Voutsadakis Ioannis A
Algoma District Cancer Program, Sault Area Hospital, Sault Ste Marie, Ontario, Canada.
Division of Clinical Sciences, Section of Internal Medicine, Northern Ontario School of Medicine, Sudbury, ON, Canada.
Tissue Barriers. 2025 Jan 2;13(1):2348852. doi: 10.1080/21688370.2024.2348852. Epub 2024 May 7.
Gastric adenocarcinoma represents an aggressive type of cancer and an important cause of cancer mortality. Progress in gastric cancer therapeutics has resulted from a better understanding of the molecular pathogenesis of the disease and introduction of targeted therapies, but most gastric cancer patients still rely on non-targeted chemotherapy as the mainstay of treatment for advanced disease.
An analysis of publicly available series from The Cancer Genome Atlas (TCGA) gastric cancer cohort was undertaken to delineate the clinical and genomic landscape of gastric cancers with suppressed expression of claudin 18 compared with cancers with non-suppressed claudin 18. Claudin 18 suppressed cancers were defined as having an mRNA expression z-score relative to normal samples (log RNA Seq V2) of less than -1. Claudin 18 non-suppressed cancers were defined as having an mRNA expression z-score relative to normal samples (log RNA Seq V2) above 0.5.
Gastric cancers with claudin 18 mRNA suppression represented 7.7% of the gastric adenocarcinomas of TCGA cohort, while non-suppressed cancers represented 46.6% of the cases. The two groups did not differ in clinical and genomic characteristics, such as mean age, histology, grade, and stage. The mutation landscape of claudin 18 suppressed cases included high mutation rates of TP53, of genes of the WNT/β-catenin pathway and of ubiquitin ligase . Moreover, a subset of both claudin 18 suppressed and non-suppressed cancers displayed mutations in Mismatch Repair (MMR) associated genes or a high tumor mutation burden (TMB). At the mRNA expression level, claudin 18 suppressed gastric cancers showed up-regulation of EMT core transcription factor Snail 2 and down-regulation of genes of HLA cluster. The survival of gastric cancer patients with claudin 18 mRNA suppression was not significantly different compared with patients with non-suppressed claudin 18.
Sub-sets of gastric cancers with claudin 18 mRNA suppression displayed characteristics of potential therapeutic interest, such as mutations in WNT and PI3K pathways and MMR defects. These may guide the development of alternative targeted therapies, in this sub-set of gastric cancers which are not candidates for claudin 18 targeting therapies.
胃腺癌是一种侵袭性癌症，也是癌症死亡的重要原因。胃癌治疗的进展源于对该疾病分子发病机制的更好理解以及靶向治疗的引入，但大多数胃癌患者仍依赖非靶向化疗作为晚期疾病的主要治疗手段。
对来自癌症基因组图谱（TCGA）胃癌队列的公开系列进行分析，以描绘与claudin 18表达未受抑制的癌症相比，claudin 18表达受抑制的胃癌的临床和基因组特征。claudin 18表达受抑制的癌症定义为相对于正常样本（log RNA Seq V2）的mRNA表达z值小于-1。claudin 18表达未受抑制的癌症定义为相对于正常样本（log RNA Seq V2）的mRNA表达z值高于0.5。
claudin 18 mRNA受抑制的胃癌占TCGA队列胃腺癌的7.7%，而未受抑制的癌症占病例的46.6%。两组在临床和基因组特征上没有差异，如平均年龄、组织学、分级和分期。claudin 18表达受抑制病例的突变图谱包括TP53、WNT/β-连环蛋白途径基因和泛素连接酶的高突变率。此外，claudin 18表达受抑制和未受抑制的癌症亚组均显示错配修复（MMR）相关基因的突变或高肿瘤突变负担（TMB）。在mRNA表达水平上，claudin 18表达受抑制的胃癌显示EMT核心转录因子Snail 2上调，HLA簇基因下调。claudin 18 mRNA受抑制的胃癌患者的生存率与claudin 18未受抑制的患者相比没有显著差异。
claudin 18 mRNA受抑制的胃癌亚组表现出潜在治疗意义的特征，如WNT和PI3K途径的突变以及MMR缺陷。这些可能指导在这一不适合claudin 18靶向治疗的胃癌亚组中开发替代靶向治疗方法。
