Multiomics Signature Reveals Network Regulatory Mechanisms in a CRC Continuum.

Area of Science:

• Epigenetics
• Cancer Biology
• Genomics

Background:

• Sporadic colorectal cancer (CRC) is a major global health concern, with progression from normal tissue through low-grade dysplasia (LGD) to high-grade dysplasia (HGD) preceding invasive cancer.
• The early epigenetic events driving the transition from LGD to HGD in CRC remain poorly understood.

Purpose of the Study:

• To identify early epigenetic drivers of colorectal cancer progression.
• To develop a DNA methylation signature for stratifying dysplasia severity and classifying CRC subtypes.

Main Methods:

• Utilized EM-seq to profile DNA methylation in LGD and HGD adenomas.
• Employed two independent bioinformatics pipelines to identify a consensus differential methylation signature (DMS) of 626 regions.
• Validated the DMS in tissue and plasma-derived cell-free DNA (cfDNA) and applied it to The Cancer Genome Atlas (TCGA) CRC dataset.

Main Results:

• Identified a 626-region DMS that effectively distinguishes LGD from HGD in both tissue and cfDNA.
• Functional annotation revealed enrichment of DMS in regulatory elements linked to transcription factor activity and cell signaling.
• The DMS classified TCGA CRC samples into three hypermethylated tumor subtypes and one normal cluster, with the most hypermethylated subtype showing poor survival and high mutation burden.

Conclusions:

• The developed DMS captures functionally relevant, antecedent epigenetic alterations in CRC progression.
• This signature enables robust stratification of dysplasia severity and CRC tumor subtypes.
• The DMS shows promise for enhancing preclinical CRC detection and molecular classification.