Pathway level subtyping identifies a slow-cycling biological phenotype associated with poor clinical outcomes in colorectal cancer

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.

Metadata

Authors/Creators:

Malla, S.B. https://orcid.org/0000-0001-5862-3815
Byrne, R.M. https://orcid.org/0000-0001-6505-6345
Lafarge, M.W.
Corry, S.M.
Fisher, N.C. https://orcid.org/0000-0003-1769-7468
Tsantoulis, P.K. https://orcid.org/0000-0003-3613-6682
Mills, M.L.
Ridgway, R.A. https://orcid.org/0000-0003-0198-8244
Lannagan, T.R.M.
Najumudeen, A.K.
Gilroy, K.L. https://orcid.org/0000-0003-4607-194X
Amirkhah, R. https://orcid.org/0000-0003-3494-271X
Maguire, S.L. https://orcid.org/0000-0001-6654-3620
Mulholland, E.J. https://orcid.org/0000-0002-1200-9825
Belnoue-Davis, H.L. https://orcid.org/0000-0003-2914-4932
Grassi, E. https://orcid.org/0000-0003-1066-927X
Viviani, M. https://orcid.org/0000-0003-4698-8870
Rogan, E.
Redmond, K.L.
Sakhnevych, S.
McCooey, A.J.
Bull, C.
Hoey, E.
Sinevici, N.
Hall, H. https://orcid.org/0000-0003-2779-2565
Ahmaderaghi, B. https://orcid.org/0000-0003-4166-6290
Domingo, E. https://orcid.org/0000-0003-4390-8767
Blake, A.
Richman, S.D. https://orcid.org/0000-0003-3993-5041
Isella, C.
Miller, C.
Bertotti, A.
Trusolino, L. https://orcid.org/0000-0002-6379-3365
Loughrey, M.B.
Kerr, E.M. https://orcid.org/0000-0002-1952-4213
Tejpar, S. https://orcid.org/0000-0003-3281-8643
Maughan, T.S.
Lawler, M.
Campbell, A.D. https://orcid.org/0000-0003-3930-1276
Leedham, S.J. https://orcid.org/0000-0003-1476-6982
Koelzer, V.H. https://orcid.org/0000-0001-9206-4885
Sansom, O.J. https://orcid.org/0000-0001-9540-3010
Dunne, P.D. https://orcid.org/0000-0001-9160-283X

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