Abstract
BackgroundAlthough recent advances in high-throughput technology have provided many insights into gastric cancer (GC), few reliable biomarkers for diffuse-type GC have been identified. Here, we aim to identify a prognostic and predictive signature of diffuse-type GC heterogeneity.MethodsWe analyzed 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 GC samples in three independent cohorts (n = 466). Log-rank and Cox regression analyses were used to estimate the association between the signature and prognosis. The signature was also characterized by somatic variant analyses and tissue microarray analysis between diffuse-type GC subtypes.ResultsTranscriptomic profiling of RNA-seq data identified a signature which revealed distinct subtypes of diffuse-type GC: the intestinal-like (INT) and core diffuse-type (COD) subtypes. The signature showed high predictability and independent clinical utility in diffuse-type GC prognosis in other patient cohorts (HR 2.058, 95% CI 1.53–2.77, P = 1.76 × 10–6). Integrative mutational and gene expression analyses demonstrated that the COD subtype was responsive to chemotherapy, whereas the INT subtype was responsive to immunotherapy with an immune checkpoint inhibitor (ICI). Tissue microarray analysis showed the practical utility of IGF1 and NXPE2 for predicting diffuse-type GC heterogeneity.ConclusionsWe present a molecular signature that can identify diffuse-type GC patients who display different clinical behaviors as well as responses to chemotherapy or ICI treatment.
Highlights
Gastric cancer (GC) is the third leading cause of cancer-related mortality and the fifth most common cancer worldwide [1]
These results indicate that the newly discovered core diffuse-type (COD) cluster may be compatible with the known poor prognosis of diffuse-type gastric cancer (GC), which may derive from EMT activity
The signature showed therapeutic relevance in that patients with the COD subtype benefit from standard chemotherapy, while patients with the INT subtype are responsive to immune checkpoint inhibitor (ICI) treatment
Summary
Gastric cancer (GC) is the third leading cause of cancer-related mortality and the fifth most common cancer worldwide [1]. There is a crucial need to molecularly characterize diffuse-type GC and identify a signature that could predict the clinical course of and suggest appropriate treatment options for diffuse-type GC. Methods We analyzed 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 GC samples in three independent cohorts (n = 466). Results Transcriptomic profiling of RNA-seq data identified a signature which revealed distinct subtypes of diffuse-type GC: the intestinal-like (INT) and core diffuse-type (COD) subtypes. The signature showed high predictability and independent clinical utility in diffuse-type GC prognosis in other patient cohorts (HR 2.058, 95% CI 1.53–2.77, P = 1.76 × 10–6). Conclusions We present a molecular signature that can identify diffuse-type GC patients who display different clinical behaviors as well as responses to chemotherapy or ICI treatment
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