Lymph node metastases develop through a wider evolutionary bottleneck than distant metastases

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. ...转移瘤的遗传多样性目前尚未得到充分阐释，但其蕴含着继发部位肿瘤演化的关键信息。本研究针对与不同临床结局相关的两类人类结直肠癌转移瘤——淋巴结转移灶与远处器官转移灶，系统探究其病灶间与病灶内异质性。我们构建了一套严谨的数学框架，用于量化转移瘤的系统发育多样性。研究结果显示，远处转移灶通常呈单系起源，且彼此间遗传相似性较高；与之相对，淋巴结转移灶则呈现出极高的病灶间遗传多样性。我们通过分析来自20名患者组成的独立临床队列的317份多区域活检样本，验证了上述发现。进一步研究证实，淋巴结转移灶的病灶内异质性水平显著高于远处转移灶。本研究结果表明，相较于淋巴结转移灶，能够播散并定植形成远处转移灶的原发肿瘤谱系数量更少，这提示两类转移部位所经受的自然选择压力水平存在差异。……