Abstract
BACKGROUND: Serrated colorectal cancer (SCC) is a rare and aggressive subtype of colorectal cancer. Identifying SCC is crucial due to its high mortality rate and limited therapeutic options. Traditional methods to identify BRAF hotspot mutations and MLH1 methylation are insufficient in clinical practice. This study aims to explore the WNT pathway alterations in the CRC and to develop a WNT-derived subtyping model to identify SCC patients by using multi-OMICs data. METHODS: We included multi-omics data of 1751 colorectal cancer patients from the TCGA and GEO databases, and single-cell transcriptome data of 33 normal and cancer tissues from the SMC study cohort. The comprehensive study process incorporated unsupervised clustering, enrichment analysis, and statistical analysis. RESULTS: In this study, we investigated WNT pathway alterations in SCC by integrating both bulk and single-cell data into the multi-OMICs framework. The SCC subtype demonstrated significant WNT pathway heterogeneity and a more stable genomic structure. These findings support the development of a WNT-derived subtyping model that accurately identifies SCC patients across different CRC cohorts. In addition, the SCC subtype also presented a distinct immune microenvironment characterized by CD8(+) T cell exhaustion. Finally, we utilized drug perturbation data to explore the potential drug targets for this severe cancer subtype. CONCLUSION: We developed a WNT-derived subtyping method to identify SCC from canonical CRC, which enhances the molecular understanding of this severe cancer subtype and provides potential therapeutic strategies. Our findings suggest that SCC patients may benefit from the HSP90 inhibitor NVP-AUY922, highlighting its potential as a targeted therapy.