Abstract 7324: Impact of BMI on immune pathways in preinvasive colorectal lesions
Authors: Fanning Lauren R. , Hamidi Bashir , Korostenskij Ivan , Seal Souvik , Crawford Tami L. , MacKenzie Todd A. , Barry Elizabeth L. , Thaxton Jessica E. , Shrubsole Martha J. , Vincent Benjamin , Baron John A. , Alekseyenko Alexander V. , Wallace Kristin 
Published: March 2024

Background: Obesity is a risk factor for colorectal neoplasia, possibly mediated by metabolic dysregulation or chronic inflammation. Circulating inflammatory cytokines have been associated with an increased risk of CRC, but no studies have examined the impact of BMI on immune gene expression in preinvasive lesions. Our analysis combines data from 3 retrospective epidemiologic studies among patients with colorectal adenomas or serrated polyps. Using a cross-sectional design, we investigate whether BMI categories (obese (OB), overweight (OW), normal (NL)) are associated with T-helper gene pathways.

Methods: For each patient, we include demographic, clinical, and specimen (archival FFPE for RNA isolation) data. Immune gene expression data was determined using the NanoString nCounter platform on a subset of cases (n=100) balanced by study site and lesion type from our cohort (n=630). Genes were normalized using a modified RUVseq methodology. We examined 4 pathways (Th1, Th2, Th17, Treg) defined by gene lists included in the NS immune v2. panel. Differences in pathway expression by BMI categories were analyzed using our distance-based methods (Wd* multivariate analysis of variance and TW2 pairwise method) adjusted for age & sex. Using linear regression analysis, we generated coefficients (p-values) for OW and OB vs NL for genes within each pathway.

Results: 86 samples passed QC. Th2 and Th1 pathways were significant for OW vs NL (p&lt;0.05) whereas Th17 was marginally significant (&lt;0.1). Several genes within the Th1, Th2, and Th17 pathways were enriched in OW vs. NL: e.g., IL2 (coeff. 0.77 (p=0.008), IL5 (coeff. 1.02, p=0.001), IL17F (coeff. 0.57, p=0.05), respectively. (Table)

Conclusion: Enrichment of genes specific to the Th pathways in OW persons suggest that metabolic immune modulation may be important in early colorectal carcinogenesis.

Differences in immune pathway and gene expression by BMI categories TW2 (p-value) Wd* (p-value) Pathways Normal (N = 22) Overweight (N = 32) Obese (N = 29) Th2 Ref. 0.017 0.15 0.038 Th1 Ref. 0.03 0.204 0.10 Th17 Ref. 0.073 0.125 0.103 MLR coefficient (p-value) Pathway Gene Overweight vs. Normal Obese vs. Normal ANOVA (p-value) Th2 IL2RA 0.34 (0.041) -0.11 (0.517) 0.010 IL4 0.58 (0.019) 0.22 (0.386) 0.052 IL5 1.02 (0.001) 0.41 (0.191) 0.004 NOTCH1 -0.05 (0.742) -0.34 (0.045) 0.078 Th1 IL12B 0.57 (0.031) 0.40 (0.136) 0.093 IL2 0.77 (0.008) 0.39 (0.179) 0.028 TBX21 0.46 (0.015) 0.19 (0.308) 0.044 Th17 IL17F 0.57 (0.050) 0.42 (0.157) 0.139 IL21 0.77 (0.004) 0.42 (0.131) 0.017 IL23R 0.29 (0.048) -0.008 (0.957) 0.047 IL6R 0.002 (0.990) 0.36 (0.039) 0.041 IRF4 -0.61 (0.007) -0.33 (0.149) 0.025 TGFB1 -0.26 (0.023) -0.19 (0.101) 0.069

Citation Format: Lauren R. Fanning, Bashir Hamidi, Ivan Korostenskij, Souvik Seal, Tami L. Crawford, Todd A. MacKenzie, Elizabeth L. Barry, Jessica E. Thaxton, Martha J. Shrubsole, Benjamin Vincent, John A. Baron, Alexander V. Alekseyenko, Kristin Wallace. Impact of BMI on immune pathways in preinvasive colorectal lesions [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 7324.