■胃癌是一种高度异质性的疾病,这是个性化治疗的主要障碍。精确的患者分类需要免疫检查点阻断应答的有效标志物。我们,因此,根据胶原基因表达情况对胃癌患者进行分组,以提示其预后和治疗反应。
■我们从四个队列中收集了1250名胃癌患者的数据。对于TCGA-STAD队列,我们根据44个胶原基因的表达水平使用共识聚类对患者进行分层,并比较不同胶原亚型的预后和临床特征.然后我们鉴定了亚型的不同转录组和遗传改变特征。我们分析了胶原亚型与化疗反应的关系,免疫疗法,和靶向治疗。我们还建立了独立于平台的胶原亚型预测因子。我们在三个验证队列(GSE84433,GSE62254和GSE15459)中验证了这些发现,并将胶原蛋白亚型分型方法与其他分子亚型分型方法进行了比较。
■我们确定了胃腺癌的两种亚型:高表达胶原亚型(CS-H)和低表达胶原亚型(CS-L)。胶原亚型是一个独立的预后因素,CS-L亚组总生存率较好。炎症反应,血管生成,和磷酸肌醇3-激酶(PI3K)/Akt途径在CS-H亚型中具有转录活性,而CS-L亚型的DNA修复活性明显更高。PIK3CA经常在CS-H亚型中扩增,而PIK3C2A,PIK3C2G,和PIK3R1在CS-L亚型中频繁缺失。CS-H亚型肿瘤对氟尿嘧啶更敏感,而CS-L亚型肿瘤对免疫检查点阻断更敏感。预测CS-L亚型对HER2靶向药物更敏感,预测CS-H亚型对血管内皮生长因子和PI3K通路靶向药物更敏感。胶原亚型分型还具有与现有的分子亚型分型方法结合以获得更好的患者分类的潜力。
我们根据胶原蛋白基因表达将胃癌分为两种亚型,并在三个验证队列中验证了这些亚型。胶原亚组在预后方面有所不同,临床特征,转录组,和遗传改变。这些亚型与患者对化疗的反应密切相关,免疫疗法,和靶向治疗。
UNASSIGNED: Gastric cancer is a highly heterogeneous disease, presenting a major obstacle to personalized treatment. Effective markers of the immune checkpoint blockade response are needed for precise patient classification. We, therefore, divided patients with gastric cancer according to
collagen gene expression to indicate their prognosis and treatment response.
UNASSIGNED: We collected data for 1250 patients with gastric cancer from four cohorts. For the TCGA-STAD cohort, we used consensus clustering to stratify patients based on expression levels of 44 collagen genes and compared the prognosis and clinical characteristics between
collagen subtypes. We then identified distinct transcriptomic and genetic alteration signatures for the subtypes. We analyzed the associations of
collagen subtypes with the responses to chemotherapy, immunotherapy, and targeted therapy. We also established a platform-independent
collagen-subtype predictor. We verified the findings in three validation cohorts (GSE84433, GSE62254, and GSE15459) and compared the collagen subtyping method with other molecular subtyping methods.
UNASSIGNED: We identified two subtypes of gastric adenocarcinoma: a high-expression collagen subtype (CS-H) and a low-expression
collagen subtype (CS-L). Collagen subtype was an independent prognostic factor, with better overall survival in the CS-L subgroup. The inflammatory response, angiogenesis, and phosphoinositide 3-kinase (PI3K)/Akt pathways were transcriptionally active in the CS-H subtype, while DNA repair activity was significantly greater in the CS-L subtype. PIK3CA was frequently amplified in the CS-H subtype, while PIK3C2A, PIK3C2G, and PIK3R1 were frequently deleted in the CS-L subtype. CS-H subtype tumors were more sensitive to fluorouracil, while CS-L subtype tumors were more sensitive to immune checkpoint blockade. CS-L subtype was predicted to be more sensitive to HER2-targeted drugs, and CS-H subtype was predicted to be more sensitive to vascular endothelial growth factor and PI3K pathway-targeting drugs. Collagen subtyping also has the potential to be combined with existing molecular subtyping methods for better patient classification.
UNASSIGNED: We classified gastric cancers into two subtypes based on collagen gene expression and validated these subtypes in three validation cohorts. The collagen subgroups differed in terms of prognosis, clinical characteristics, transcriptome, and genetic alterations. The subtypes were closely related to patient responses to chemotherapy, immunotherapy, and targeted therapy.