美国纪念斯隆凯特琳癌症中心Elli Papaemmanuil和Gunes Gundem共同合作，近期取得重要工作进展。他们研究提出了高危神经母细胞瘤转移扩散过程中的克隆演化过程。相关研究成果2023年5月11日在线发表于《自然—遗传学》杂志上。

据介绍，高危神经母细胞瘤患者通常表现为广泛的转移性疾病，尽管进行了强化治疗，但仍经常复发。由于迄今为止大多数研究都集中在诊断-复发对上，人们对转移性传播和疾病进展的遗传和克隆转移扩散动力学的理解仍然有限。

研究人员使用来自283名患者的470个序列和空间分离样本的基因组图谱，表征了从诊断到进展和终末期转移疾病的亚型特异性遗传演化轨迹。克隆追踪将疾病的起始时间定为胚胎发生。在疾病定义基因座（MYCN、TERT、MDM2-CDK4）上持续获得结构变异，然后靶向共享途径的突变趋同演化，成为进展的主要特征。在诊断时，转移性克隆已经在远处建立，在那里它们可以保持休眠，但几年后会导致复发，并在治疗后通过转移灶的再转移和多克隆接种传播。

附：英文原文

Title: Clonal evolution during metastatic spread in high-risk neuroblastoma

Author: Gundem, Gunes, Levine, Max F., Roberts, Stephen S., Cheung, Irene Y., Medina-Martnez, Juan S., Feng, Yi, Arango-Ossa, Juan E., Chadoutaud, Loic, Rita, Mathieu, Asimomitis, Georgios, Zhou, Joe, You, Daoqi, Bouvier, Nancy, Spitzer, Barbara, Solit, David B., Dela Cruz, Filemon, LaQuaglia, Michael P., Kushner, Brian H., Modak, Shakeel, Shukla, Neerav, Iacobuzio-Donahue, Christine A., Kung, Andrew L., Cheung, Nai-Kong V., Papaemmanuil, Elli

Issue&Volume: 2023-05-11

Abstract: 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.

DOI: 10.1038/s41588-023-01395-x

Source: https://www.nature.com/articles/s41588-023-01395-x