Abstract 3726: Physical activity levels are associated with transcriptomic pathways in colon tumors and tumor-adjacent visceral adipose tissue: Results from the ColoCare Study

Abstract Physical activity has consistently been associated with improved colon cancer survival, yet the biological mechanisms for this association are not yet fully understood. We investigated the transcriptome of colon tumors and tumor-adjacent visceral adipose tissue (VAT) in relation to colon cancer patients’ physical activity levels. Methods: Fresh-frozen tumor and VAT samples were collected from 134 stage I-III colon cancer patients recruited at Huntsman Cancer Institute, Utah, and Heidelberg University Hospital, Germany, and profiled with bulk RNA sequencing. Habitual physical activity levels were self-reported by the International Physical Activity Questionnaire and patients were classified as either active (>7.5 metabolic equivalents per week (MET hrs/week), or 150 minutes/week of moderate to vigorous activity) or as inactive (< 2.5 MET hrs/week or <1 hour of light activity). To evaluate robustness and consistency of findings, patients were also categorized as >7.5 MET hrs/week vs. < 3.5 MET hrs/week. Normalized differentially expressed genes were identified (DESeq2 R package) and analyses were adjusted for age, sex, body mass index (BMI), study site and tumor stage. Gene set enrichment analysis identified enriched pathways within the 2024 Hallmark gene sets. Significance was assessed using false discovery rate padj <0.05. Results: Active patients (n=57) were on average younger (61+14 years vs. 64+14 years), with less disease severity (84% Stage II/III, 95% Stage II/III), lower BMI (26.8+5 kg/m2 vs. 32.1+7 kg/m2) compared to inactive patients (n=55). There were 21 and 27 significant gene sets (padj <0.05) in colon tumor tissue and VAT, respectively, when comparing active to inactive patients. Colon tumors of active patients displayed downregulation of oncogenic pathways relative to the inactive patients, including epithelial mesenchymal transition and angiogenesis (|Normalized Enrichment Score (NES)|>1.5, padj < 0.05). Tumors from active patients also exhibited downregulation of oxidative phosphorylation (|NES|>1.5, padj < 0.05) relative to inactive patients. VAT of active patients had significantly upregulated oxidative phosphorylation, fatty acid metabolism and glycolysis relative to inactive patients (|NES|>1.4, padj < 0.05). These tumor and adipose gene set results were consistent across the comparison of >7.5 MET hrs/week vs. < 3.5 MET hrs/week. Conclusions: Colon tumors from patients meeting or exceeding physical activity guidelines displayed significant downregulation of oncogenic pathways relative to tumors from inactive patients. Similarly, VAT of active patients had transcriptional profiles promoting metabolic pathways. These findings suggest that physical activity levels meeting or exceeding the current guidelines are associated with favorable gene expression both in tumors and tumor-adjacent VAT. Citation Format: Victoria Maria Bandera, Caroline Himbert, Elaine M. Glenny, Tengda Lin, Sheetal Hardikar, Aik Choon Tan, Jennifer Ose, Victoria Damerell, Patricia Erickson, Richard Viskochil, Christy Warby, Olena Aksonova, Chris Stubben, David Nix, Kenneth Boucher, Peter Schirmacher, Ildiko Strehli, 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 D. Hursting, Cornelia M. Ulrich. Physical activity levels are associated with transcriptomic pathways in colon tumors and tumor-adjacent visceral adipose tissue: Results from the ColoCare Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3726.