Key genes and pathway differences between serrated polyps and conventional adenomas: insights from multi-omics

Area of Science:

• Genomics
• Molecular Biology
• Cancer Research

Background:

• Colorectal cancer (CRC) arises from distinct pathways: serrated polyps (SP) and traditional adenomas.
• Key cell types and genes driving malignant progression in these pathways remain unidentified.
• A multi-omics approach is needed to elucidate cellular and genetic drivers of CRC transformation.

Purpose of the Study:

• To identify pivotal cell populations and genes involved in the cancerous transformation of SP and traditional adenomas.
• To investigate the distinct cellular and molecular mechanisms underlying serrated and conventional adenoma development.
• To leverage multi-omics data for a comprehensive understanding of CRC pathogenesis.

Main Methods:

• Utilized scPagwas to integrate CRC genome-wide association study (GWAS) data with single-cell sequencing of intestinal polyps.
• Employed transcriptome-wide association studies (TWAS), fine-mapping, and SMR analyses to identify CRC-associated risk genes.
• Conducted cell communication, gene set enrichment analysis (GSEA), Mendelian randomization (MR), and phenome-wide association studies (PheWAS) for pathway and phenotype analysis.

Main Results:

• Serrated-specific cells (SSC) were identified as the primary epithelial population linked to CRC genetic risk.
• Six robust risk genes, including MIR4435-2HG and SMAD9, were identified through integrated TWAS, fine-mapping, and SMR analyses.
• Distinct transcriptional programs and pathway differences (e.g., TGF-β signaling) were observed between SSC and adenoma-specific cells (ASC).

Conclusions:

• Sessile serrated adenomas and conventional adenomas (CA) originate from distinct epithelial cell types (SSC and ASC, respectively).
• Identified lesion-specific molecular features provide a basis for improved preoperative detection of colorectal polyps.
• These findings pave the way for developing adjunct molecular tools for high-risk polyp assessment in colorectal cancer screening.