Abstract
BACKGROUND: As two major colorectal cancer (CRC) pathways, serrated polyps (SP) and traditional adenomas show distinct cellular and molecular features, yet the key cell types and causal genes driving their malignant progression remain unknown. This study aimed to investigate the pivotal cellular groups and genes in the cancerous transformation of SP and traditional adenomas using multi-omics approach. METHODS: scPagwas (pathway-based polygenic regression method) was used to integrate CRC genome-wide association study (GWAS) data with single-cell sequencing in intestinal polyps, identifying cell groups and genes associated with phenotypic traits. Transcriptome-wide association studies (TWAS) analysis and fine-mapping, based on summary-level expression quantitative trait loci (eQTLs), were utilized to further screen for CRC-associated risk genes. Cell communication and gene set enrichment analysis (GSEA) determined receptor differences and pathway expression variations between SP and traditional adenomas. Mendelian randomization (MR) and phenome-wide association study analyses were used to investigate the connections between crucial genes and specific phenotypes. RESULTS: Serrated-specific cells (SSC) were identified as the epithelial population most strongly associated with CRC genetic risk, whereas adenoma-specific cells (ASC) showed no significant enrichment. Integrating TWAS, fine-mapping, and SMR analyses, we identified six robust risk genes-MIR4435-2HG, SMAD9, PITPNC1, LIMCH1, POU2AF2, and HES6. SSC and ASC displayed distinct transcriptional programs, with pathway analysis highlighting differences in TGF-β signaling and oxidative phosphorylation. Notably, MIR4435-2HG and SMAD9 emerged as particularly important genes, as they were consistently identified across scPagwas, TWAS and fine-mapping analyses, exhibited strong and contrasting specificity for SSC cells and ASC cells respectively, and demonstrated clear pathway relevance to serrated and conventional adenoma biology. CONCLUSIONS: This multi-omics analysis reveals that the development of sessile serrated adenomas and conventional adenomas (CA) is associated with distinct epithelial origins, with serrated lesions linked to SSC cells and CA linked to ASC cells. These lesion-specific molecular features provide a mechanistic basis for improving preoperative detection and for developing adjunct molecular tools for high-risk polyp assessment.