Abstract：
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
UNASSIGNED: 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.
摘要：
■胃腺癌代表侵袭性癌症类型和癌症死亡的重要原因。胃癌治疗的进展是由于对疾病的分子发病机制有了更好的理解和靶向治疗的引入。但大多数胃癌患者仍依赖非靶向化疗作为晚期疾病治疗的主要手段。
■对来自癌症基因组图谱（TCGA）胃癌队列的公开系列进行了分析，以描绘与claudin18表达抑制的胃癌相比，claudin18表达抑制的胃癌的临床和基因组景观。紧密连接蛋白18抑制的癌症被定义为具有相对于正常样品(logRNASeqV2)小于-1的mRNA表达z得分。紧密连接蛋白18非抑制性癌症被定义为相对于正常样品(logRNASeqV2)具有高于0.5的mRNA表达z得分。
■claudin18mRNA抑制的胃癌占TCGA组的胃腺癌的7.7%，而非抑制癌症占病例的46.6%。两组在临床和基因组特征上没有分歧，比如平均年龄，组织学,grade,和舞台。claudin18抑制病例的突变景观包括TP53，WNT/β-catenin途径基因和泛素连接酶FBXW7的高突变率。此外，claudin18抑制和非抑制癌症的一个子集显示错配修复(MMR)相关基因突变或高肿瘤突变负担(TMB).在mRNA表达水平，claudin18抑制胃癌显示EMT核心转录因子Snail2上调和HLA簇基因下调。与claudin18mRNA抑制的胃癌患者相比，claudin18mRNA抑制的胃癌患者的生存率没有显着差异。
■具有claudin18mRNA抑制的胃癌亚组显示出潜在治疗兴趣的特征，如WNT和PI3K通路中的突变和MMR缺陷。这些可以指导替代靶向治疗的发展，在这一胃癌亚组中，这些胃癌不是claudin18靶向治疗的候选人。
■对来自癌症基因组图谱（TCGA）胃癌队列的公开系列进行了分析，以描绘与claudin18表达抑制的胃癌相比，claudin18表达抑制的胃癌的临床和基因组景观。紧密连接蛋白18抑制的癌症被定义为具有相对于正常样品(logRNASeqV2)小于-1的mRNA表达z得分。紧密连接蛋白18非抑制性癌症被定义为相对于正常样品(logRNASeqV2)具有高于0.5的mRNA表达z得分。
■claudin18mRNA抑制的胃癌占TCGA组的胃腺癌的7.7%，而非抑制癌症占病例的46.6%。两组在临床和基因组特征上没有分歧，比如平均年龄，组织学,grade,和舞台。claudin18抑制病例的突变景观包括TP53，WNT/β-catenin途径基因和泛素连接酶FBXW7的高突变率。此外，claudin18抑制和非抑制癌症的一个子集显示错配修复(MMR)相关基因突变或高肿瘤突变负担(TMB).在mRNA表达水平，claudin18抑制胃癌显示EMT核心转录因子Snail2上调和HLA簇基因下调。与claudin18mRNA抑制的胃癌患者相比，claudin18mRNA抑制的胃癌患者的生存率没有显着差异。
■具有claudin18mRNA抑制的胃癌亚组显示出潜在治疗兴趣的特征，如WNT和PI3K通路中的突变和MMR缺陷。这些可以指导替代靶向治疗的发展，在这一胃癌亚组中，这些胃癌不是claudin18靶向治疗的候选人。
