骨肉瘤（OS）是一种罕见但侵袭性的恶性肿瘤。尽管先前有报道，但对该病的分子特征尚不明确，并且对中国患者的OS了解甚少。本研究分析了73例中国OS病例的基因组特征。在我们的OS患者群中，TP53、NCOR1、LRP1B、ATRX、RB1和TFE3是最常突变的基因。此外，还对西方OS患者的基因组分析进行了研究。值得注意的是，中国和西方OS患者群之间的突变谱、碱基替换模式和肿瘤突变负荷存在显著差异。特定的分子机制，包括DNA损伤修复（DDR）基因突变、拷贝数变异（CNV）存在、非整倍体和肿瘤内异质性，与疾病进展相关。此外，30.1%的OS患者携带临床可操作的基因变异，主要富集在PI3K、MAPK、DDR和RTK信号通路中。具有DDR变异和CNV的特定分子亚型与远处转移无病生存和无事件生存显著相关，并且在所有具有不同特征的亚组中观察到这种相关性。这些发现全面阐明了OS的基因组特征，并揭示了该疾病的新的预后因子，有助于理解该疾病，并推动该人群的精准医学。本文受版权保护。保留所有权利。

Osteosarcoma (OS) is a rare but aggressive malignancy. Despite previous reports, molecular characterization of this disease is not well understood, and little is known regarding OS in Chinese patients. Herein, we analyzed the genomic signatures of 73 Chinese OS cases. TP53, NCOR1, LRP1B, ATRX, RB1 and TFE3 were the most frequently mutated gene in our OS cohort. In addition, the genomic analysis of Western OS patients was performed. Notably, there were remarkable disparities in mutational landscape, base substitution pattern and tumor mutational burden between the Chinese and Western OS cohorts. Specific molecular mechanisms, including DNA damage repair (DDR) gene mutations, copy number variation (CNV) presence, aneuploidy and intratumoral heterogeneity, were associated with disease progression. Additionally, 30.1% of OS patients carried clinically actionable alterations, which were mainly enriched in PI3K, MAPK, DDR and RTK signaling pathways. A specific molecular subtype incorporating DDR alterations and CNVs was significantly correlated with distant-metastasis-free survival and event-free survival, and this correlation was observed in all subgroups with different characteristics. These findings comprehensively elucidated the genomic profile and revealed novel prognostic factors in OS, which would contribute to understanding this disease and promoting precision medicine of this population.This article is protected by copyright. All rights reserved.