Primary Gastric Cancer Expression Profiles (UK Patient Cohort)

Genome-wide mRNA expression profiles of 31 primary gastric tumors from the UK patient cohort. 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 25 unique GC cell lines, and 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: gastric cancer, cell culture Profiling of 31 primary gastric tumors on Affymetrix GeneChip Human Genome U133 Array Set HG-U133A. All tumors were collected with approvals from the St James's University Hospital, United Kingdom and the Research Ethics Review Committee.

本数据集包含来自英国患者队列的31例原发性胃肿瘤的全基因组mRNA表达谱。胃癌（Gastric Cancer, GC）是全球范围内第二大癌症相关死亡病因，不同原发性胃肿瘤在多种致癌通路的失调模式上呈现显著异质性。本研究旨在明确胃癌中对患者生存与治疗反应具有稳健影响的核心致癌通路。我们采用基于基因表达特征与连通性分析的硅基（in silico）分析策略，对25株独立胃癌细胞系以及来自3个独立患者队列的301例原发性胃癌的致癌通路激活模式进行了系统绘制。在先前已被报道与胃癌相关的11条致癌通路中，我们鉴定出3条主要失调通路：增殖/干细胞通路、核因子κB（NF-κB）通路以及Wnt/β-连环蛋白（Wnt/b-catenin）通路，上述通路在超过70%的胃肿瘤中均存在失调现象。我们通过多种增殖相关、Wnt通路相关及NF-κB相关实验检测，在多株胃癌细胞系中对通路预测结果进行了实验验证，体外实验结果显示这些细胞系的通路激活模式与预测结果高度一致。仅通过单条致癌通路对患者进行分层，并未观察到其临床结局存在一致性的显著差异。然而，按照致癌通路组合对患者进行分组后，则呈现出显著且稳定的生存差异（例如高增殖/高NF-κB组与低增殖/低NF-κB组），这提示胃癌的肿瘤生物学行为可能受多条致癌通路的协同调控。本研究结果证实，可通过致癌通路激活特征对胃癌进行分类，从而获得具有生物学与临床相关性的胃癌亚组。关键词：胃癌；细胞培养；本研究采用Affymetrix GeneChip人类基因组U133芯片组HG-U133A对31例原发性胃肿瘤开展了表达谱分析。所有肿瘤样本均经英国圣詹姆斯大学医院及研究伦理审查委员会批准后采集。