Quantitative evidence for early metastatic seeding in colorectal cancer
结直肠癌早期转移种子的定量证据
摘要：
Both the timing and molecular determinants of metastasis are unknown, hindering treatment and prevention efforts.Here we characterize the evolutionary dynamics of this lethal process by analyzing exome-sequencing data from 118 biopsies from 23 patients with colorectal cancer with metastases to the liver or brain.The data show that the genomic divergence between the primary tumor and metastasis is low and that canonical driver genes were acquired early.Analysis within a spatial tumor growth model and statistical inference framework indicates that early disseminated cells commonly (81%, 17 out of 21 evaluable patients) seed metastases while the carcinoma is clinically undetectable (typically, less than 0.01 cm^3).We validated the association between early drivers and metastasis in an independent cohort of 2,751 colorectal cancers, demonstrating their utility as biomarkers of metastasis.This conceptual and analytical framework provides quantitative in vivo evidence that systemic spread can occur early in colorectal cancer and illuminates strategies for patient stratification and therapeutic targeting of the canonical drivers of tumorigenesis.
转移的时间和分子决定因素都是未知的，阻碍了治疗和预防工作。在这里，我们通过分析来自23例结直肠癌转移到肝脏或脑部的患者的118个活组织检查的外显子组测序数据来描述这种致命过程的进化动力学。数据显示原发性肿瘤与转移之间的基因组差异较小，并且早期获得了经典驱动基因。空间肿瘤生长模型和统计推断框架内的分析表明，早期播散的细胞通常（21％，21个可评估患者中的17个）种子转移，而癌临床上检测不到（通常小于0.01平方公分）。我们验证了2,751例结肠直肠癌的独立队列中早期驱动与转移之间的关联，证明了它们作为转移生物标志物的效用。这种概念和分析框架提供了定量的体内证据，证明系统性扩散可以在结肠直肠癌的早期发生，并阐明了患者分层和肿瘤发生的规范驱动因素的治疗靶向的策略。
结直肠癌早期转移种子的定量证据
摘要：
Both the timing and molecular determinants of metastasis are unknown, hindering treatment and prevention efforts.Here we characterize the evolutionary dynamics of this lethal process by analyzing exome-sequencing data from 118 biopsies from 23 patients with colorectal cancer with metastases to the liver or brain.The data show that the genomic divergence between the primary tumor and metastasis is low and that canonical driver genes were acquired early.Analysis within a spatial tumor growth model and statistical inference framework indicates that early disseminated cells commonly (81%, 17 out of 21 evaluable patients) seed metastases while the carcinoma is clinically undetectable (typically, less than 0.01 cm^3).We validated the association between early drivers and metastasis in an independent cohort of 2,751 colorectal cancers, demonstrating their utility as biomarkers of metastasis.This conceptual and analytical framework provides quantitative in vivo evidence that systemic spread can occur early in colorectal cancer and illuminates strategies for patient stratification and therapeutic targeting of the canonical drivers of tumorigenesis.
转移的时间和分子决定因素都是未知的，阻碍了治疗和预防工作。在这里，我们通过分析来自23例结直肠癌转移到肝脏或脑部的患者的118个活组织检查的外显子组测序数据来描述这种致命过程的进化动力学。数据显示原发性肿瘤与转移之间的基因组差异较小，并且早期获得了经典驱动基因。空间肿瘤生长模型和统计推断框架内的分析表明，早期播散的细胞通常（21％，21个可评估患者中的17个）种子转移，而癌临床上检测不到（通常小于0.01平方公分）。我们验证了2,751例结肠直肠癌的独立队列中早期驱动与转移之间的关联，证明了它们作为转移生物标志物的效用。这种概念和分析框架提供了定量的体内证据，证明系统性扩散可以在结肠直肠癌的早期发生，并阐明了患者分层和肿瘤发生的规范驱动因素的治疗靶向的策略。
