Department of Pathology, Institute of Clinical Pathology, Shantou University Medical College, Shantou, China.
Department of Pathology, Institute of Clinical Pathology, Shantou University Medical College, Shantou, China; Department of Cardiology, The Second Affiliated Hospital of Shantou University Medical College, Shantou, China.
Lab Invest. 2024 Oct;104(10):102127. doi: 10.1016/j.labinv.2024.102127. Epub 2024 Aug 23.
The high mortality rate of esophageal squamous cell carcinoma (ESCC) is exacerbated by the absence of early diagnostic markers. The pronounced heterogeneity of mutations in ESCC renders copy number alterations (CNAs) more prevalent among patients. The identification of CNA genes within esophageal squamous dysplasia (ESD), a precancerous stage of ESCC, is crucial for advancing early detection efforts. Utilization of liquid biopsies via droplet-based digital PCR (ddPCR) offers a novel strategy for detecting incipient tumor traces. This study undertook a thorough investigation of CNA profiles across ESCC development stages, integrating data from existing databases and prior investigations to pinpoint and confirm CNA markers conducive to early detection of ESCC. Targeted sequencing was employed to select potential early detection genes, followed by the establishment of prediction models for ESCC early detection using ddPCR. Our analysis revealed widespread CNAs during the ESD stage, mirroring the CNA landscape observed in ESCC. A total of 40 CNA genes were identified as highly frequent in both ESCC and ESD lesions, through a comprehensive gene-level CNA analysis encompassing ESD and ESCC tissues, ESCC cell lines, and pan-cancer data sets. Subsequent validation of 5 candidate markers via ddPCR underscored the efficacy of combined predictive models encompassing PIK3CA, SOX2, EGFR, MYC, and CCND1 in early ESCC screening, as evidenced by the area-under-the-curve values exceeding 0.92 (P < .0001) across various detection contexts. The findings highlighted the significant utility of CNA genes in the early screening of ESCC, presenting robust models that could facilitate early detection, broad-scale population screening, and adjunctive diagnosis.
食管鳞状细胞癌（ESCC）的高死亡率因缺乏早期诊断标志物而加剧。ESCC 突变的明显异质性使得拷贝数改变（CNAs）在患者中更为普遍。在 ESCC 的癌前阶段食管鳞状上皮内瘤变（ESD）中鉴定 CNA 基因对于推进早期检测工作至关重要。利用基于液滴的数字 PCR（ddPCR）进行液体活检为检测早期肿瘤痕迹提供了一种新策略。本研究全面调查了 ESCC 发展阶段的 CNA 图谱，整合了现有数据库和先前研究的数据，以确定和确认有利于 ESCC 早期检测的 CNA 标志物。通过靶向测序选择潜在的早期检测基因，然后使用 ddPCR 建立 ESCC 早期检测的预测模型。我们的分析显示，在 ESD 阶段存在广泛的 CNA，与 ESCC 中观察到的 CNA 景观相吻合。通过对 ESD 和 ESCC 组织、ESCC 细胞系和泛癌数据集进行全面的基因水平 CNA 分析，共鉴定出 40 个在 ESCC 和 ESD 病变中高频出现的 CNA 基因。随后通过 ddPCR 对 5 个候选标志物进行验证，强调了包含 PIK3CA、SOX2、EGFR、MYC 和 CCND1 的联合预测模型在早期 ESCC 筛查中的有效性，在各种检测环境下，曲线下面积值均超过 0.92（P <.0001）。研究结果突出了 CNA 基因在 ESCC 早期筛查中的重要作用，提出了稳健的模型，可以促进早期检测、大规模人群筛查和辅助诊断。
