Colorectal Adenoma Subtypes Exhibit Signature Molecular Profiles: Unique Insights into the Microenvironment of Advanced Precancerous Lesions for Early Detection Applications

Background: Colorectal cancer (CRC) is characterized by uncontrolled growth of malignant colonic or rectal crypt epithelium. About 85% of CRCs evolve through a stepwise progression from dysplastic colorectal adenomas. Better understanding of the evolution from adenoma to carcinoma can provide a window of opportunity not only for early detection and therapeutic intervention but potentially also for cancer prevention strategies. Methods: This study investigates the heterogeneous methylation, copy number alteration (CNA), and mutation signals of histological adenoma subtypes in the context of progression from normal colon to Advanced Precancerous Lesions (APLs) and early-stage CRC. Results: Differential methylation analysis revealed 2,321 significantly altered regions among APLs: 137 hypermethylated regions between serrated vs. tubular, 2,093 between serrated vs. tubulovillous, and 91 between tubular vs. tubulovillous adenoma subtypes, respectively. The most differentiating pathways for serrated adenomas belonged to cAMP signaling and regulation of pluripotency of stem cells, while regions separating tubular and tubulovillous subtypes were enriched for WNT signaling. CNA events were mostly present in tubular or tubulovillous adenomas, with the most frequent signals seen in chromosomes 7, 12, 19 and 20. In contrast, early-stage CRC exhibited signals in chromosomes 7, 8 and 20, indicating different processes between APL and early-stage CRC. Mutations reinforce subtype level differences, showing specific alterations in each subtype. Conclusions: These findings are especially important for developing early detection or cancer prevention tests trying to capture adenoma signatures.