DOI: 10.6084/m9.figshare.30178149
title: Consensus molecular subtypes and gene expression in early-onset colorectal cancer

description: The incidence of early-onset colorectal cancer (EOCRC) is rising in many countries. The drivers of this growing incidence are unclear, and we aimed to determine whether there is a distinct pattern of gene expression in EOCRC compared with late-onset colorectal cancer (LOCRC). Transcriptomic analysis was carried out on pretreatment tumors from a cohort of 19 EOCRC patients and compared to a control group of 196 LOCRC aged over 65 years. RNA sequencing was used to analyze differential gene expression and gene-set enrichment, as well as assign consensus molecular subtypes (CMS). Thirteen genes were significantly overexpressed in the EOCRC group, including <i>HOXA11</i>, <i>STMN2</i> and <i>DASH2</i>, and 12 genes overexpressed in the LOCRC group, including <i>ZG16</i> and <i>MARCO</i>. Gene-set enrichment analysis showed that many of the gene-sets in the EOCRC group were related to cell cycle, while those enriched in the LOCRC group were predominantly related to immune function. When grouping CMS subtypes, LOCRC tended to be immune-rich (CMS1/CMS4), while EOCRC were predominantly CMS2/3. Our results add to the growing literature that EOCRC is a distinct disease from LOCRC. EOCRC have fewer immune-associated gene-sets compared to LOCRC and very low rates of CMS1 and CMS4 subtypes. This may have implications for prognosis and targeted treatments. The incidence of early-onset colorectal cancer (EOCRC) is rising, yet its molecular drivers remain poorly understood.Transcriptomic analysis of 19 EOCRC tumors versus 196 late-onset cases identified distinct gene expression profiles.EOCRC tumors showed overexpression of genes related to cell cycle, while LOCRC samples were enriched for immune-related genes.Gene-set enrichment analysis revealed that EOCRC tumors had significant enrichment in cell-cycle and DNA repair pathways, contrasting with immune pathway enrichment in LOCRC.Consensus molecular subtype (CMS) classification showed EOCRC tumors were predominantly CMS2/3 (immune-excluded), with significantly fewer CMS1/4 (immune-rich) tumors than LOCRC.Findings support the hypothesis that EOCRC is a distinct molecular entity with potential implications for targeted therapies and prognostication. The incidence of early-onset colorectal cancer (EOCRC) is rising, yet its molecular drivers remain poorly understood. Transcriptomic analysis of 19 EOCRC tumors versus 196 late-onset cases identified distinct gene expression profiles. EOCRC tumors showed overexpression of genes related to cell cycle, while LOCRC samples were enriched for immune-related genes. Gene-set enrichment analysis revealed that EOCRC tumors had significant enrichment in cell-cycle and DNA repair pathways, contrasting with immune pathway enrichment in LOCRC. Consensus molecular subtype (CMS) classification showed EOCRC tumors were predominantly CMS2/3 (immune-excluded), with significantly fewer CMS1/4 (immune-rich) tumors than LOCRC. Findings support the hypothesis that EOCRC is a distinct molecular entity with potential implications for targeted therapies and prognostication.