ABSTRACT: Gastric cancer (GC) is highly heterogeneous in the stromal and immune microenvironment, genome instability (GI), and oncogenic signatures. However, a classification of GC by combining these features remains lacking. Using the consensus clustering algorithm, we clustered GCs based on the activities of 15 pathways associated with immune, DNA repair, oncogenic, and stromal signatures in three GC datasets. We identified three GC subtypes: immunity-deprived (ImD), stroma-enriched (StE), and immunity-enriched (ImE). ImD showed low immune infiltration, high DNA damage repair activity, high tumor aneuploidy level, high intratumor heterogeneity (ITH), and frequent TP53 mutations. StE displayed high stromal signatures, low DNA damage repair activity, genomic stability, low ITH, and poor prognosis. ImE had strong immune infiltration, high DNA damage repair activity, high tumor mutation burden, prevalence of microsatellite instability, frequent ARID1A mutations, elevated PD-L1 expression, and favorable prognosis. Based on the expression levels of four genes (TAP2, SERPINB5, LTBP1, and LAMC1) in immune, DNA repair, oncogenic, and stromal pathways, we developed a prognostic model (IDOScore). The IDOScore was an adverse prognostic factor and correlated inversely with immunotherapy response in cancer. Our identification of new GC subtypes provides novel insights into tumor biology and has potential clinical implications for the management of GCs.
