Soft tissue sarcomas (STSs) are aggressive tumors with few efficient systemic therapies. Poly(ADP-ribose) polymerase-1 (PARP1) inhibitors represent an emerging therapeutic option in tumors with genomic instability. The genomics of STSs is complex in more than half of cases, suggesting a high level of inherent DNA damage and genomic instability. Thus, STSs could be efficiently targeted with PARP inhibitors. Promising preclinical results have been reported, but few data are available regarding PARP1 expression in clinical samples. We examined PARP1 mRNA expression in 1464 clinical samples of STS, including 1432 primary tumors and 32 relapses, and searched for correlations with clinicopathological features, including metastasis-free survival (MFS). Expression was heterogeneous across the samples, not different between primary and secondary tumors, and was correlated to PARP1 DNA copy number. In the 1432 primary tumors, the 'PARP1-high' samples were associated with younger patients, more frequent locations at the extremities, superficial trunk and head and neck, more leiomyosarcomas and other STSs and less liposarcomas and myxofibrosarcomas, more grade 3, more high-risk CINSARC tumors, and more 'chromosomically instable' tumors. They were associated with shorter MFS, independently of other significant prognostic features, including the CINSARC signature. We found a strong involvement of genes overexpressed in the 'PARP1-high' samples in cell cycle, DNA replication, and DNA repair. PARP1 expression refines the prediction of MFS in STSs, and similar expression exists in secondary and primary tumors, supporting the development of PARP1 inhibitors.

中文翻译：

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PARP1在软组织肉瘤中的表达是不良预后因素和新的潜在治疗靶点。

软组织肉瘤（STS）是侵袭性肿瘤，几乎没有有效的全身疗法。聚（ADP-核糖）聚合酶-1（PARP1）抑制剂代表了具有基因组不稳定的肿瘤的新兴治疗选择。在超过一半的情况下，STS的基因组学很复杂，这表明高水平的固有DNA损伤和基因组不稳定。因此，可以使用PARP抑制剂有效地靶向STS。临床前结果已有报道，但有关PARP1在临床样品中表达的数据很少。我们检查了1464例STS临床样品中的PARP1 mRNA表达，包括1432例原发肿瘤和32例复发，并研究了与临床病理特征（包括无转移生存（MFS））的相关性。样品中的表达是异质的，在原发性和继发性肿瘤之间没有差异，并与PARP1 DNA拷贝数相关。在1432例原发性肿瘤中，“ PARP1高”样本与年轻患者，四肢部位，躯干浅表和头颈部位位置更频繁，平滑肌肉瘤和其他STS少，脂肉瘤和粘液性纤维原发性肉瘤，3级，更高风险的CINSARC肿瘤，以及更多的“染色体不稳定”肿瘤。它们与较短的MFS相关，与其他重要的预后特征无关，包括CINSARC签名。我们发现细胞周期，DNA复制和DNA修复中'PARP1-high'样品中过表达的基因大量参与。PARP1的表达改善了STS中MFS的预测，并且在继发性和原发性肿瘤中也存在类似的表达，从而支持PARP1抑制剂的发展。