鉴定和验证甲状腺癌的新型衰老相关生物标志物，以预测预后和免疫治疗。

Identification and validation of a novel senescence-related biomarker for thyroid cancer to predict the prognosis and immunotherapy.

机构信息

Department of Thyroid and Breast Surgery, Ningbo First Hospital, Ningbo, Zhejiang, China.

Department of Thyroid and Breast Surgery, Ningbo Hospital of Zhejiang University, Ningbo, Zhejiang, China.

出版信息

Front Immunol. 2023 Jan 24;14:1128390. doi: 10.3389/fimmu.2023.1128390. eCollection 2023.

DOI:10.3389/fimmu.2023.1128390

PMID:36761753

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9902917/

Abstract

INTRODUCTION

Cellular senescence is a hallmark of tumors and has potential for cancer therapy. Cellular senescence of tumor cells plays a role in tumor progression, and patient prognosis is related to the tumor microenvironment (TME). This study aimed to explore the predictive value of senescence-related genes in thyroid cancer (THCA) and their relationship with the TME.

METHODS

Senescence-related genes were identified from the Molecular Signatures Database and used to conduct consensus clustering across TCGA-THCA. Differentially expressed genes (DEGs) were identified between the clusters used to perform multivariate Cox regression and least absolute shrinkage and selection operator regression (LASSO) analyses to construct a senescence-related signature. TCGA dataset was randomly divided into training and test datasets to verify the prognostic ability of the signature. Subsequently, the immune cell infiltration pattern, immunotherapy response, and drug sensitivity of the two subtypes were analyzed. Finally, the expression of signature genes was detected across TCGA-THCA and GSE33630 datasets, and further validated by RT-qPCR.

RESULTS

Three senescence clusters were identified based on the expression of 432 senescence-related genes. Then, 23 prognostic DEGs were identified in TCGA dataset. The signature, composed of six genes, showed a significant relationship with survival, immune cell infiltration, clinical characteristics, immune checkpoints, immunotherapy response, and drug sensitivity. Low-risk THCA shows a better prognosis and higher immunotherapy response than high-risk THCA. A nomogram with perfect stability constructed using signature and clinical characteristics can predict the survival of each patient. The validation part demonstrated that ADAMTSL4, DOCK6, FAM111B, and SEMA6B were expressed at higher levels in the tumor tissue, whereas lower expression of MRPS10 and PSMB7 was observed.

DISCUSSION

In conclusion, the senescence-related signature is a promising biomarker for predicting the outcome of THCA and has the potential to guide immunotherapy.

摘要

简介

细胞衰老是肿瘤的一个标志，具有癌症治疗的潜力。肿瘤细胞的衰老会影响肿瘤的进展，患者的预后与肿瘤微环境（TME）有关。本研究旨在探讨衰老相关基因在甲状腺癌（THCA）中的预测价值及其与 TME 的关系。

方法

从分子特征数据库中确定衰老相关基因，并对 TCGA-THCA 进行共识聚类。在聚类之间识别差异表达基因（DEGs），用于进行多变量 Cox 回归和最小绝对收缩和选择算子回归（LASSO）分析，以构建衰老相关特征。TCGA 数据集随机分为训练集和测试集，以验证特征的预后能力。然后，分析两种亚型的免疫细胞浸润模式、免疫治疗反应和药物敏感性。最后，在 TCGA-THCA 和 GSE33630 数据集上检测特征基因的表达，并通过 RT-qPCR 进一步验证。

结果

根据 432 个衰老相关基因的表达，确定了三个衰老簇。然后，在 TCGA 数据集中识别出 23 个预后 DEGs。该特征由 6 个基因组成，与生存、免疫细胞浸润、临床特征、免疫检查点、免疫治疗反应和药物敏感性有显著关系。低风险 THCA 的预后优于高风险 THCA，且对免疫治疗的反应更好。使用特征和临床特征构建的具有完美稳定性的诺莫图可预测每位患者的生存情况。验证部分表明，ADAMTSL4、DOCK6、FAM111B 和 SEMA6B 在肿瘤组织中表达水平较高，而 MRPS10 和 PSMB7 的表达水平较低。