转移性乳腺癌是一种致命的疾病,5年生存率很低。在活体患者中追踪转移扩散是困难的,因此知之甚少。
通过快速尸检,我们从一名三阴性转移性乳腺癌患者的3个时间点和8个器官中收集了30个肿瘤样本.采样的大量地点,结合深度全基因组测序和先进的计算分析,使我们能够以亚克隆分辨率全面重建肿瘤的演化。
最独特的,我们在该患者中观察到的肿瘤演变的先前未报道的方面是存在“亚克隆孵化器”,“定义为转移部位,其中在最初在培养箱部位进化的亚克隆定植其他部位和器官之前发生大量肿瘤进化。总的来说,我们确定了四个离散的转移性扩张波,每一个都产生了一些新的,遗传上相似的转移位点,也富集了特定的器官(例如,腹部vs骨骼和大脑)。在该患者中,肺部在促进转移扩散方面发挥了关键作用:肺部是原发性乳腺病变转移的第一个部位,这个部位的亚克隆可能是所有四个后续转移波的来源,肺部的多个部位充当亚克隆孵化器。最后,功能注释显示,该患者中许多已知的驱动因素或促进转移的肿瘤突变被一些人共享,但不是所有的转移部位,强调需要对患者的转移进行更全面的调查,以进行有效的临床干预。
我们的分析显示,在患者的转移培养箱部位存在大量的肿瘤演变,具有潜在的重要临床意义。我们的研究表明,大量转移部位的采样为研究转移演变提供了前所未有的细节。
Metastatic breast cancer is a deadly disease with a low 5-year survival rate. Tracking metastatic spread in living patients is difficult and thus poorly understood.
Via rapid autopsy, we have collected 30 tumor samples over 3 timepoints and across 8 organs from a triple-negative metastatic breast cancer patient. The large number of sites sampled, together with deep whole-genome sequencing and advanced computational analysis, allowed us to comprehensively reconstruct the tumor\'s evolution at subclonal resolution.
The most unique, previously unreported aspect of the tumor\'s evolution that we observed in this patient was the presence of \"
subclone incubators,\" defined as metastatic sites where substantial tumor evolution occurs before colonization of additional sites and organs by subclones that initially evolved at the incubator site. Overall, we identified four discrete waves of metastatic expansions, each of which resulted in a number of new, genetically similar metastasis sites that also enriched for particular organs (e.g., abdominal vs bone and brain). The lung played a critical role in facilitating metastatic spread in this patient: the lung was the first site of metastatic escape from the primary breast lesion, subclones at this site were likely the source of all four subsequent metastatic waves, and multiple sites in the lung acted as
subclone incubators. Finally, functional annotation revealed that many known drivers or metastasis-promoting tumor mutations in this patient were shared by some, but not all metastatic sites, highlighting the need for more comprehensive surveys of a patient\'s metastases for effective clinical intervention.
Our analysis revealed the presence of substantial tumor evolution at metastatic incubator sites in a patient, with potentially important clinical implications. Our study demonstrated that sampling of a large number of metastatic sites affords unprecedented detail for studying metastatic evolution.