英国欧洲生物信息学研究所Isidro Cortés-Ciriano等研究人员合作发现，持续的染色体碎裂，是导致骨肉瘤基因组复杂性和克隆演化的根本原因。相关论文于2025年1月14日在线发表在《细胞》杂志上。

据介绍，骨肉瘤是最常见的原发性骨癌，发病高峰出现在儿童和年轻成人中。

通过多区域全基因组测序，研究人员发现染色体碎裂（chromothripsis）是一个持续的突变过程，在74%的骨肉瘤中亚克隆性发生。染色体碎裂产生高度不稳定的衍生染色体，其持续演化推动了致癌突变的获得、克隆多样化以及不同类型肉瘤和癌症中的肿瘤内异质性。

此外，研究人员还描述了一种新的机制，称为丧失-易位-扩增（LTA）染色体碎裂，这一机制在约一半的儿童和成人高等级骨肉瘤中介导了突发性演化。

当单个双链断裂触发TP53失活和通过断裂-融合-桥接循环进行的致癌基因扩增时，就会发生LTA染色体碎裂。该机制在骨肉瘤中尤其常见，并且在其他由TP53突变驱动的癌症中未被检测到。最后，研究人员确定了全基因组杂合性丧失的水平作为高等级骨肉瘤的一个强预后指标。

附：英文原文

Title: Ongoing chromothripsis underpins osteosarcoma genome complexity and clonal evolution

Author: Jose Espejo Valle-Inclan, Solange De Noon, Katherine Trevers, Hillary Elrick, Ianthe A.E.M. van Belzen, Sonia Zumalave, Carolin M. Sauer, Mélanie Tanguy, Thomas Butters, Francesc Muyas, Alistair G. Rust, Fernanda Amary, Roberto Tirabosco, Adam Giess, Alona Sosinsky, Greg Elgar, Adrienne M. Flanagan, Isidro Cortés-Ciriano

Issue&Volume: 2025-01-14

Abstract: Osteosarcoma is the most common primary cancer of the bone, with a peak incidence in children and young adults. Using multi-region whole-genome sequencing, we find that chromothripsis is an ongoing mutational process, occurring subclonally in 74% of osteosarcomas. Chromothripsis generates highly unstable derivative chromosomes, the ongoing evolution of which drives the acquisition of oncogenic mutations, clonal diversification, and intra-tumor heterogeneity across diverse sarcomas and carcinomas. In addition, we characterize a new mechanism, termed loss-translocation-amplification (LTA) chromothripsis, which mediates punctuated evolution in about half of pediatric and adult high-grade osteosarcomas. LTA chromothripsis occurs when a single double-strand break triggers concomitant TP53 inactivation and oncogene amplification through breakage-fusion-bridge cycles. It is particularly prevalent in osteosarcoma and is not detected in other cancers driven by TP53 mutation. Finally, we identify the level of genome-wide loss of heterozygosity as a strong prognostic indicator for high-grade osteosarcoma.

DOI: 10.1016/j.cell.2024.12.005

Source: https://www.cell.com/cell/abstract/S0092-8674(24)01418-1