Dong Xubin, Jin Cong, Chen Danxiang, Chen Yizuo, Ye Zhi-Qiang, Zhang Xiaohua, Huang Xiaoli, Zhang Wei, Gu Dian-Na
Department of Breast Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Department of Thyroid Surgery, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China.
Front Oncol. 2021 Sep 16;11:737867. doi: 10.3389/fonc.2021.737867. eCollection 2021.
Genomic instability (GI) is among the top ten characteristics of malignancy. Long non-coding RNAs (lncRNAs) are promising cancer biomarkers that are reportedly involved in GI. So far, the clinical value of GI-related lncRNAs (GIlncs) in papillary thyroid cancer (PTC) has not been clarified.
Integrative analysis of lncRNA expression and somatic mutation profiles was performed to identify GIlncs. Analysis of differentially expressed lncRNAs in the group with high- and low- cumulative number of somatic mutations revealed significant GIlncs in PTC. Univariate and multivariate Cox proportional hazard regression analyses were performed to identify hub-GIlncs.
A computational model based on four lncRNAs (, , , and ) was identified as a quantitative index using an discovery cohort. GILS score was significantly associated with poor prognosis, as validated in the TCGA dataset and further tested in our local RNA-Seq cohort. Moreover, a combination of clinical characteristics and the composite GILS-clinical prognostic nomogram demonstrates satisfactory discrimination and calibration. Furthermore, the GILS score and , , , and were also associated with driver mutations and multiple clinical-pathological variables, respectively. Moreover, RNA-Seq confirmed the expression patterns of , , , and in PTC and normal thyroid tissues. Biological experiments demonstrated that downregulated or overexpressed affect PTC cell proliferation, migration, and invasion . Activation of the stromal and immune cell infiltration was also observed in the high group in the PTC microenvironment.
In summary, we identified a signature for clinical outcome prediction in PTC comprising four lncRNAs associated with GI. A better understanding of the GI providing an alternative evaluation of the progression risk of PTC. Our study also demonstrated as a novel oncogenic lncRNA and verified its phenotype in PTC.
基因组不稳定（GI）是恶性肿瘤的十大特征之一。长链非编码RNA（lncRNAs）是很有前景的癌症生物标志物，据报道其参与了基因组不稳定过程。到目前为止，与GI相关的lncRNAs（GIlncs）在甲状腺乳头状癌（PTC）中的临床价值尚未明确。
对lncRNA表达和体细胞突变谱进行综合分析以鉴定GIlncs。分析体细胞突变累积数量高和低的组中差异表达的lncRNAs，揭示PTC中显著的GIlncs。进行单变量和多变量Cox比例风险回归分析以鉴定核心GIlncs。
使用一个发现队列，基于四种lncRNAs（ 、 、 和 ）的计算模型被确定为一个定量指标。GILS评分与预后不良显著相关，在TCGA数据集中得到验证，并在我们本地的RNA测序队列中进一步测试。此外，临床特征与综合GILS - 临床预后列线图的组合显示出令人满意的区分度和校准度。此外，GILS评分与 、 、 和 还分别与驱动突变和多个临床病理变量相关。此外，RNA测序证实了 、 、 和 在PTC和正常甲状腺组织中的表达模式。生物学实验表明，下调或过表达 会影响PTC细胞的增殖、迁移和侵袭 。在PTC微环境的高 组中也观察到基质和免疫细胞浸润的激活。
总之，我们鉴定了一个用于预测PTC临床结局的特征，其包含与GI相关的四种lncRNAs。对基因组不稳定的更好理解为PTC进展风险提供了另一种评估方法。我们的研究还证明 是一种新型致癌lncRNA，并在PTC中验证了其表型。
