O189: Exploring the polyclonal origins of intestinal tumours

Abstract Introduction Some reports have shown that a proportion of intestinal tumours in the human colorectal cancer (CRC) predisposition syndrome Familial Adenomatous Polyposis (FAP) may have a multi-ancestral structure, challenging the widely-held monoclonal theory of tumour initiation. The nature of these polyclonal tumours and the reasons for their existence have not yet been elucidated. Methods Intestinal tumorigenesis was promoted through chemical mutagenesis in Villin-CreERT2-Apcfl/+ mice containing a multicolour reporter. The clonal status of tumours was determined with confocal microscopy. Targeted cancer driver sequencing was performed to determine if certain driver mutations were associated with monoclonal or polyclonal routes of tumour formation. Finally, transcriptomic analysis was performed to identify differentially expressed pathways. Results Confocal imaging reveals that more than 40% of tumours are heterotypic, and therefore polyclonal. Transcriptomic profiling of clones within these tumours demonstrates a non-cell autonomous interplay between Myc and Ras pathways, suggestive of oncogenic cooperation between adjacent clones. Strikingly, sequencing reveals that the nature of the Apc mutation dictates clonal architecture. Using a large publicly available dataset of sporadic CRCs, these mutational differences are confirmed, suggesting a role for differential Wnt activation in tumour initiation. Conclusions Taken together, these data suggest that a significant proportion of intestinal tumours arise through clonal cooperation, and that early RAS/MAPK pathway activation may obviate the need for this. Clonal cooperation appears to be at play not just in FAP but also in sporadic CRCs. Uncovering this mechanism may pave the way for therapeutics aimed at reducing tumour burden in patients with FAP.