140P - Colorectal adenoma subtypes exhibit distinct molecular profiles- implications to early detection

Background

Colorectal adenomas (AA) are pre-cursors for 85% of the cancers. Methylation and copy-number alterations are well described in colorectal cancer (CRC) context. We aimed to investigate these signals on AA sub-types.

Methods

Whole-genome Enzymatic Sequencing was performed on advanced adenoma (AA) and adjacent control (CNT) tissues of serrated (14), tubular (26), tubulovillous (24) and villous (10) patient samples, alongside colorectal cancer (CRC) stage I samples (23). Differential methylation analysis pipeline was applied, first to identify regions that are significantly altered between all AA subgroups and CNT tissue and then further investigated for sub-type and CRC I level differences. Additionally, mutation and copy-number alteration (CNA) detection were performed, alongside pathway enrichment.

Results

Initial differential methylation analysis revealed 7725 regions significantly altered between AA and CNT tissue. 137 and 2093 and 91 of those were hypermethylated between serrated vs tubular, serrated vs tubulovillous, tubular vs tubulovillous sub-types respectively. Main pathways, differentiating serrated adenomas from the rest, belong to cAMP signalling, regulation of pluripotency of stem cells, while regions separating tubular and tubulovillous were enriched for WNT signalling. These differential signals could not be seen in stage I CRC samples, which presented CNT-like methylation. The CNA signals were mostly present in tubular or tubulovillous samples. The most frequent signals could be seen in chr7, 12, 19 and 20. Majority of CRC I exhibited CNA in chr 7, 8 and 20, indicating difference processes to be in place between AA and CRC I progression. Differences could also be observed on sub-type level, when looking at tumour mutational burden and specific mutations in APC and KRAS genes.

Conclusions

Colorectal adenoma histological subtypes show distinctly different methylation, CNA and mutational signals, between groups and compared CRC I. These findings are especially important when developing early detection or cancer prevention tests trying to capture adenoma (sub-type level) signatures. These results have been followed by plasma-based biomarker detection studies for pre-cancer screening intent.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

Universal Diagnostics S.A.

Funding

Universal Diagnostics S.A.

Disclosure

F.M. Mancuso, P. Canal Noguer, K. Kruusmaa: Financial Interests, Personal, Full or part-time Employment: Universal Diagnostics.