Sudhir B Malla, Ryan M Byrne, Maxime W Lafarge, Shania M Corry, Natalie C Fisher, Petros K Tsantoulis, Megan L Mills, Rachel A Ridgway, Tamsin R M Lannagan, Arafath K Najumudeen, Kathryn L Gilroy, Raheleh Amirkhah, Sarah L Maguire, Eoghan J Mulholland, Hayley L Belnoue-Davis, Elena Grassi, Marco Viviani, Emily Rogan, Keara L Redmond, Svetlana Sakhnevych, Aoife J McCooey, Courtney Bull, Emily Hoey, Nicoleta Sinevici, Holly Hall, Baharak Ahmaderaghi, Enric Domingo, Andrew Blake, Susan D Richman, Claudio Isella, Crispin Miller, Andrea Bertotti, Livio Trusolino, Maurice B Loughrey, Emma M Kerr, Sabine Tejpar, Timothy S Maughan, Mark Lawler, Andrew D Campbell, Simon J Leedham, Viktor H Koelzer, Owen J Sansom, Philip D Dunne
Molecular stratification using gene-level transcriptional data has identified subtypes with distinctive genotypic and phenotypic traits, as exemplified by the consensus molecular subtypes (CMS) in colorectal cancer (CRC). Here, rather than gene-level data, we make use of gene ontology and biological activation state information for initial molecular class discovery. In doing so, we defined three pathway-derived subtypes (PDS) in CRC: PDS1 tumors, which are canonical/LGR5+ stem-rich, highly proliferative and display good prognosis; PDS2 tumors, which are regenerative/ANXA1+ stem-rich, with elevated stromal and immune tumor microenvironmental lineages; and PDS3 tumors, which represent a previously overlooked slow-cycling subset of tumors within CMS2 with reduced stem populations and increased differentiated lineages, particularly enterocytes and enteroendocrine cells, yet display the worst prognosis in locally advanced disease...
February 13, 2024: Nature Genetics