Malla, Sudhir B. and Byrne, Ryan M. and Lafarge, Maxime W. and Corry, Shania M. and Fisher, Natalie C. and Tsantoulis, Petros K. and Mills, Megan L. and Ridgway, Rachel A. and Lannagan, Tamsin R. M. and Najumudeen, Arafath K. and Gilroy, Kathryn L. and Amirkhah, Raheleh and Maguire, Sarah L. and Mulholland, Eoghan J. and Belnoue-Davis, Hayley L. and Grassi, Elena and Viviani, Marco and Rogan, Emily and Redmond, Keara L. and Sakhnevych, Svetlana and McCooey, Aoife J. and Bull, Courtney and Hoey, Emily and Sinevici, Nicoleta and Hall, Holly and Ahmaderaghi, Baharak and Domingo, Enric and Blake, Andrew and Richman, Susan D. and Isella, Claudio and Miller, Crispin and Bertotti, Andrea and Trusolino, Livio and Loughrey, Maurice B. and Kerr, Emma M. and Tejpar, Sabine and S:CORT consortium and Maughan, Timothy S. and Lawler, Mark and Campbell, Andrew D. and Leedham, Simon J. and Koelzer, Viktor H. and Sansom, Owen J. and Dunne, Philip D. (2024) Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer. Nature Genetics, 56 (3). pp. 458-472. ISSN 1061-4036

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Abstract

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. These PDS3 phenotypic traits are evident across numerous bulk and single-cell datasets, and demark a series of subtle biological states that are currently under-represented in pre-clinical models and are not identified using existing subtyping classifiers.

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Title Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer
Creators Malla, Sudhir B. and Byrne, Ryan M. and Lafarge, Maxime W. and Corry, Shania M. and Fisher, Natalie C. and Tsantoulis, Petros K. and Mills, Megan L. and Ridgway, Rachel A. and Lannagan, Tamsin R. M. and Najumudeen, Arafath K. and Gilroy, Kathryn L. and Amirkhah, Raheleh and Maguire, Sarah L. and Mulholland, Eoghan J. and Belnoue-Davis, Hayley L. and Grassi, Elena and Viviani, Marco and Rogan, Emily and Redmond, Keara L. and Sakhnevych, Svetlana and McCooey, Aoife J. and Bull, Courtney and Hoey, Emily and Sinevici, Nicoleta and Hall, Holly and Ahmaderaghi, Baharak and Domingo, Enric and Blake, Andrew and Richman, Susan D. and Isella, Claudio and Miller, Crispin and Bertotti, Andrea and Trusolino, Livio and Loughrey, Maurice B. and Kerr, Emma M. and Tejpar, Sabine and S:CORT consortium and Maughan, Timothy S. and Lawler, Mark and Campbell, Andrew D. and Leedham, Simon J. and Koelzer, Viktor H. and Sansom, Owen J. and Dunne, Philip D.
Identification Number 10.1038/s41588-024-01654-5
Date March 2024
Divisions College of Medical Veterinary and Life Sciences > School of Cancer Sciences
Publisher Nature Research
Additional Information Correction at https://eprints.gla.ac.uk/328016/. This work was supported by a Cancer Research UK (CRUK) early detection grant (P.D.D.; A29834), a CRUK International accelerator program (ACRCelerate) (P.D.D., O.J.S., S.J.L., M.L. and T.S.M.; A26825), a UK Medical Research Council (MRC) and CRUK co-funded Stratified Medicine Consortium program grant (S:CORT) (P.D.D., M.L. and T.S.M.; MR/M016587/1), an MRC National Mouse Genetics Network program (P.D.D. and S.J.L.; MC_PC_21042), CRUK Beatson institute funding (O.J.S.; A21139, A17196 and A31287). CRUK program grant (S.J.L.; DRCNPG-Jun22\100002), Lee Placito Medical Research Fund (E.J.M.; University of Oxford), Health Data Research UK Grant (M.L.), AIRC– Associazione Italiana per la Ricerca sul Cancro, Investigator Grants 20697 (A.B.) and 22802 (L.T.), Promedica Foundation F-87701-41-01 (V.H.K.), a My First AIRC Grant (C.I.; ID 19047); AIRC 5×1000 grant 21091 (L.T., A.B.); European Research Council Consolidator Grant 724748 BEAT (A.B.); H2020 grant agreement no. 754923 COLOSSUS (L.T.); H2020 INFRAIA grant agreement no. 731105 EDIReX (A.B.); Fondazione Piemontese per la Ricerca sul Cancro-ONLUS, 5×1000 Ministero della Salute 2016 (L.T.); BOF-Fundamental Clinical Research mandate from KU Leuven and by the Belgian Foundation Against Cancer (S.T.; FAF-C/2018/1301).
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