Abstract 6422: Colorectal polyp subtype discovery reveals a diverse phenotypic landscape beyond classic histological and developmental pathways

Abstract Background: Bowel cancer screening has increased detection of colorectal precursors. Despite this increased incidence, while transcriptional characterisation and molecular subtyping approaches are well established in colorectal tumours, similar biological discovery approaches in colorectal polyps have been limited. While some multi-omics studies have defined biological patterns aligned to serrated and adenoma histological pathways, these have generally been performed in small collections of samples. This project aims to define, for the first time, a comprehensive map of the phenotypic landscapes in n=2600+ colorectal polyps, using both gene-level and pathway-level approaches in parallel. Approach: Using screening-detected index polyps with detailed clinicopathological data collected as part of the INtegrated TeChnologies for Improved Polyp SurveillencE (INCISE) project, we molecular profiled n=2642 samples using transcriptomics, genomics, digital pathology and immunohistochemistry. Results: Within a training dataset (n=1737), statistically-guided approaches revealed two subgroups, with one subgroup enriched in rectal samples, crypt base signalling, and iCMS2 classification, while the second subgroup is enriched in right sided samples, crypt top signalling and iCMS3 classification. While these subgroups aligned with well-established clinical and biological features, they could each be further subdivided based on phenotypic signalling; resulting in four biologically distinct Polyp Specific Subtypes (PSS) (PSS1: n=403; PSS2: n=380; PSS3: n=382; PSS4: n=476; Mixed: n=96). PSS1 lesions are proliferative, intestinal stem cell-rich, conventional adenomas aligned with iCMS2 signalling, whereas PSS4 polyps display a slower-cycling phenotype with enterocyte cell lineage identity patterns reminiscent of the PDS3 CRC phenotype. PSS2 polyps are heterogeneous in their PDS and iCMS classifications and are repressed for many cancer hallmarks, yet are enriched for KRAS mutant lesions. Histological assessments reveal that almost all serrated polyps are found within a single subtype, PSS3, however these lesions only account for ∼20% of polyps within PSS3, with the remaining ∼80% of samples being adenomas that are transcriptionally indistinguishable from serrated samples. While developed in polyps, the PSS classes were highly predictive of relapse in a localised colorectal cancer cohort, suggesting these early traits can dictate future outcomes in cancer patients. Conclusions: The INCISE dataset has enabled for the first time a comprehensive assessment of the phenotypic landscape of human colorectal polyps, which has revealed at least four biologically distinct molecular subtypes and biological patterns that transcend even the most well-established histological classification and mutational drivers. Citation Format: Natalie C. Fisher, Sudhir Malla, Raheleh Amirkhah, Aula Ammar, Shania Corry, Ryan Byrne, Courtney Bull, Jessica Edwards, Jennifer Hay, Mark Johnstone, Ditte Andersen, Noori Maka, Gerard Lynch, Stephen McSorley, Joanne Edwards, Philip Dunne. Colorectal polyp subtype discovery reveals a diverse phenotypic landscape beyond classic histological and developmental pathways [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 6422.