# Multiomics Signature Reveals Network Regulatory Mechanisms in a CRC Continuum

## TL;DR

This study identifies a methylation signature that helps track the progression of colorectal cancer from early stages to tumors, offering potential for better detection and classification.

## Contribution

The study introduces a novel multiomics methylation signature that distinguishes dysplasia severity and tumor subtypes in CRC progression.

## Key findings

- A methylation signature of 626 regions effectively distinguishes low-grade from high-grade dysplasia in tissue and plasma DNA.
- The signature identifies three CRC tumor subtypes with increasing hypermethylation and one normal cluster.
- The most hypermethylated subtype shows poor survival, high mutation burden, and disrupted transcriptional networks.

## Abstract

Sporadic colorectal cancer (CRC), the third leading cause of cancer-related death globally, arises through a continuum from normal tissue to adenomas, progressing from low-grade (LGD) to high-grade dysplasia (HGD); yet, the early epigenetic drivers of this transition remain unclear. To investigate these events, we profiled LGD and HGD adenomas using EM-seq, and identified a consensus differential methylation signature (DMS) of 626 regions through two independent bioinformatics pipelines. This signature effectively distinguished LGD from HGD in both tissue and plasma-derived cell-free DNA (cfDNA), highlighting specific methylation patterns. Functional annotation indicated enrichment for regulatory elements associated with transcription factor activity and cell signaling. Applying the DMS to the TCGA CRC dataset revealed three tumor subtypes with increasing hypermethylation and one normal cluster. The most hypermethylated subtype exhibited poor survival, high mutation burden, and disrupted transcriptional networks. While overlapping with classical CpG Island Methylator Phenotype (CIMP) categories, the DMS captured a broader spectrum of methylation alterations. These findings suggest that the DMS captures functionally relevant, antecedent epigenetic alterations in CRC progression, enabling the robust stratification of dysplasia severity and tumor subtypes. This signature holds promise for enhancing preclinical detection and molecular classification, and warrants further evaluation in larger prospective cohorts.