Wu Xiangyan, Ye Yuhan, Vega Kenneth J, Yao Jiannan
Key Laboratory of Gastrointestinal Cancer (Fujian Medical University), Ministry of Education, Fuzhou 350122, China.
Fujian Key Laboratory of Tumor Microbiology, Department of Medical Microbiology, Fujian Medical University, Fuzhou 350122, China.
Cancers (Basel). 2022 Jul 31;14(15):3740. doi: 10.3390/cancers14153740.
Background: Gastric adenocarcinoma (GAC) is highly heterogeneous and closely related to colorectal cancer (CRC) both molecularly and functionally. GAC is currently subtyped using a system developed by TCGA. However, with the emergence of immunotherapies, this system has failed to identify suitable treatment candidates. Methods: Consensus molecular subtypes (CMSs) developed for CRC were used for molecular subtyping in GAC based on public expression cohorts, including TCGA, ACRG, and a cohort of GAC patients treated with the programmed cell death 1 (PD-1) inhibitor pembrolizumab. All aspects of each subtype, including clinical outcome, molecular characteristics, oncogenic pathway activity, and the response to immunotherapy, were fully explored. Results: CMS classification was efficiently applied to GAC. CMS4, characterized by EMT activation, stromal invasion, angiogenesis, and the worst clinical outcomes (median OS 24.2 months), was the predominant subtype (38.8%44.3%) and an independent prognostic indicator that outperformed classical TCGA subtyping. CMS1 (20.9%21.5%) displayed hypermutation, low SCNV, immune activation, and best clinical outcomes (median OS > 120 months). CMS3 (17.95%25.7%) was characterized by overactive metabolism, KRAS mutation, and intermediate outcomes (median OS 85.6 months). CMS2 (14.6%16.3%) was enriched for WNT and MYC activation, differentiated epithelial characteristics, APC mutation, lack of ARID1A, and intermediate outcomes (median OS 48.7 months). Notably, CMS1 was strongly correlated with immunotherapy biomarkers and favorable for the anti-PD-1 drug pembrolizumab, whereas CMS4 was poorly responsive but became more sensitive after EMT-based stratification. Conclusions: Our study reveals the practical utility of CMS classification for GAC to improve clinical outcomes and identify candidates who will respond to immunotherapy.
胃腺癌（GAC）具有高度异质性，在分子和功能上均与结直肠癌（CRC）密切相关。目前，GAC是使用TCGA开发的系统进行亚型分类的。然而，随着免疫疗法的出现，该系统未能识别出合适的治疗候选者。方法：基于公开的表达队列，包括TCGA、ACRG以及一组接受程序性细胞死亡1（PD-1）抑制剂帕博利珠单抗治疗的GAC患者，将为CRC开发的共识分子亚型（CMS）用于GAC的分子亚型分类。对每个亚型的各个方面进行了全面探索，包括临床结局、分子特征、致癌途径活性以及对免疫疗法的反应。结果：CMS分类有效地应用于GAC。以EMT激活、基质侵袭、血管生成以及最差临床结局（中位总生存期24.2个月）为特征的CMS4是主要亚型（38.8%44.3%），并且是优于经典TCGA亚型分类的独立预后指标。CMS1（20.9%21.5%）表现出高突变、低体细胞拷贝数变异（SCNV）、免疫激活以及最佳临床结局（中位总生存期>120个月）。CMS3（17.95%25.7%）的特征是代谢过度活跃、KRAS突变以及中等结局（中位总生存期85.6个月）。CMS2（14.6%16.3%）富含WNT和MYC激活、分化的上皮特征、APC突变、缺乏ARID1A以及中等结局（中位总生存期48.7个月）。值得注意的是，CMS1与免疫疗法生物标志物密切相关，对抗PD-1药物帕博利珠单抗敏感，而CMS4反应较差，但在基于EMT的分层后变得更敏感。结论：我们的研究揭示了CMS分类对GAC的实际应用价值，可改善临床结局并识别对免疫疗法有反应的候选者。
