Higher intra-tumoral expression of pro-coagulation genes is a predictor of angiogenesis, epithelial mesenchymal transition and worse patient survival in gastric cancer.

Coagulation regulates angiogenesis in cancer, and is associated with tumor development and metastasis. To date, there have been no studies quantifying the state of intra-tumoral coagulation. We measured intra-tumoral coagulation gene expression using the "Hallmark-COAGULATION" gene set in the MSigDB, performing gene set variation analysis and then assigning a "coagulation score" to quantify gene expression. Clinical, histologic, and genetic data were analyzed in 807 gastric cancer patients from the TCGA_STAD and GSE84437 databases. Tumors with increased expression of pro-coagulation genes were consistently associated with higher AJCC T-categories (p = 0.018), lymph node metastasis (p = 0.036), and stage (p = 0.006) in both cohorts. Patients with high coagulation scores were found to have worse disease-specific survival and overall survival (OS) (p = 0.019 and 0.011, respectively) in TCGA, and worse OS in GSE84437 cohort (p = 0.012). Higher expression of pro-coagulation genes correlated with increased intra-tumoral angiogenesis, as well as increased proportions of lymphatic and microvascular endothelial cells, endothelial cells, and pericytes, calculated by xCell algorithm. High coagulation scores were significantly associated with low tumor mutation burden, but not with intratumor heterogeneity and homologous recombination deficiency. Gastric cancers with high coagulation scores contained higher amounts of M1 macrophages and dendritic cells, and low numbers of Th1 cells (all P<0.001). Genes for epithelial mesenchymal transition (EMT), myogenesis, apical junction, transforming growth factor (TGF)-β signaling, and angiogenesis were enriched in high coagulation score-gastric cancers (all false discovery rate <0.25). In conclusion, gastric cancers expressing higher levels of pro-coagulation genes demonstrate increased angiogenesis, EMT, TGF-β signaling and worse patient prognosis. AJCR