Yin Xiaolei, Li Xiaopeng, Mi Lili, Hou Jiaojiao, Yin Fei
Department of Gastroenterology, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
Medical Record Room, The Fourth Hospital of Hebei Medical University, Shijiazhuang, Hebei, China.
Front Mol Biosci. 2025 Jul 22;12:1640881. doi: 10.3389/fmolb.2025.1640881. eCollection 2025.
Small cell carcinoma of the esophagus (SCCE) is an infrequent but highly aggressive cancer with a poor prognosis. Given its low incidence, there is a lack of validated biomarkers to guide risk stratification and inform treatment decisions.
We extracted Differentially expressed genes (DEGs) from the GSE111044 dataset using standard bioinformatics workflows. A network of interacting proteins was assembled to determine hub genes, and TOP2A and CDK1 were selected for immunohistochemical (IHC) validation in 76 SCCE tumor samples. IHC staining scores were analyzed for associations with clinicopathological features. Survival analysis was conducted using Kaplan-Meier estimations and Cox regression modeling to pinpoint independent prognostic factors. To further assess the clinical utility, TOP2A expression was combined with VALSG staging for risk stratification.
A comparison between SCCE and adjacent normal tissues revealed 1,202 DEGs. PPI network analysis highlighted two hub genes, TOP2A and CDK1, which IHC validated in 76 SCCE samples. High TOP2A expression was significantly associated with advanced TNM stage (p = 0.020) and deeper tumor invasion (p = 0.004). Multivariate Cox analysis identified high TOP2A expression (HR = 1.92, 95% CI: 1.30-2.82, p = 0.001) and VALSG stage (HR = 2.20, 95% CI: 1.07-4.50, p = 0.031) as independent predictors of prognosis. Time-dependent ROC analysis indicated that the AUCs for the VALSG stage alone were 0.626, 0.638, and 0.602 at 1-, 2-, and 3-year time intervals, respectively. TOP2A alone yielded slightly higher AUCs of 0.719, 0.632, and 0.676. Notably, the combination of TOP2A and VALSG provided the greatest predictive accuracy, achieving AUCs recorded at 0.721, 0.734, and 0.773 at the respective time points.
This study suggests that TOP2A is a novel, independent prognostic biomarker in SCCE. When integrated with the VALSG staging system, TOP2A expression enhances risk stratification and may serve as a useful adjunct in clinical prognostication. These findings support its clinical utility while emphasizing the necessity for future studies to include prospective validation.
食管小细胞癌（SCCE）是一种罕见但侵袭性很强的癌症，预后较差。鉴于其发病率低，缺乏经过验证的生物标志物来指导风险分层和制定治疗决策。
我们使用标准生物信息学工作流程从GSE111044数据集中提取差异表达基因（DEG）。组装相互作用蛋白网络以确定核心基因，并选择TOP2A和CDK1在76例SCCE肿瘤样本中进行免疫组织化学（IHC）验证。分析IHC染色评分与临床病理特征的相关性。使用Kaplan-Meier估计和Cox回归模型进行生存分析，以确定独立的预后因素。为进一步评估临床实用性，将TOP2A表达与VALSG分期相结合进行风险分层。
SCCE与相邻正常组织的比较揭示了1202个DEG。蛋白质-蛋白质相互作用（PPI）网络分析突出了两个核心基因TOP2A和CDK1，它们在76例SCCE样本中经IHC验证。TOP2A高表达与晚期TNM分期（p = 0.020）和更深的肿瘤浸润（p = 0.004）显著相关。多变量Cox分析确定TOP2A高表达（HR = 1.92，95%CI：1.30 - 2.82，p = 0.001）和VALSG分期（HR = 2.20，95%CI：1.07 - 4.50，p = 0.031）是预后的独立预测因素。时间依赖性ROC分析表明，单独VALSG分期在1年、2年和3年时间间隔时的曲线下面积（AUC）分别为0.626、0.638和0.602。单独TOP2A产生的AUC略高，分别为0.719、0.632和0.676。值得注意的是，TOP2A和VALSG的组合提供了最大的预测准确性，在各个时间点的AUC分别为0.721、0.734和0.773。
本研究表明TOP2A是SCCE中一种新的独立预后生物标志物。当与VALSG分期系统结合时，TOP2A表达增强了风险分层，可作为临床预后评估的有用辅助手段。这些发现支持了其临床实用性，同时强调未来研究进行前瞻性验证的必要性。
