Molecular and clinical characterization of a claudin (CLDN)-low subtype of gastric cancer (GC).

Abstract

67 Background: A CLDN-low subtype has been identified in breast and bladder cancers and is characterized by low expression of tight junction proteins CLDN, enrichment for epithelial-to-mesenchymal transition (EMT) and tumor initiating cell (TIC) features. Given the genomically stable (GS) subtype of GC defined by TCGA has features suggestive of CLDN-low tumors, we evaluated whether the CLDN-low subtype also exists in GC. Methods: 415 tumors from TCGA GC mRNA dataset were clustered on the CLDN, EMT and TIC gene sets with significance testing using SigClust2 to identify CLDN-low GC. A minimal set of genes that could accurately classify CLDN-low GC was defined by prediction analysis of microarrays (PAM). Tumors identified by SigClust2 or the PAM were called CLDN-low GC regardless of the original subtype call. The 300 GCs in the Asian Cancer Research Group (ACRG) dataset [GSE62254] were used to validate the predictor. We characterized clinical and molecular (gene expression, mutation and copy number alteration) features of CLDN-low GC. Results: We identified 46 tumors that had consensus enrichment for CLDN-low features in TCGA. CLDN-low tumors were most commonly diffuse (35/42=83%, 4 tumors=mixed) and GS (36/46=78%). CLDN-low GC showed high expression of immune gene signatures including T and NK cell signatures, but not an immunosuppression signature. Compared to GS subtype, CLDN-low GC had increased frequency of CD44, GATA4, and GATA6 amplification. In ACRG, 28/300 GCs were CLDN-low using the PAM predictor. The CLDN-low GC in ACRG was phenotypically similar to the CLDN-low GC in TCGA based on the CLDN, EMT and TIC gene signatures. Clinically, CLDN-low GC was associated with the shortest overall survival of the 5 subtypes (CLDN-low plus TCGA defined 4 subtypes). Notably, a hazard ratio comparing CLDN-low GC vs GS was 2.10 (95%CI; 1.07-4.11) in TCGA and 2.32 (95%CI; 1.18-4.55) in ACRG cohort, adjusting for age and pathological stage. Conclusions: We identified a CLDN-low GC which has a poor prognosis likely related to the resistance to conventional chemotherapy due to its EMT and TIC-like properties. Further development of targeted therapies against these molecular features is warranted to improve the outcome of CLDN-low GC.