Abstract A170: Transcriptomic profiling identifies dysregulation of S100 signaling associated with colorectal cancer disparities within a Hispanic cohort

Abstract

Colorectal cancer (CRC) is the second leading cause of cancer-related mortality in the United States, with the incidence of early-onset CRC (diagnosis at <50 years) increasing significantly over the past decade. Although early-stage (Stages I/II) CRC is associated with higher survival rates, minority populations such as Hispanics continue to experience poorer clinical outcomes. Hispanic patients are more frequently diagnosed with advanced-stage (Stages III/IV) CRC than Non-Hispanic White (NHW) patients. These disparities likely arise from a combination of genetic and non-genetic factors. Identifying population-specific molecular differences and the signaling pathways they affect may improve early detection and facilitate the development of targeted therapeutic strategies for high-risk populations. To investigate the molecular mechanisms underlying early-onset disease and ethnicity-associated CRC disparities, we performed transcriptomic profiling of CRC tissues and normal tissues adjacent to tumors (NATs) from Hispanic and NHW patients. Our analysis identified 311 differentially expressed genes (DEGs; log2 fold change ≥2.0 / ≤-2.0 and a false discovery rate of 0.05) that were consistently dysregulated in both early-onset and late-stage CRC and were unique to Hispanics. Ingenuity Pathway Analysis of these Hispanic-specific DEGs revealed significant enrichment of biological pathways involved in cell proliferation and tumor progression. Among the enriched pathways, S100 family signaling emerged as a prominent pathway alongside multiple cell-cycle regulatory pathways. These population-specific pathway dysregulations provide insights into the molecular differences underlying CRC disparities. Dysregulation of S100 signaling has previously been implicated in CRC initiation, progression, metastasis, and therapeutic resistance through interactions with the WNT/β-catenin, RAGE, MAPK, and NF-κB signaling pathways. Consistent with these observations, our analysis identified differential expression of several S100 pathway-associated DEGs, including FOS, NCF1, MAPK10, and MAPK11 in Hispanic CRC. Experimental validation confirmed the expression patterns of these genes in Hispanic CRC tissues and patient-derived organoid models. Notably, FOS exhibited significantly higher expression in the early-stage Hispanic patient-derived organoid model compared with the corresponding NHW organoid model, whereas NCF1, a key regulator of reactive oxygen species production, was significantly upregulated in Hispanic CRC compared with NHW CRC. Overall, our findings identify transcriptomic signatures within a Hispanic cohort that may contribute to CRC disparities and highlight components of the S100 signaling pathway as potential biomarkers for improved screening and risk stratification. Ongoing functional validation using gene knockdown in Hispanic patient-derived organoid models will define the biological significance of these candidate genes and evaluate their potential as biomarkers for precision-based early detection and as therapeutic targets for high-risk CRC populations. Soumya Nair, Sourav Roy. Transcriptomic profiling identifies dysregulation of S100 signaling associated with colorectal cancer disparities within a Hispanic cohort [abstract]. In: Proceedings of the 19th AACR Conference on the Science of Cancer Health Disparities; 2026 Oct 18-21; Atlanta, GA. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2026;35(10 Suppl):Abstract nr A170.