Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Computational Oncology Service, Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
Nat Genet. 2023 Jun;55(6):1022-1033. doi: 10.1038/s41588-023-01395-x. Epub 2023 May 11.
Patients with high-risk neuroblastoma generally present with widely metastatic disease and often relapse despite intensive therapy. As most studies to date focused on diagnosis-relapse pairs, our understanding of the genetic and clonal dynamics of metastatic spread and disease progression remain limited. Here, using genomic profiling of 470 sequential and spatially separated samples from 283 patients, we characterize subtype-specific genetic evolutionary trajectories from diagnosis through progression and end-stage metastatic disease. Clonal tracing timed disease initiation to embryogenesis. Continuous acquisition of structural variants at disease-defining loci (MYCN, TERT, MDM2-CDK4) followed by convergent evolution of mutations targeting shared pathways emerged as the predominant feature of progression. At diagnosis metastatic clones were already established at distant sites where they could stay dormant, only to cause relapses years later and spread via metastasis-to-metastasis and polyclonal seeding after therapy.
高危神经母细胞瘤患者通常表现为广泛转移的疾病，尽管接受了强化治疗，但仍经常复发。由于迄今为止的大多数研究都集中在诊断-复发对上，因此我们对转移扩散和疾病进展的遗传和克隆动力学的理解仍然有限。在这里，我们使用来自 283 名患者的 470 个连续和空间分离样本的基因组分析，通过进展和终末期转移疾病来描述从诊断到进展的特定亚型的遗传进化轨迹。克隆追踪将疾病起始时间追溯到胚胎发生。在疾病定义性基因座（MYCN、TERT、MDM2-CDK4）上不断获得结构变异，随后针对共享途径的突变趋同进化，成为进展的主要特征。在诊断时，转移克隆已经在远处建立，在那里它们可以休眠，直到多年后复发，并在治疗后通过转移-转移和多克隆播种扩散。
