Unraveling metabolism heterogeneity in colorectal cancer and its implications in pan-cancer cohort.

Abstract

e16016 Background: Colorectal cancer (CRC) molecular subtype has been emphasized and links to biological and clinical behavior. However, comprehensive metabolism of CRC has not been characterized. Subtype-specific metabolic differences and immunometabolism phenotypes remain unclear. Therefore, this study performed metabolism clustering and explore its relation with immune phenotypes as well as prognosis predictive value. Methods: Transcriptome of TCGA CRC cohort was utilized to generate 113 KEGG metabolism pathway scores via GSVA algorithm. Consensus clustering were used to identify metabolism subtypes. Bioinformatic algorithms were applied in classification and survival analysis. Results: Energy metabolism-oriented subtype, featured by nitrogen metabolism and immune-inflamed, correlated with good prognosis (log rank P < 0.001). Pyrimidine synthesis activated most in nucleotide metabolism-oriented subtype, which was immune-deserted. Stroma metabolism-oriented subtype, characterized by glycosaminoglycan (GAG) biosynthesis and immune-suppressive phenotype, was an independent risk factor for overall survival (multivariate Cox: HR = 2.30 95% CI 1.23-4.28, P = 0.009). Clinical cohort from Nanfang Hospital composed of RNA-Seq data from 26 pre- and post-treatment samples in mCRC patients receiving mFOLFOX+Bevacizumab were classified. 22 were identified and 8 of them were pre-treatment, 4 of which were nucleotide subtype being 100% PR. The rest were stroma subtype with SD or PD, indicating drug resistance in stroma subtype. Interestingly, GAG chondroitin sulfate featured in stroma subtype outperformed other metabolisms in predicting negative prognosis (HR = 1.42 95% CI 1.18-1.71, P < 0.001). We then tested GAG metabolism in TCGA pan-cancer cohort. Chondroitin sulfate and heparan sulfate metabolism subtype correlated inversely with bladder (HR = 1.23 95% CI 1.06-1.43, P = 0.007) and breast cancer (HR = 1.27 95% CI 1.10-1.47, P = 0.001) patients’ survival, respectively. Keratan sulfate subtype predicted worse survival in glioblastoma, pancreatic and liver cancer (HR = 1.31 95% CI 1.09-1.57, P = 0.003; HR = 1.31 95% CI 1.06-1.61, P = 0.01; HR = 1.23 95% CI 1.04-1.46, P = 0.02). These indicated a pan-cancer relevant role of GAG disorder. Conclusions: CRC metabolism subtypes unraveled metabolism heterogeneity with prognosis value. CRC stroma subtype and other stroma-involved cancers share active GAG metabolism, which may lighten common targeting strategies in multiple stroma-accompanied cancers.