Identification and validation of platinum resistance signature in gastric cancer.

[BACKGROUND] Platinum was the first drug with proven activity against gastric cancer (GC), the combination with fluoropyrimidine is the standard first-line systemic therapy for patients of GC. However, a major cause of treatment failure still is the existence of drug resistance. The purpose of this study is to identify and validate the platinum-related genes in GC and to construct a multi-gene joint signature for predicting the prognosis of GC patients.

[METHODS] Based on 326 platinum-related genes from GeneCards, GO and KEGG analysis were applied for differentially expressed genes in GC, UniCox regression analysis was used to select effective genes and Lasso-Cox regression was utilized to construct a prognosis model. Stratified analysis, CNV landscape, TMB and MSI status, HLA gene expression, GSEA and GSVA analysis, immune activities, immunotherapy sensitivities were evaluated in the resistant high and low groups. Drug resistant cell lines, PDO and PDX models were used to validate this signature.

[RESULTS] GO analysis of 140 differentially expressed genes were involved in many processes and KEGG pathways were enriched in platinum resistance and cancer. UniCox regression analysis was screened out 21 genes and conducted a platinum resistance scoring model. Stratified analysis indicated that the drug resistance score had a good predictive value in subgroups divided by T-stage, age and race. CNV changes were more occurred in the score-high group, and most model genes were negatively correlated with TMB, MSI and HLA gene expression. The immune score in resistant group was significantly higher, within more mast cell, regulatory T cell and dendritic cell infiltrated in. In vitro and in vivo models showed that 21 platinum resistance genes had varying degrees of upregulation under CDDP chemotherapy pressure.

[CONCLUSIONS] The 21 gene-signature for platinum was developed to predict response to platinum chemotherapy for GC patients. It is worthwhile to further evaluate the molecular biology and the clinical applications of this signature.