Molecular alterations in claudin 18 suppressed and non-suppressed gastric adenocarcinomas to guide targeted therapies.

IF 3.6 Q2 MEDICINE, RESEARCH & EXPERIMENTAL

Tissue Barriers Pub Date : 2024-05-07 DOI:10.1080/21688370.2024.2348852

Ioannis A Voutsadakis

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引用次数: 0

Abstract

Background: 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.

Methods: 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.

Results: 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 FBXW7. 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.

Conclusion: 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.

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克劳丁 18 抑制型和非抑制型胃腺癌的分子改变，为靶向疗法提供指导。

背景：胃腺癌是一种侵袭性癌症，也是导致癌症死亡的重要原因。对胃癌分子发病机制的深入了解和靶向疗法的引入推动了胃癌治疗的进步，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：方法：我们对癌症基因组图谱（TCGA）胃癌队列中公开发表的系列数据进行了分析，以确定克劳丁18表达受抑制的胃癌与克劳丁18表达未受抑制的胃癌相比在临床和基因组方面的情况。相对于正常样本（对数 RNA Seq V2）的 mRNA 表达 z 值小于-1，即为 Claudin 18 受抑制的癌症。相对于正常样本（log RNA Seq V2），mRNA表达量z-score高于0.5的癌症定义为Claudin 18非抑制型癌症：在TCGA队列的胃腺癌中，克劳丁18 mRNA表达受抑制的胃癌占7.7%，而未受抑制的胃癌占46.6%。两组患者在平均年龄、组织学、分级和分期等临床和基因组特征方面没有差异。克劳丁18抑制病例的突变情况包括TP53、WNT/β-catenin通路基因和泛素连接酶FBXW7的高突变率。此外，在克劳丁18抑制型和非抑制型癌症中，都有一部分出现了错配修复（MMR）相关基因的突变或高肿瘤突变负荷（TMB）。在 mRNA 表达水平上，受 claudin 18 抑制的胃癌表现出 EMT 核心转录因子蜗牛 2 的上调和 HLA 簇基因的下调。与未受Claudin 18抑制的胃癌患者相比，受Claudin 18 mRNA抑制的胃癌患者的生存率无明显差异：结论：Claudin 18 mRNA受抑制的胃癌亚组显示出具有潜在治疗意义的特征，如WNT和PI3K通路突变以及MMR缺陷。这些特征可能会指导开发替代性靶向疗法，用于治疗不适合采用 claudin 18 靶向疗法的胃癌亚组。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Tissue Barriers MEDICINE, RESEARCH & EXPERIMENTAL-

CiteScore

6.60

自引率

6.50%

发文量

期刊介绍： Tissue Barriers is the first international interdisciplinary journal that focuses on the architecture, biological roles and regulation of tissue barriers and intercellular junctions. We publish high quality peer-reviewed articles that cover a wide range of topics including structure and functions of the diverse and complex tissue barriers that occur across tissue and cell types, including the molecular composition and dynamics of polarized cell junctions and cell-cell interactions during normal homeostasis, injury and disease state. Tissue barrier formation in regenerative medicine and restoration of tissue and organ function is also of interest. Tissue Barriers publishes several categories of articles including: Original Research Papers, Short Communications, Technical Papers, Reviews, Perspectives and Commentaries, Hypothesis and Meeting Reports. Reviews and Perspectives/Commentaries will typically be invited. We also anticipate to publish special issues that are devoted to rapidly developing or controversial areas of research. Suggestions for topics are welcome. Tissue Barriers objectives: Promote interdisciplinary awareness and collaboration between researchers working with epithelial, epidermal and endothelial barriers and to build a broad and cohesive worldwide community of scientists interesting in this exciting field. Comprehend the enormous complexity of tissue barriers and map cross-talks and interactions between their different cellular and non-cellular components. Highlight the roles of tissue barrier dysfunctions in human diseases. Promote understanding and strategies for restoration of tissue barrier formation and function in regenerative medicine. Accelerate a search for pharmacological enhancers of tissue barriers as potential therapeutic agents. Understand and optimize drug delivery across epithelial and endothelial barriers.