GEMINI (Gastric Encyclopedia of Molecular Interactions and Nodes for Intervention) Phases A-C, normal skin fibroblasts. Homo sapiens

Genome-wide mRNA expression profiles of normal skin fibroblasts, used as one of the (normal) references in the study. Gastric cancer (GC) is the second leading cause of global cancer mortality, with individual gastric tumors displaying significant heterogeneity in their deregulation of various oncogenic pathways. We aim to identify major oncogenic pathways in GC that robustly impact patient survival and treatment response. We used an in silico strategy based on gene expression signatures and connectivity analytics to map patterns of oncogenic pathway activation in 301 primary gastric cancers from three independent patient cohorts. Of 11 oncogenic pathways previously implicated in GC, we identified three predominant pathways (proliferation/stem cell, NF-kB, and Wnt/b-catenin) deregulated in the majority (>70%) of gastric tumors. Using a variety of proliferative, Wnt, and NF-kB-related assays, we experimentally validated the pathway predictions in multiple GC cell lines showing similar pathway activation patterns in vitro. Patients stratified at the level of individual pathways did not exhibit consistent differences in clinical outcome. However, patients grouped by oncogenic pathway combinations demonstrated robust and significant survival differences (e.g., high proliferation/high NF-kB vs. low proliferation/low NF-kB), suggesting that tumor behavior in GC is likely influenced by the combined effects of multiple oncogenic pathways. Our results demonstrate that GCs can be successfully taxonomized by oncogenic pathway activity into biologically and clinically relevant subgroups. Keywords: normal skin fibroblasts, cell culture Overall design: Profiling A Normal Skin Fibroblast Cell Line on Affymetrix GeneChip Human Genome U133 Plus 2.0 Array

本研究中作为正常对照样本之一的正常皮肤成纤维细胞的全基因组mRNA表达谱。胃癌（GC）是全球第二大癌症致死病因，不同个体的胃癌肿瘤在多种致癌通路的失调模式上存在显著异质性。本研究旨在鉴定胃癌中显著影响患者生存与治疗应答的核心致癌通路。我们采用基于基因表达特征与连接性分析的计算机模拟（in silico）策略，对来自3个独立患者队列的301例原发性胃癌样本的致癌通路激活模式进行了映射分析。在先前已被报道与胃癌相关的11种致癌通路中，我们鉴定出3种主要通路（增殖/干细胞通路、核因子κB（NF-kB）及Wnt/β-连环蛋白（Wnt/β-catenin）通路）在超过70%的胃癌肿瘤中存在失调。通过一系列增殖相关、Wnt通路相关及NF-kB相关实验检测，我们在多种胃癌细胞系中对该通路预测结果进行了实验验证，体外实验显示这些细胞系具有相似的通路激活模式。按单个通路分层的患者并未表现出临床结局的一致性差异。然而，基于致癌通路组合进行分组的患者则展现出显著且稳定的生存差异（例如，高增殖/高NF-kB组与低增殖/低NF-kB组相比），这提示胃癌的肿瘤行为可能受多种致癌通路的协同效应影响。本研究结果表明，胃癌可通过致癌通路活性成功划分为具有生物学与临床相关性的亚组。关键词：正常皮肤成纤维细胞、细胞培养 实验设计概要：在Affymetrix GeneChip人类基因组U133 Plus 2.0芯片上对一株正常皮肤成纤维细胞系进行表达谱分析。