Deep Pathomic Learning Defines Prognostic Subtypes and Molecular Drivers in Colorectal Cancer

TL;DR

This study introduces a deep learning model using histopathological images to accurately predict colorectal cancer prognosis, outperforming traditional staging and revealing molecular insights for personalized treatment.

Contribution

Developed and validated the TDAM-CRC model that integrates multi-omics data for improved prognostic prediction and molecular understanding in colorectal cancer.

Findings

TDAM-CRC outperforms existing models and clinical staging.

High-risk subtype linked to metabolic reprogramming and immunosuppression.

MRPL37 identified as an independent prognostic biomarker.

Abstract

Precise prognostic stratification of colorectal cancer (CRC) remains a major clinical challenge due to its high heterogeneity. The conventional TNM staging system is inadequate for personalized medicine. We aimed to develop and validate a novel multiple instance learning model TDAM-CRC using histopathological whole-slide images for accurate prognostic prediction and to uncover its underlying molecular mechanisms. We trained the model on the TCGA discovery cohort (n=581), validated it in an independent external cohort (n=1031), and further we integrated multi-omics data to improve model interpretability and identify novel prognostic biomarkers. The results demonstrated that the TDAM-CRC achieved robust risk stratification in both cohorts. Its predictive performance significantly outperformed the conventional clinical staging system and multiple state-of-the-art models. The TDAM-CRC risk score was confirmed as an independent prognostic factor in multivariable analysis. Multi-omics analysis revealed that the high-risk subtype is closely associated with metabolic reprogramming and an immunosuppressive tumor microenvironment. Through interaction network analysis, we identified and validated Mitochondrial Ribosomal Protein L37 (MRPL37) as a key hub gene linking deep pathomic features to clinical prognosis. We found that high expression of MRPL37, driven by promoter hypomethylation, serves as an independent biomarker of favorable prognosis. Finally, we constructed a nomogram incorporating the TDAM-CRC risk score and clinical factors to provide a precise and interpretable clinical decision-making tool for CRC patients. Our AI-driven pathological model TDAM-CRC provides a robust tool for improved CRC risk stratification, reveals new molecular targets, and facilitates personalized clinical decision-making.