An Individualized Stemness-related Signature to Predict Prognosis and Immunotherapy Responses for Gastric Cancer Using Single-cell and Bulk Tissue Transcriptomes

Background: Currently, many stemness-related signatures have been developed for gastric cancer (GC) to predict prognosis and immunotherapy outcomes. However, due to batch effects, these signatures cannot accurately analyze patients one by one, rendering them impractical in real clinical scenarios. Therefore, we aimed to develop an individualized and clinically applicable signature based on GC stemness.

Methods: Malignant epithelial cells from single-cell RNA-Seq data of GC were used to identify stemness-related signature genes based on the CytoTRACE score. Using two bulk tissue datasets as training data, the enrichment scores of the signature genes were applied to classify samples into two subtypes. Then, using the identified subtypes as criteria, we developed an individualized stemness-related signature based on the within-sample relative expression orderings of genes.

Results: We identified 175 stemness-related signature genes, which exhibited significantly higher AUCell scores in poorly differentiated GCs compared to differentiated GCs. In training datasets, GC samples were classified into two subtypes with significantly different survival times and genomic characteristics. Utilizing the two subtypes, an individualized signature was constructed containing 47 gene pairs. In four independent testing datasets, GC samples classified as high risk exhibited significantly shorter survival times, higher infiltration of M2 macrophages, and lower immune responses compared to low-risk samples. Moreover, the potential therapeutic targets and corresponding drugs were identified for the high-risk group, such as CD248 targeted by ontuxizumab.

Conclusions: We developed an individualized stemness-related signature, which can accurately predict the prognosis and efficacy of immunotherapy for each GC sample.