Epigenetic reprogramming by promoter hypomethylation is linked to aberrant gene expression and transcriptomic plasticity in colorectal cancer

Promoter hypomethylation in 1,183 colorectal cancer samples defines two largely non-overlapping CIMP-negative subgroups marked by APOLD1 or ELF5 overexpression and distinct cell states.

• Why it matters: CRC shows high phenotypic plasticity, but how DNA methylation shapes cancer cell-intrinsic transcriptomic heterogeneity and metastatic cell states is unclear.
• What they did: The study linked DNA methylation to transcriptomic heterogeneity across multiregional primary tumors, liver metastases, and tumor organoids, identifying promoter hypomethylation–expression associations.
• The result: APOLD1 tumors were highly proliferative, while ELF5 tumors were slow-cycling and linked to good survival in early-stage disease, with ELF5 metastases showing ex vivo sensitivity to PI3K/mTOR inhibition.

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