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<p>Colon adenocarcinoma (COAD) is biologically heterogeneous, yet the relationships among microsatellite instability (MSI), tumour mutational burden (TMB), and intratumour heterogeneity (ITH) remain incompletely understood. We analysed TCGA-COAD transcriptomic, mutational, and clinical data and used GSE39582, GSE17536, and GSE161158 for external validation. MSI tumours showed higher TMB and ITH than MSS tumours. MSI was strongly correlated with TMB, whereas ITH showed weaker correlations with both markers and was associated with poorer overall survival in unadjusted analysis. After adjustment for MSI and TMB, RBM15B, EIF3A, YTHDC1, and FTO remained associated with ITH. ITH-high tumours also showed broad differences in immune-cell transcriptional signatures. In a tumour-purity-balanced sensitivity analysis, seven immune-cell signatures retained directions consistent with the full cohort, supporting selective immune microenvironmental alterations associated with ITH. Integration of differential expression analysis, WGCNA, and GSVA identified 30 heterogeneity-associated genes and 24 ITH-associated metabolic pathways. A seven-pathway metabolic risk model showed reproducible prognostic stratification in TCGA and three independent GEO cohorts. GDSC-based prediction further identified nine ITH-associated candidate compounds. Exploratory in vitro evaluation showed inter-cell-line differences in basal m6A levels, Ribociclib sensitivity, wound closure, apoptotic signals, and treatment-associated m6A changes across colorectal cancer cell lines with distinct molecular backgrounds. These findings indicate that MSI, TMB, and transcriptome-derived ITH capture related but partially non-overlapping features of COAD and support the potential value of ITH-associated molecular and metabolic features for prognostic stratification and candidate drug prioritisation.</p>

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An intratumor heterogeneity-associated metabolic signature predicts prognosis and candidate drug prioritisation in colon adenocarcinoma

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年7月29日

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  • Gan Gao,
  • Yurou Guo,
  • Nannan Liu,
  • Liwei Zhuang

摘要

Colon adenocarcinoma (COAD) is biologically heterogeneous, yet the relationships among microsatellite instability (MSI), tumour mutational burden (TMB), and intratumour heterogeneity (ITH) remain incompletely understood. We analysed TCGA-COAD transcriptomic, mutational, and clinical data and used GSE39582, GSE17536, and GSE161158 for external validation. MSI tumours showed higher TMB and ITH than MSS tumours. MSI was strongly correlated with TMB, whereas ITH showed weaker correlations with both markers and was associated with poorer overall survival in unadjusted analysis. After adjustment for MSI and TMB, RBM15B, EIF3A, YTHDC1, and FTO remained associated with ITH. ITH-high tumours also showed broad differences in immune-cell transcriptional signatures. In a tumour-purity-balanced sensitivity analysis, seven immune-cell signatures retained directions consistent with the full cohort, supporting selective immune microenvironmental alterations associated with ITH. Integration of differential expression analysis, WGCNA, and GSVA identified 30 heterogeneity-associated genes and 24 ITH-associated metabolic pathways. A seven-pathway metabolic risk model showed reproducible prognostic stratification in TCGA and three independent GEO cohorts. GDSC-based prediction further identified nine ITH-associated candidate compounds. Exploratory in vitro evaluation showed inter-cell-line differences in basal m6A levels, Ribociclib sensitivity, wound closure, apoptotic signals, and treatment-associated m6A changes across colorectal cancer cell lines with distinct molecular backgrounds. These findings indicate that MSI, TMB, and transcriptome-derived ITH capture related but partially non-overlapping features of COAD and support the potential value of ITH-associated molecular and metabolic features for prognostic stratification and candidate drug prioritisation.