Department of Musculoskeletal Oncology, the First Affiliated Hospital of Sun Yat-sen University, Guangzhou, China.
Guangdong Provincial Key Laboratory of Orthopedics and Traumatology, Guangzhou, China.
Theranostics. 2020 Jul 25;10(21):9477-9494. doi: 10.7150/thno.45763. eCollection 2020.
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. 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 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). 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 . 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. 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.
患有晚期软组织肉瘤（STS）的患者预后不佳，治疗选择有限。同源重组修复（HRR）途径的缺陷会导致 DNA 修复错误和基因突变，从而导致肿瘤发生。BRCAness 描述的是 HRD 缺乏（HRD）而无胚系 BRCA1/2 突变的肿瘤。然而，STS 中 BRCAness 的特征在很大程度上仍不清楚。因此，本研究旨在通过 STS 的全外显子组测序（WES）探索 BRCAness 的基因组和分子特征，以期找到 STS 治疗的潜在靶点。
对中山大学第一附属医院的 22 例 STS 样本进行 WES，以揭示可能的基因组和分子特征。然后使用 The Cancer Genome Atlas（TCGA）数据库和 的 224 例 STS 样本数据验证这些特征。分析了 BRCAness 的潜在生物标志物。在 STS 细胞系、细胞系衍生的异种移植（CDX）和患者衍生的异种移植（PDX）中评估了针对 STS 的靶向药物敏感性和联合治疗筛选。
与癌症的 30 种体细胞突变特征相比，使用非负矩阵分解在 22 例 STS 样本中鉴定到 HRD 特征的高余弦相似度（0.75）。单核苷酸多态性表明 22 例 STS 样本中 BRCA1/2 的突变率较低（分别为 11.76%和 5.88%）。然而，拷贝数变异分析表明广泛的染色体不稳定性；此外，54.55%的 STS 样本（12/22）具有 BRCAness 特征。随后，在 TCGA 和 中也检测到类似的基因组和分子特征。聚（ADP-核糖）聚合酶（PARP）-1 可能是 HRD 和治疗反应的有希望的反映。此外，PAR 形成水平与 PARP-1 相关。随后，STS 细胞系对 PARP 抑制剂（PARPi）、尼拉帕利敏感。此外，基于五种常见 PARPi 的筛选试验和多柔比星、异环磷酰胺、达卡巴嗪和替莫唑胺（TMZ）之间的联合试验，尼拉帕利和 TMZ 在 STS 细胞系中最具协同作用。在 CDX 和 PDX 中也显示了尼拉帕利和 TMZ 联合的协同作用和安全性。
BRCAness 可能是大多数 STS 病例的常见基因组和分子特征。PARP-1 和 PAR 可能是评估患者 HRD 的合适且可行的治疗诊断生物标志物。STS 对 PARPi 敏感。此外，尼拉帕利和 TMZ 的联合具有协同作用。尼拉帕利和 TMZ 可能是 STS 患者有前途的靶向治疗策略。
