同源重组修复（HRR）缺陷与肿瘤的恶化预后和转移发展相关。确定HRR缺陷（HRD）在临床上具有重要意义，因为它与治疗易感性相关，并且在肉瘤中仍未得到充分研究。在这里，我们展示了特定的肉瘤实体显示出高水平的基因组不稳定标记和HRR基因的分子改变，同时具有复杂的染色体不稳定模式。此外，携带HRDness特征的肉瘤表现出明显的SARC-HRD转录标记，在患者来源的肉瘤细胞中预测PARP抑制剂的敏感性。同时，HRDhigh肉瘤细胞缺乏RAD51核状聚焦在DNA损伤时的形成，进一步说明了HRR的缺陷。我们进一步确定WEE1激酶是HRDness肉瘤的治疗易感性，并展示了联合DNA损伤剂和DNA修复通路抑制剂的临床受益。总之，我们提供了一种个性化的肿瘤学方法，成功地治疗了肉瘤患者。 © 2023作者。根据CC BY 4.0许可证的条款发表。

Defects in homologous recombination repair (HRR) in tumors correlate with poor prognosis and metastases development. Determining HRR deficiency (HRD) is of major clinical relevance as it is associated with therapeutic vulnerabilities and remains poorly investigated in sarcoma. Here, we show that specific sarcoma entities exhibit high levels of genomic instability signatures and molecular alterations in HRR genes, while harboring a complex pattern of chromosomal instability. Furthermore, sarcomas carrying HRDness traits exhibit a distinct SARC-HRD transcriptional signature that predicts PARP inhibitor sensitivity in patient-derived sarcoma cells. Concomitantly, HRDhigh sarcoma cells lack RAD51 nuclear foci formation upon DNA damage, further evidencing defects in HRR. We further identify the WEE1 kinase as a therapeutic vulnerability for sarcomas with HRDness and demonstrate the clinical benefit of combining DNA damaging agents and inhibitors of DNA repair pathways ex vivo and in the clinic. In summary, we provide a personalized oncological approach to treat sarcoma patients successfully.© 2023 The Authors. Published under the terms of the CC BY 4.0 license.