e15643 Background: Colorectal cancer (CRC) is a major global health concern as it is the second most fatal cancer worldwide. While incidence in average onset colorectal cancer (AOCRC, > 50 years) is declining, early onset colorectal cancer (EOCRC, < 50 years) is rising globally. The reasons for this phenomenon are poorly understood. Multiomic profiling holds promise for determining aetiology and guiding treatment strategies. Methods: Patients diagnosed with CRC were enrolled in this pilot translational study with acquisition of tumour, adjacent normal tissue, blood and faeces. Here we present the data from tumour samples. Seventy-nine patients were included, comprising 38 patients with EOCRC, and 41 with AOCRC. Tumour tissue was obtained from fresh frozen specimens. Targeted genomic, proteomic and transcriptomic analyses were performed, through targeted panel sequencing, LC/MS and RNAseq respectively. Data integration strategies included pathway enrichment analysis, immune cell deconvolution, metabolic reaction enrichment analysis (MaREA), and cross-omics correlation. Clinical, molecular and survival outcomes were compared between EOCRC and AOCRC groups. Results: Integrated multiomic profiling identified 6,726 transcripts and 5,957 proteins. Targeted genomic sequencing detected somatic mutations in 50% of tumours. Tumour sidedness was prognostically relevant, with right sided tumours enriched for KRAS (G12V) and PIK3CA (E545K) mutations and associated with inferior overall survival (p = 0.007). Proteomic and transcriptomic analyses demonstrated that EOCRC exhibits a molecular profile distinct from AOCRC, characterised by enrichment of immunosuppressive processes and activation of sirtuin (SIRT1) and RHO GTPase signalling. Metabolic reaction enrichment analysis identified EOCRC specific vulnerabilities, including reduced glutathione biosynthesis, impaired pyruvate dehydrogenase activity, and altered nucleotide synthesis, consistent with increased oxidative stress sensitivity and glycolytic reliance. NQO1 emerged as a candidate biomarker with concordant transcriptomic and proteomic upregulation. Clinically, EOCRC patients presented with more advanced disease yet demonstrated improved overall survival compared with AOCRC (p = 0.02). Targeted genomic profiling had potential clinical utility, with 20% of patients demonstrating actionable changes in management and 45% harbouring alterations relevant at relapse. Conclusions: EOCRC represents a biologically distinct subtype of MSS colorectal cancer, defined by immunosuppressive signalling and altered metabolic dependencies not observed in AOCRC. These findings support age informed molecular stratification and identify candidate biomarkers and metabolic vulnerabilities that may inform targeted therapeutic strategies for this rapidly rising patient population.
Reilly et al. (Thu,) studied this question.