Obesity-associated colorectal cancer and the association with chemokine signaling and tumor remodeling pathways.

Abstract

194 Background: Obesity is a known risk factor for colorectal cancer (CRC) that promotes systemic inflammation and T-cell dysfunction, yet the specific characteristics of the tumor immune microenvironment (TIME) in this context are not well-defined. Furthermore, the landscape of genomic driver mutations exclusive to CRC patients with obesity remains poorly understood. Therefore, a comprehensive analysis is required to characterize the unique immunological and genomic features of CRC in patients with obesity, which could clarify mechanisms of tumor progression and lead to personalized therapeutic approach for this population. Methods: We performed a retrospective analysis using genomic and transcriptomic data from colorectal cancer (CRC) patients at our institution (RPCCC, N=107) stratified by body mass index (BMI) – Obesity (BMI ≥30), overweight (25≤ BMI <30) and normal (18≤ BMI <25). Differential gene expression and gene set enrichment analyses were performed to identify differentially expressed immune-related genes and altered metabolic pathways; immune deconvolution was performed to explore tumor immune microenvironment composition using CIBERSORT. Concurrently, genomic data from the RPCC cohort as well as the TCGA colorectal cancer dataset (N=307) were explored to compare the alteration frequency of selected genes ( APC, KRAS, TP53, SMAD4, PIK3CA, BRAF, NRAS, TGFBR2, MLH1, MSH2, MSH6, PMS2, CTNNB1, and PTEN ) using a Fisher’s exact test. Statistical models were adjusted for covariates such as age, gender, and disease stage to isolate the effects of obesity. Results: Overall, 107 patients in the RPCCC cohort and 307 patients in the TCGA cohort were included. In the RPCC cohort, male was more seen in the obesity group (p=0.023) but disease stage was well balanced across BMI groups (p=0.330). Gene set enrichment analysis revealed epithelial mesenchymal transition, extracellular matrix, collagen formation and degradation pathways more enriched in the obesity group than the normal BMI group (normalized enrichment score >=2.5, adjusted p value <0.05 for all pathway). Although immune cell compositions via the immune deconvolution analysis did not differ between obesity and normal BMI groups except for M0 macrophages more enriched in patients with normal BMI (p=0.039), differential gene expression analysis revealed higher expression of several immune-related genes including CCL2, CXCL12, TDO2, CXCL5 , and CD70 in the obesity group. The alteration frequency of selected genes was not significantly different between obesity and normal BMI groups. Conclusions: Obesity-associated colorectal cancer is defined by tumor remodeling and distinct immune programs that drive progression. Specific chemokines, tryptophan metabolism, and CD70 could serve as a tailored therapeutic target in this disease entity which warrants further investigation.