Alnwisser Bushra, Alshehri Salman, Qattan Amal, Zou Minjing, Aboussekhra Abdelilah, Alzahrani Ali S, Shi Yufei
Department of Molecular Oncology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
King Abdulaziz and His Companions Foundation for Giftedness and Creativity, Riyadh, Saudi Arabia.
Front Oncol. 2025 May 19;15:1536270. doi: 10.3389/fonc.2025.1536270. eCollection 2025.
Distant metastasis (DM) is the most important prognostic factor affecting the overall survival (OS) of thyroid cancer. The current study aimed to discover prognostic biomarkers to predict thyroid cancer survival, particularly papillary thyroid carcinoma (PTC), the most common subtype of thyroid cancer.
Four RNA sequencing (RNA-Seq) datasets of experimental lung metastasis from four transgenic mouse models of PTC, follicular thyroid cancer (FTC), poorly differentiated thyroid cancer (PDTC), and anaplastic thyroid cancer (ATC) were integrated to screen for candidate genes involved in DM. The Cancer Genome Atlas-Thyroid Cancer (TCGA-THCA) dataset was used to validate the candidate genes.
A total of 105 upregulated and 25 downregulated differentially expressed genes (DEGs) were identified to be present in all four datasets. Regulation of cytokine production, inflammation, immune checkpoint regulation, and MAPK/ERK cascade were major enriched pathways in metastatic tumor cells. Seven genes were identified whose overexpression was present in 63 of 498 PTC patients (13%) and was associated with poor OS (p < 0.01). Clinically, the seven-gene expression signature was associated with older age at the diagnosis, late stage of tumor, tall cell variant, and higher aneuploidy and hypoxia score. Mutation load was increased in patients with seven-gene expression signature: 26 samples had more than one driver mutation (47%, 26/55). Deep deletions in other chromosomal loci were frequently found in patients with BRAFV600E mutations. In contrast, only 7% of patients without a seven-gene expression signature had more than one driver mutation (24/243). Increased chromosomal instability was also observed in patients with a seven gene expression signature.
The seven-gene expression signature is associated with poor prognosis and chromosomal instability. These genes may be useful biomarkers for risk stratification for DM and help decision-making in initial surgical recommendations.
远处转移（DM）是影响甲状腺癌总生存期（OS）的最重要预后因素。本研究旨在发现预测甲状腺癌生存的预后生物标志物，尤其是甲状腺癌最常见的亚型——乳头状甲状腺癌（PTC）。
整合了来自PTC、滤泡状甲状腺癌（FTC）、低分化甲状腺癌（PDTC）和未分化甲状腺癌（ATC）四种转基因小鼠模型的四个实验性肺转移RNA测序（RNA-Seq）数据集，以筛选参与DM的候选基因。使用癌症基因组图谱-甲状腺癌（TCGA-THCA）数据集验证候选基因。
在所有四个数据集中共鉴定出105个上调和25个下调的差异表达基因（DEG）。细胞因子产生的调节、炎症、免疫检查点调节和MAPK/ERK级联是转移肿瘤细胞中的主要富集途径。鉴定出七个基因，其过表达存在于498例PTC患者中的63例（13%）中，并且与较差的OS相关（p<0.01）。临床上，七基因表达特征与诊断时年龄较大、肿瘤晚期、高细胞变体以及更高的非整倍体和缺氧评分相关。具有七基因表达特征的患者突变负荷增加：26个样本有不止一个驱动突变（47%，26/55）。在BRAFV600E突变患者中经常发现其他染色体位点的深度缺失。相比之下，没有七基因表达特征的患者中只有7%有不止一个驱动突变（24/243）。在具有七基因表达特征的患者中也观察到染色体不稳定性增加。
七基因表达特征与不良预后和染色体不稳定性相关。这些基因可能是DM风险分层的有用生物标志物，并有助于在初始手术建议中做出决策。
