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

Nat Commun. 2024 May 21;15(1):4342. doi: 10.1038/s41467-024-48706-2.


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.

MeSH terms

  • Aged
  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / metabolism
  • Colorectal Neoplasms* / classification
  • Colorectal Neoplasms* / genetics
  • Colorectal Neoplasms* / mortality
  • Colorectal Neoplasms* / pathology
  • Female
  • Gene Expression Profiling / methods
  • Gene Expression Regulation, Neoplastic*
  • Genetic Heterogeneity*
  • Humans
  • Male
  • Middle Aged
  • Prognosis
  • Single-Cell Analysis / methods
  • Transcriptome*
  • Tumor Microenvironment* / genetics