱动因素，而是与耐药性相关。