Hypermethylated Colorectal Cancer Tumours Present a Myc-Driven Hypermetabolism with a One-Carbon Signature Associated with Worsen Prognosis

Abstract

Colorectal cancer (CRC) is the second cause of cancer-related death; the CpG-island methylation pathway (CIMP) is associated with KRAS/BRAF mutations, two oncogenes rewiring cell metabolism, worse prognosis, and resistance to classical chemotherapies. Despite this, the question of a possible metabolic rewiring in CIMPs has never been investigated. Here, we analyse whether metabolic dysregulations are associated with tumour methylation by evaluating the transcriptome of CRC tumours. CIMP-high patients were found to present a hypermetabolism, activating mainly carbohydrates, folates, sphingolipids, and arachidonic acid metabolic pathways. A third of these genes had epigenetic targets of Myc in their proximal promoter, activating carboxylic acid, tetrahydrofolate interconversion, nucleobase, and oxoacid metabolisms. In the Myc signature, the expression of GAPDH, TYMS, DHFR, and TK1 was enough to predict methylation levels, microsatellite instability (MSI), and mutations in the mismatch repair (MMR) machinery, which are strong indicators of responsiveness to immunotherapies. Finally, we discovered that CIMP tumours harboured an increase in genes involved in the one-carbon metabolism, a pathway critical to providing nucleotides for cancer growth and methyl donors for DNA methylation, which is associated with worse prognosis and tumour hypermethylation. Transcriptomics could hence become a tool to help clinicians stratify their patients better.