Multiregional transcriptomics identifies congruent consensus subtypes with prognostic value beyond tumor heterogeneity of colorectal cancer

Jonas Langerud, Ina A. Eilertsen, Seyed H. Moosavi, Solveig M. K. Klokkerud, Henrik M. Reims, Ingeborg F. Backe, Merete Hektoen, Ole H. Sjo, Marine Jeanmougin, Sabine Tejpar, Arild Nesbakken, Ragnhild A. Lothe and Anita Sveen ()
Additional contact information
Jonas Langerud: Oslo University Hospital
Ina A. Eilertsen: Oslo University Hospital
Seyed H. Moosavi: Oslo University Hospital
Solveig M. K. Klokkerud: Oslo University Hospital
Henrik M. Reims: Oslo University Hospital
Ingeborg F. Backe: Oslo University Hospital
Merete Hektoen: Oslo University Hospital
Ole H. Sjo: Oslo University Hospital
Marine Jeanmougin: Oslo University Hospital
Sabine Tejpar: Katholieke Universiteit Leuven
Arild Nesbakken: University of Oslo
Ragnhild A. Lothe: Oslo University Hospital
Anita Sveen: Oslo University Hospital

Nature Communications, 2024, vol. 15, issue 1, 1-16

Abstract: Abstract Intra-tumor heterogeneity compromises the clinical value of transcriptomic classifications of colorectal cancer. We investigated the prognostic effect of transcriptomic heterogeneity and the potential for classifications less vulnerable to heterogeneity in a single-hospital series of 1093 tumor samples from 692 patients, including multiregional samples from 98 primary tumors and 35 primary-metastasis sets. We show that intra-tumor heterogeneity of the consensus molecular subtypes (CMS) is frequent and has poor-prognostic associations independently of tumor microenvironment markers. Multiregional transcriptomics uncover cancer cell-intrinsic and low-heterogeneity signals that recapitulate the intrinsic CMSs proposed by single-cell sequencing. Further subclassification identifies congruent CMSs that explain a larger proportion of variation in patient survival than intra-tumor heterogeneity. Plasticity is indicated by discordant intrinsic phenotypes of matched primary and metastatic tumors. We conclude that multiregional sampling reconciles the prognostic power of tumor classifications from single-cell and bulk transcriptomics in the context of intra-tumor heterogeneity, and phenotypic plasticity challenges the reconciliation of primary and metastatic subtypes.

Date: 2024
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DOI: 10.1038/s41467-024-48706-2

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