Molecular signatures of BRCAness analysis identifies PARP inhibitor Niraparib as a novel targeted therapeutic strategy for soft tissue Sarcomas
Molecular signatures of BRCAness analysis identifies PARP inhibitor Niraparib as a novel targeted therapeutic strategy for soft tissue Sarcomas
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BRCAness 分析的分子特征表明 PARP 抑制剂 Niraparib 是软组织肉瘤的新型靶向治疗策略
DOI：
10.7150/thno.45763
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发表时间：
2020-01-01
期刊：
影响因子：
12.4
通讯作者：
Xie, Xianbiao
中科院分区：
文献类型：
--
作者：
Li, Hongyi;Tu, Jian;Xie, Xianbiao
背景：晚期软组织肉瘤（STS）患者预后不佳，缺乏有效的治疗选择。同源重组修复（homologous recombination repair， HRR）途径的缺陷会积累DNA修复错误和基因突变，从而导致肿瘤的发生。BRCAness是指在没有种系BRCA1/2突变的情况下HRR缺陷（HRD）的肿瘤。然而，STS中BRCAness的特征在很大程度上仍然未知。因此，本研究旨在利用全外显子组测序（WES）探索STS中BRCAness的基因组和分子景观，旨在寻找治疗STS的潜在靶点。方法：对中山大学第一附属医院的22例STS样本进行WES检测，揭示可能的基因组和分子特征。然后使用来自The Cancer Genome Atlas （TCGA）数据库的224个STS样本数据和体外数据验证这些特征。对BRCAness的潜在生物标志物进行分析。在STS细胞系、细胞系来源的异种移植物（CDX）和患者来源的异种移植物（PDX）中评估STS化疗药物的靶向药物敏感性和联合治疗筛选。结果：与30种癌症体细胞突变特征相比，利用非负矩阵分解，在22个STS样本中发现了高余弦相似性（0.75）的HRD特征。单核苷酸多态性表明22例STS样本BRCA1/2的突变率较低（分别为11.76%和5.88%）。然而，拷贝数变异分析显示了广泛的染色体不稳定性；54.55%（12/22）的STS样本携带BRCAness性状。随后，在TCGA和体外的224份STS样本中也检测到相似的基因组和分子特征。聚（adp -核糖）聚合酶(PARP)-1有望反映HRD和治疗反应。此外，还发现PAR形成水平与PARP-1相关。随后，测定STS细胞系对PARP抑制剂（PARPi）尼拉帕尼敏感。此外，基于5种常见PARPis的筛选试验和多柔比星、异环磷酰胺、达卡巴嗪、替莫唑胺（TMZ）的联合试验，尼拉帕尼和TMZ在STS细胞株中协同作用最强。尼拉帕尼与TMZ联合治疗CDX和PDX的协同效应和安全性也得到了证实。结论：BRCAness可能是大多数STS病例的共同基因组和分子特征。PARP-1和PAR可能是评估HRD患者的潜在合适和可行的治疗性生物标志物。STSs对PARPi敏感。此外，尼拉帕尼与TMZ联合用药具有协同作用。尼拉帕尼和TMZ可能是一种有希望的STS患者靶向治疗策略。
Background: Patients with advanced soft tissue sarcomas (STS) have a dismal prognosis with few effective therapeutic options. A defect in the homologous recombination repair (HRR) pathway can accumulate DNA repair errors and gene mutations, which can lead to tumorigenesis. BRCAness describes tumors with an HRR deficiency (HRD) in the absence of a germline BRCA1/2 mutation. However, the characteristics of BRCAness in STS remain largely unknown. Thus, this study aimed to explore the genomic and molecular landscape of BRCAness using whole exome sequencing (WES) in STS, aiming to find a potential target for STS treatment. Methods: WES was performed in 22 STS samples from the First Affiliated Hospital of Sun Yat-sen University to reveal the possible genomic and molecular characteristics. The characteristics were then validated using data of 224 STS samples from The Cancer Genome Atlas (TCGA) database and in vitro data. The analysis of the potential biomarker for BRCAness was performed. Targeted drug susceptibility and combination therapy screening of chemotherapeutics for STS were evaluated in STS cell lines, cell-line-derived xenografts (CDX), and patient-derived xenografts (PDX). Results: Compared with 30 somatic mutation signatures of cancers, high cosine-similarity (0.75) was identified for HRD signatures in the 22 STS samples using nonnegative matrix factorization. Single nucleotide polymorphism indicated a low mutation rate of BRCA1/2 in the 22 STS samples (11.76% and 5.88%, respectively). However, copy number variation analyses demonstrated widespread chromosomal instability; furthermore, 54.55% of STS samples (12/22) carried BRCAness traits. Subsequently, similar genomic and molecular characteristics were also detected in the 224 STS samples from TCGA and in vitro. Poly (ADP-ribose) polymerases (PARP)-1 could be a promising reflection of HRD and therapeutic response. Furthermore, the level of PAR formation was found to be correlated with PARP-1. Subsequently, STS cell lines were determined to be sensitive to PARP inhibitor (PARPi), niraparib. Moreover, based on the screening test of the five common PARPis and combination test among doxorubicin, ifosfamide, dacarbazine, and temozolomide (TMZ), niraparib and TMZ were the most synergistic in STS cell lines. The synergistic effect and safety of niraparib and TMZ combination were also shown in CDX and PDX. Conclusions: BRCAness might be the common genomic and molecular characteristics of majority of STS cases. PARP-1 and PAR could be potential proper and feasible theranostic biomarkers for assessing HRD in patients. STSs were sensitive to PARPi. Moreover, the combination of niraparib and TMZ showed synergistic effect. Niraparib and TMZ could be a promising targeted therapeutic strategy for patients with STS.