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.
Highlights
Gastric cancer (GC) is the second leading cause of cancer deaths in the world[1] and prevails in East Asia[2]
Stromal, DNA damage repair, or oncogenic pathways, we expected, the activity of epithelial–mesenchymal transition (EMT) was significantly higher in StE than clustered GCs in three datasets
We classified GCs based on the enrichment levels of 15 pathways associated with immune, DNA damage repair, oncogenic, and stromal signatures
Summary
Gastric cancer (GC) is the second leading cause of cancer deaths in the world[1] and prevails in East Asia[2]. Abundant evidence indicates that GC is highly heterogeneous[3]. Based on the pathohistological classification, GC includes following three subtypes: intestinal, diffuse, and indeterminate[4]. GC includes four subtypes defined by The Cancer Genome Atlas (TCGA): Epstein–Barr virus (EBV) associated, microsatellite instable (MSI), genomically stable (GS), and chromosomal instability (CIN)[5]. The four molecular subtypes defined by the Asian Cancer Research Group (ACRG), include microsatellite stable (MSS)/epithelial–mesenchymal transition (EMT), MSI, MSS/p53+, and MSS/p53−6. The high heterogeneity in GC brings great challenges to the successful treatment of this disease[3]. Traditional treatment strategies, including surgery, chemotherapy, and radiotherapy, often have limited efficacy for the refractory or metastatic GCs7. Targeted therapies for GC, such as targeting HER2, EGFR, FGFR, KIT, c-Met, VEGFR, and CLDN18.2, are currently under investigation, most targeted therapies demonstrated moderate effect or drug resistance[8]
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