Although recent advances in high-throughput technology have provided many insights into gastric cancer (GC), few reliable biomarkers for handling diffuse type GC are identified. Here, we aim to identify a prognostic and predictive signature predicting heterogeneous clinical courses of diffuse type GC.
We analysed RNA-seq based transcriptome data to identify a molecular signature in 150 gastric tissue samples including 107 diffuse type GCs. The predictive value of the signature was verified using other diffuse type GCs in three independent cohorts (n = 466). Various statistical methods, including log-rank and Cox regression analyses, were used to estimate an association between the signature and prognosis. The signature was also characterized by somatic variant assessments and tissue microarray analysis between diffuse type GC subtypes.
Transcriptomic profiling revealed two distinct subtypes of diffuse type GC including intestinal-like (INT) and core diffuse type (COD) subgroups. We generated a signature, namely COD-signature, reflecting the best characteristics of subtypes. When estimating prognostic value in other cohorts, COD-signature showed a strong predictability and an independent clinical utility in diffuse type GC prognosis (hazard ratio = 2.058, 95% confidence interval = 1.53-2.77, P < 0.001; Table). Integrative mutation and gene expression analyses demonstrated that COD subtype was responsive to chemotherapy, whereas INT subtype showed responsiveness to immunotherapy with immune-check point inhibitor (ICI). Tissue microarray analysis showed practical utility of IGF1 and NXPE2 proteins for predicting diffuse type GC’s heterogeneity. Univariate and multivariate Cox regression analysis of overall survival in diffuse type gastric cancer Abbreviations: HR, hazard ratio; CI, confidence interval; INT, intestinal-like; COD, core diffuse type.Variables Univariate Multivariate n HR (95% CI) P-value n HR (95% CI) P-value Age 402 1.013 (1.001 - 1.025) 0.037 402 1.02 (1.007 - 1.032) 0.003 Gender (Male or Female) 402 1.074 (0.805 - 1.433) 0.625 AJCC Stage (I, II, III or IV) 402 2.516 (2.088 - 3.032) <0.001 2.67 (2.204 - 3.235) <0.001 Tumour site (cardia, body, antrum or whole) 402 0.985 (0.777 - 1.248) 0.9 COD-signature (INT or COD subtypes) 402 1.675 (1.257 - 2.234) <0.001 2.058 (1.53 - 2.766) <0.001
The COD-signature represents a promising diagnostic tool for the identification of diffuse type GC patients who would display different clinical behaviours as well as response to chemotherapy or ICI treatment.
Korea Research Institute of Bioscience and Biotechnology Chungnam National University, College of Medicine Seoul National University, Faculty of Medicine.
Korea Research Institute of Bioscience and Biotechnology.
All authors have declared no conflicts of interest.