Chen Lihua, Li Jiajia, Wu Xiaohua, Zheng Zhong
Department of Gynecologic Oncology, Fudan University Shanghai Cancer Center, Shanghai, China.
Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
Front Oncol. 2021 Jun 11;11:687899. doi: 10.3389/fonc.2021.687899. eCollection 2021.
The genomic abnormalities associated with uterine leiomyosarcoma (uLMS) have not been fully elucidated to date.
To understand the pathogenesis of uLMS and to identify driver mutations and potential therapeutic targets in uLMS.
Three matched tumor-constitutional DNA pairs from patients with recurrent uLMS were subjected to whole-exome capture and next-generation sequencing. The role of the selected gene in uLMS was analyzed by the CCK-8 assay and colony formation assay after specific siRNA knockdown.
We identified four genes with somatic SNVs, namely, SLC39A7, GPR19, ZNF717, and TP53, that could be driver mutations. We observed that 30.7% (4/13) of patients with uLMS had TP53 mutations as analyzed by direct sequencing. Analysis of somatic copy number variants (CNVs) showed regions of chromosomal gain at 1q21-23, 19p13, 17q21, and 17q25, whereas regions of chromosomal loss were observed at 2q35, 2q37, 1p36, 10q26, 6p22, 8q24, 11p15, 11q12, and 9p21. The gene was amplified in two patients and mutated in another (: NM_030974: exon2: c.G264C, p.E88D). Amplification of the gene was associated with shorter PFS and OS in soft tissue sarcoma, as shown by TCGA database analysis. Knockdown of expression was observed to decrease cell growth and colony formation in uterine sarcoma cell lines.
Exome sequencing revealed mutational heterogeneity of uLMS. The gene was amplified in uLMS and could be a candidate oncogene.
迄今为止，与子宫平滑肌肉瘤（uLMS）相关的基因组异常尚未完全阐明。
了解uLMS的发病机制，并确定uLMS中的驱动突变和潜在治疗靶点。
对3例复发性uLMS患者的肿瘤-外周血DNA配对样本进行全外显子组捕获和二代测序。在特异性siRNA敲低后，通过CCK-8检测和集落形成检测分析所选基因在uLMS中的作用。
我们鉴定出4个具有体细胞单核苷酸变异（SNV）的基因，即SLC39A7、GPR19、ZNF717和TP53，它们可能是驱动突变。通过直接测序分析，我们观察到30.7%（4/13）的uLMS患者存在TP53突变。体细胞拷贝数变异（CNV）分析显示，染色体在1q21-23、19p13、17q21和17q25区域有增益，而在2q35、2q37、1p36、10q26、6p22、8q24、11p15、11q12和9p21区域观察到染色体缺失。该基因在2例患者中扩增，在另一例患者中发生突变（：NM_030974：外显子2：c.G264C，p.E88D）。如TCGA数据库分析所示，该基因的扩增与软组织肉瘤较短的无进展生存期（PFS）和总生存期（OS）相关。在子宫肉瘤细胞系中观察到敲低该基因的表达可降低细胞生长和集落形成。
外显子组测序揭示了uLMS的突变异质性。该基因在uLMS中扩增，可能是一个候选癌基因。
