Transcriptional metabolic profiling young onset colorectal cancer (CRC) patients.

Abstract

3509 Background: Patients diagnosed with colorectal cancer (CRC) at age < 50 years typically present with more advanced disease, resulting in poor therapeutic response and clinical outcomes. Therefore, there is an unmet need to understand the differences in transcriptional profiles between younger (<50) and older ( > 50) CRC patients. Methods: Using TCGA (n = 397; > 50 = 349; < 50 = 48) and Oncology Research Information Exchange network (ORIEN) CRC datasets (n = 460; > 50 = 364 ; < 50 = 96), patients were separated into younger and older populations. Baseline characteristics of the patients in this analysis are provided in the accompanying table. Subsequently, their transcriptional profiles were compared and assessed via differential gene expression analysis (DESeq2), gene set enrichment analysis (GSEA), immune deconvolution (TIMER2.0), and metabolic pathway analysis (MetaPhOR). These pathways were then mapped to assess transcriptional dysregulation, and patterns of predicted metabolic flux. Results: Comparisons of older and younger groups revealed a large number of significantly differentially expressed transcripts (n = 2629), enrichment in younger groups of metabolic pathways (amino acids and lipids), oncogenes (MYC targets and NRAS targets), and cellular processes. In the older group we found enrichment of methylation and histone modification, immune response, and other metabolic pathways, like androgens. Metabolic pathway analysis revealed consistent alterations in steroid hormone metabolism and kynurenine metabolism, which were largely upregulated in the over 50 group. Additionally, pathways associated with response to both CTLA4 and PDL1 treatment were largely upregulated in the over 50 group. This transcriptional signature may be associated with a pre-disposition to different clinical outcomes and therapeutic response for agents targeting these pathways. Conclusions: Overall, this study has revealed differences in transcriptional metabolic profiles and other drivers of disease, as well as immune profiles, between younger and older CRC populations. This biology should be explored in the future, as new avenues for treatment in younger CRC populations. [Table: see text]