Li Guozhuang, Wu Nan, Ghabrial Jen, Stinnett Victoria, Klausner Melanie, Morsberger Laura, Long Patty, Baraban Ezra, Gross John M, Zou Ying S
State Key Laboratory of Complex Severe and Rare Diseases, Department of Orthopedic Surgery, Peking Union Medical College Hospital, Peking Union Medical College and Chinese Academy of Medical Sciences, Beijing 100730, China.
Beijing Key Laboratory of Big Data Innovation and Application for Skeletal Health Medical Care, Beijing 100730, China.
Biomolecules. 2025 Jun 7;15(6):833. doi: 10.3390/biom15060833.
Chromoanagenesis is a catastrophic genomic phenomenon involving sudden, extensive rearrangements within one or a few cell cycles. In osteosarcoma, the most prevalent malignant bone tumor in children and adolescents, these events dramatically alter the genomic landscape, frequently disrupting key tumor suppressor genes like and , amplifying oncogene expression, and propelling tumor progression and evolution. This review elucidates how key chromoanagenic mechanisms, such as chromothripsis and chromoanasynthesis, arise from replication stress and impaired DNA repair pathways, ultimately contributing to genomic instability in osteosarcoma. Chromothripsis features prominently in osteosarcoma, occurring in up to 62% of tumor regions and driving intratumoral heterogeneity through persistent genomic crises. Next-generation sequencing, optical genome mapping, and emerging technologies like single-cell sequencing empower researchers to detect and characterize these complex structural variants, demonstrating how a single catastrophic event can profoundly influence osteosarcoma progression over time. While targeted therapies for osteosarcoma have proven elusive, innovative strategies harnessing comprehensive genomic profiling and patient-derived preclinical models hold promise for uncovering tumor-specific vulnerabilities tied to chromoanagenesis. Ultimately, unraveling how these rapid, large-scale rearrangements fuel osteosarcoma's aggressive nature will not only refine disease classification and prognosis but also pave the way for novel therapeutic approaches to enhance patient outcomes.
染色体骤变是一种灾难性的基因组现象，涉及在一个或几个细胞周期内突然发生的广泛重排。在骨肉瘤（儿童和青少年中最常见的恶性骨肿瘤）中，这些事件会极大地改变基因组格局，经常破坏诸如 和 等关键肿瘤抑制基因，放大癌基因表达，并推动肿瘤进展和演变。本综述阐明了诸如染色体碎裂和染色体合成等关键染色体骤变机制是如何由复制应激和受损的DNA修复途径产生的，最终导致骨肉瘤中的基因组不稳定。染色体碎裂在骨肉瘤中显著存在，在高达62%的肿瘤区域发生，并通过持续的基因组危机驱动肿瘤内异质性。新一代测序、光学基因组图谱绘制以及单细胞测序等新兴技术使研究人员能够检测和表征这些复杂的结构变异，展示了单个灾难性事件如何随着时间的推移深刻影响骨肉瘤的进展。虽然骨肉瘤的靶向治疗尚未成功，但利用全面基因组分析和患者来源的临床前模型的创新策略有望揭示与染色体骤变相关的肿瘤特异性脆弱性。最终，弄清楚这些快速、大规模的重排如何助长骨肉瘤的侵袭性不仅将完善疾病分类和预后，还将为改善患者预后的新型治疗方法铺平道路。
