Ontology-led molecular classification of colorectal cancer uncovers distinct tumour subtypes with therapeutic and clinical relevance

Utilising transcriptional gene signatures from the gene set database, pathway-level unsupervised class discovery and classifier development from KRAS mutant CRC revealed three groups, named KM1, KM2 and KM3 (Chapter 4). The biological and prognostic evaluation revealed that KM1 were MYC driven cell-cycle activated, tubular, LGR5+ stem-like tumours with good prognosis, KM2 were stromal/immune rich, of serrated origin and regenerative stem-like biology with diverse pathway activation, including TGF-β activation, EMT and immune responses, and an intermediate prognosis.

A novel finding of this classification was KM3, with large repression of pathways such as cell cycle, EMT, KRAS signalling activity, but elevation in neurotransmitter- and enteroendocrine-like biology, highly differentiated tumours, the potential inclusion of epigenetic dysregulation in maintaining stem plasticity, and a clinically worse prognosis (Chapter 5).<br><br>In summary, this thesis provides a new pathway-driven classifier for CRC that includes a novel, previously uncharacterised subset of CRC subtype as KM3 with clinically poor outcome, which provides a unique biological phenotype that needs further research to translate into the clinic.<br>