Abstract 3406: Transcriptomic analysis reveals differentially expressed pathways in colon tumors of cancer patients with vs without obesity: Results from the ColoCare Study
Authors: Bandera Victoria M. , Lin Tengda , Himbert Caroline , Glenny Elaine M. , Tan Aik Choon , Ose Jennifer , Warby Christy , Aksonova Olena , Carpanese Alessandro , Stubben Chris , Nix David , Boucher Kenneth , Schirmacher Peter , Strehli Ildiko , Jedrzkiewicz Jolanta , Huang Lyen C. , Cohan Jessica N. , Brobeil Alexander , Schneider Martin A. , Kahlert Christoph , Siegel Erin M. , Toriola Adetunji T. , Shibata David , Li Christopher I. , Figueiredo Jane C. , Gigic Biljana , Roper Jatin , Hursting Stephen , Ulrich Cornelia M. 
Published: March 2024

Abstract
Despite the rise of global obesity rates and obesity’s implication in increased colon cancer risk, the understanding of mechanisms underlying these associations and opportunities for interception are limited. This work leveraged transcriptomic data from colon tumors to identify pathways and biologically relevant functions that characterize the tumors among obese vs nonobese individuals. Fresh-frozen colon tumor samples were collected from 155 patients who underwent surgery without neoadjuvant treatment as part of the ColoCare Study at Huntsman Cancer Institute, Utah, and Heidelberg University Hospital, Germany. RNA was sequenced using the NovaSeq X. The DESeq2 R package identified differentially expressed genes stratified by body mass index (BMI) at diagnosis (&gt;30 kg/m2 vs &lt;30 kg/m2) adjusting for age, sex, study site, and tumor stage. Genes with padj &lt; 0.2 were entered into Ingenuity Pathway Analysis (IPA) software for pathway and expression analyses. Significant pathways were identified using Fischer’s Exact Test as the probability of molecules’ association with canonical pathways due to chance. The analysis was also repeated testing a median BMI categorization of &gt;27.7 kg/m2 vs &lt;27.7 kg/m2 using padj &lt; 0.1 for IPA entry. Patients were 49% female, 63±14 years old, 47% stage III with a mean baseline BMI of 28.8±6.0 kg/m2. In colon tumors of those with &gt;BMI 30 kg/m2, 213 genes were differentially expressed compared to BMI &lt;30 kg/m2. IPA identified five upregulated pathways (neurovascular coupling signaling, adrenergic receptor signaling, activation of N-methyl-D-aspartate receptors and postsynaptic events, response to elevated platelet cytosolic Ca2+, docosahexaenoic acid signaling) and one downregulated pathway (WNT/B-catenin signaling) in patients with vs without obesity (p &lt;0.05). The top predicted functional pathways, based on activation z-scores, identified in expression analysis included significant activation in chromosomal instability and aberration, size of body, phosphorylation of L-tyrosine, protein kinase cascade, and cell death and survival categories among colon tumors in obese patients. Using a median BMI categorization, 458 genes and 35 pathways were differentially expressed in those with BMI &gt; 27.7 kg/m2 vs &lt; 27.7 kg/m2. Both BMI models had good agreement with 5 pathways consistently significantly (z-score &gt; |2|) up- or down-regulated, including predicted downregulation of organismal death and increased body size and phosphorylation of L-tyrosine in the higher BMI group. Colon tumors from patients with a higher BMI had pathways associated with more aggressive tumors, such as increased chromosomal instability and decreased cell death. Our ongoing work investigates the role of the adipose-tissue tumor microenvironment among patients, and the potential for interception using parallel mouse models.
Citation Format: Victoria M. Bandera, Tengda Lin, Caroline Himbert, Elaine M. Glenny, Aik Choon Tan, Jennifer Ose, Christy Warby, Olena Aksonova, Alessandro Carpanese, Chris Stubben, David Nix, Kenneth Boucher, Peter Schirmacher, Ildiko Strehli, Jolanta Jedrzkiewicz, Lyen C. Huang, Jessica N. Cohan, Alexander Brobeil, Martin A. Schneider, Christoph Kahlert, Erin M. Siegel, Adetunji T. Toriola, David Shibata, Christopher I. Li, Jane C. Figueiredo, Biljana Gigic, Jatin Roper, Stephen Hursting, Cornelia M. Ulrich. Transcriptomic analysis reveals differentially expressed pathways in colon tumors of cancer patients with vs without obesity: Results from the ColoCare Study [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3406.