转录组和SNP分析揭示结直肠癌中的早发性和种族相关性特征

Colorectal cancer (CRC) is the second deadliest cancer in the United States, with early-onset (age < 50) cases rising significantly over the past decade. Although early-stage (I/II) CRC is treatable with a higher survival rate, these tumors often present with poor outcomes, particularly among minority groups like Hispanics. Hispanics experience higher rates of late-stage (III/IV) diagnosis than Non-Hispanic Whites (NHW), suggesting that both genetic and non-genetic factors may contribute to this disparity. To identify potential biological contributors to early-onset and ethnicity-associated disparities, we investigated transcriptomic and genotypic biomarkers that may improve screening and prognosis. We performed RNA sequencing on CRC tissues and normal tissues adjacent to the tumor (NATs) from Hispanic and NHW patients. Gene level quantification was obtained using two independent pipelines - Rsubread and Salmon. DESeq2 analysis, identified 996 differentially expressed genes (DEGs, log2 foldchange ≥ 2.0 and ≤ -2.0 and a false discovery rate of 0.05) common to both the tools between CRC and NAT samples. When analyzed within each ethnic cohort 1251 DEGs were identified in Hispanics and 899 in NHWs. Notably, within the Hispanic group, 311 DEGs were common between early-onset and late-stage Hispanic CRC samples compared to NHWs. Pathway enrichment analyses using Ingenuity Pathway Analysis and Gene Set Enrichment Analysis revealed significant dysregulation of the cell cycle regulatory pathways including the Mitotic G2-G2/M phases, Mitotic G1 phase and G1/S transition, as well as Cell cycle checkpoints, pathways critical for apoptosis, and tumor progression. Interaction analysis further revealed 138 DEGs (log2 foldchange ≥ 1.0 and ≤ -1.0 and p- value ≤ 0.05) display a significant association with CRC occurrence in the Hispanic cohort. Additionally, variant discovery and annotation using the Genome Analysis Toolkit (GATK) and Snpeff workflows, identified 383 variants either unique to or abundant in Hispanic CRC samples and predicted to have high or moderate functional impact. Among these, analysis of SNP-associated genes revealed that the downregulation of NCF1, carrying the rs10614 variant, was significantly correlated with tumor status in the Hispanic CRC cohort. Reduced NCF1 expression is associated with ROS deficiency induced colitis-mediated tumorigenesis. Overall, our findings reveal Hispanic-specific transcriptomic and genotypic signatures that may underlie CRC disparities and identify potential biomarkers for improved screening. Further functional studies in Hispanic patient tissues and patient-derived organoid models will help elucidate the biological roles of these genes and variants, ultimately promoting the development of early-screening strategies and targeted therapies for high-risk populations.