Abstract PR007: Tumor-adjacent visceral adipose tissue displays an altered transcriptomic landscape in early-onset colorectal cancer patients: Results from the ColoCare Study

Abstract Introduction: Obesity is commonly characterized by high levels of internal (visceral) adiposity. Visceral adipose tissue (VAT) is highly metabolically active and secretes proteins and metabolites in paracrine and endocrine signaling pathways. The phenotype of tumor-adjacent VAT may be an unexplored factor for risk and progression of early-onset colorectal cancer (EOCRC). Thus, we aimed to identify transcriptomic differences in tumor-adjacent visceral adipose tissue (VAT) in patients with EOCRC (50 years at diagnosis) vs. those diagnosed with later-onset colorectal cancer (LOCRC; 50 years at diagnosis). Methods: VAT samples were collected from 332 patients with stage 0-III colorectal cancer enrolled in the ColoCare Study and recruited at Huntsman Cancer Institute (Utah), Heidelberg University Hospital (Germany), University of Tennessee Health Science Center (Tennessee), and Moffitt Cancer Center (Florida). Patients in our study were treatment naïve. VAT tissue was collected 1-3 cm from the colorectal tumor during surgery. VAT transcriptomes were measured with bulk RNA sequencing. Participants were classified as EOCRC vs. LOCRC. Normalized differentially expressed genes were identified (DESeq2), with analyses adjusted for sex, body mass index (BMI), study site, and tumor stage. Gene set enrichment analysis (GSEA) identified enriched pathways within the 2025 Hallmark gene sets. Significance was assessed using false discovery rate (FDR) p-adj0. 05. We replicated our analyses, adjusting for tumor site (colon vs. rectal), to account for potential differences by anatomical subgroup. Results: Patients with EOCRC (n=45, average age: 41±9 years) had higher disease stages compared to LOCRC patients (n=287, average age: 66±10 years) (EOCRC: 64% Stage III vs LOCRC: 39% Stage III) and similar BMI (EOCRC: 28. 8±7. 0 kg/m2 vs. LOCRC: 28. 5±5. 9 kg/m2). GSEA revealed 5 significantly enriched gene sets (FDR p-adj0. 05) in VAT when comparing EOCRC to LOCRC patients. VAT of EOCRC patients exhibited upregulation of immune pathways (Interferon Alpha Response, Interferon Gamma Response, TNFA Signaling via NF- κB), and fibrosis Hallmark pathways (Epithelial Mesenchymal Transition) (Normalized Enrichment Score (NES) 1. 5, p-adj0. 05). Additionally, the VAT of patients with EOCRC showed upregulation of the glycolysis gene set relative to LOCRC (NES1. 5, p-adj0. 05). These pathways remained significantly enriched regardless of tumor site adjustment. Conclusions: VAT of patients with EOCRC displays a differential gene expression landscape relative to LOCRC patients, suggesting enhanced immune, fibrotic, and metabolic activity. These findings suggest that tumor-adjacent VAT physiology may be a relevant factor of the tumor-microenvironment in EOCRC progression. Citation Format: Victoria M. Bandera, Patricia Erickson, Caroline Himbert, Elaine M. Glenny, Tengda Lin, Sheetal Hardikar, Aik Choon Tan, Jennifer Ose, Victoria Damerell, Christy Warby, Olena Aksonova, Chris Stubben, David Nix, Kenneth Boucher, Peter Schirmacher, Ildiko Strehli, Megan Mclaws, Alejandro Sanchez, Jolanta Jedrzkiewicz, Lyen C. Huang, Vaia Florou, Jessica N. Cohan, Alexander Brobeil, Hans-Ulrich Kauczor, Christoph Kahlert, Meghana Karchi, Elizabeth H. Wood, Doratha A. Byrd, Erin M. Siegel, Adetunji T. Toriola, David Shibata, Christopher I. Li, Jane C. Figueiredo, Biljana Gigic, Jatin Roper, Stephen Hursting, Cornelia M. Ulrich. Tumor-adjacent visceral adipose tissue displays an altered transcriptomic landscape in early-onset colorectal cancer patients: Results from the ColoCare Study abstract. In: Proceedings of the AACR Special Conference in Cancer Research: The Rise in Early-Onset Cancers—Knowledge Gaps and Research Opportunities; 2025 Dec 10-13; Montreal, QC, Canada. Philadelphia (PA): AACR; Clin Cancer Res 2025;31 (23Suppl): Abstract nr PR007.