食管腺癌（EAC）和胃腺癌（GAC）的预后仍然不佳，迫切需要新的治疗方法。Claudin 6（CLDN6）是一种只存在于健康组织中很少的胚胎抗原，在几种癌症中上调表达，因此具有很好的治疗潜力。本研究评估了一个大型高加索人群的EAC和GAC队列中CLDN6的表达情况。从癌症基因组图谱计划获取了89个EAC和371个GAC的RNA-Seq数据，并根据与生存相关的表达水平确定EAC/GAC病例的CLDN6 mRNA表达的分类标准。针对CLDN6表达水平高于或低于这个分类标准的组别，利用DESeq进行了差异基因表达分析，并利用Enrichr工具确定了失调的生物通路。此外，利用一种CLDN6特异性免疫组化抗体（克隆58-4B-2）对800多个EAC和近600个GAC的CLDN6蛋白表达进行了评估，该抗体目前在I/II期试验中用于确定CLDN6阳性肿瘤患者（NCT05262530；NCT04503278）。还将CLDN6的表达与组织病理参数和总生存期（OS）进行了相关性分析。CLDN6 mRNA水平较高的EAC和GAC显示出与细胞周期、DNA复制和受体/细胞外基质相互作用相关的通路过度表达。在未经治疗的亚组和接受新辅助治疗的队列中，CLDN6蛋白表达与EAC和GAC的较短OS相关。多元分析表明，在EAC中，CLDN6蛋白表达是独立的不良预后因子，与较短的OS相关（HR：1.75，p = 0.01），在GAC中也是如此（HR：2.74，p = 0.028）。CLDN6 mRNA的高表达与调控细胞生长、增殖和细胞-基质相互作用的不同生物通路的失调相关。从临床上看，CLDN6蛋白的表达是EAC和GAC有价值的不良预后标志物。 © 2023. BioMed Central Ltd., 华盛顿大学的一部分

The prognosis of esophageal adenocarcinoma (EAC) and gastric adenocarcinoma (GAC) remains poor, and new therapeutic approaches are urgently needed. Claudin 6 (CLDN6) is an oncofetal antigen that is largely absent in healthy tissues and upregulated in several cancers, making it a promising therapeutical target. In this study, the expression of CLDN6 was assessed in an large Caucasian EAC and GAC cohort.RNA-Seq data from 89 EACs and 371 GACs were obtained from The Cancer Genome Atlas project and EAC/GAC cases were stratified by CLDN6 mRNA expression based on a survival-associated cutoff. For groups with CLDN6 expression above or below this cutoff, differential gene expression analyses were performed using DESeq, and dysregulated biological pathways were identified using the Enrichr tool. Additionally, CLDN6 protein expression was assessed in more than 800 EACs and almost 600 GACs using a CLDN6-specific immunohistochemical antibody (clone 58-4B-2) that is currently used in Phase I/II trials to identify patients with CLDN6-positive tumors (NCT05262530; NCT04503278). The expression of CLDN6 was also correlated with histopathological parameters and overall survival (OS).EACs and GACs with high CLDN6 mRNA levels displayed an overexpression of pathways regulating the cell cycle, DNA replication, and receptor / extracellular matrix interactions. CLDN6 protein expression was associated with shorter OS in EAC and GAC, both in treatment-naïve subgroups and cohorts receiving neoadjuvant therapy. In multivariate analysis, CLDN6 protein expression was an independent adverse prognostic factor in EAC associated with a shorter OS (HR: 1.75; p = 0.01) and GAC (HR: 2.74; p = 0.028).High expression of CLDN6 mRNA is associated with the dysregulation of distinct biological pathways regulating cell growth, proliferation, and cell-matrix interactions. Clinically, the expression of CLDN6 protein is a valuable adverse prognostic marker in EAC and GAC.© 2023. BioMed Central Ltd., part of Springer Nature.