Genetic diversity among metastases is poorly understood but contains important information about disease evolution at secondary sites. Here we investigate inter- and intra-lesion heterogeneity for two types of metastases that associate with different clinical outcomes: lymph node and distant organ metastases in human colorectal cancer. We develop a rigorous mathematical framework for quantifying metastatic phylogenetic diversity. Distant metastases are typically monophyletic and genetically similar to each other. Lymph node metastases, in contrast, display high levels of inter-lesion diversity. We validate these findings by analyzing 317 multi-region biopsies from an independent cohort of 20 patients. We further demonstrate higher levels of intra-lesion heterogeneity in lymph node than in distant metastases. Our results show that fewer primary tumor lineages seed distant metastases than lymph node metastases, indicating that the two sites are subject to different levels of selection. Thus, lymph node and distant metastases develop through fundamentally different evolutionary mechanisms.

转移之间的遗传多样性知之甚少，但包含有关继发部位疾病演变的重要信息。在这里，我们调查了两种与不同临床结果相关的转移灶的病灶内和病灶内异质性：人结直肠癌的淋巴结转移和远处器官转移。我们开发了严格的数学框架来量化转移的系统发育多样性。远处转移通常是单系的，并且在遗传上彼此相似。相反，淋巴结转移显示出高水平的病灶间多样性。我们通过分析来自20个患者的独立队列中的317个多区域活检来验证这些发现。我们进一步证明，与远处转移相比，淋巴结内病变内异质性水平更高。我们的结果表明，远处转移的原发肿瘤谱系比淋巴结转移少，这表明两个部位的选择水平不同。因此，淋巴结和远处转移是通过根本不同的进化机制发展的。