Kleeman SO, Koelzer VH, Jones HJS, et al. - A harmonized multi-omic analysis of identification (n = 684) and validation cohorts (n = 578) of colorectal tumors grouped from publicly accessible data and the Stratification in Colorectal Cancer Consortium was undertaken in order to exploit differential Wnt target gene expression to create a mutation-agnostic biomarker for ligand-dependent (LD) tumors. Wnt disrupting mutations were respectively exclusive. In a subset of stromal-rich tumors, desmoplastic stromal upregulation of RSPO may counterbalance for the absence of epithelial mutation. With targeted hypermethylation of some genes (AXIN2, NKD1) occurring even in CpG island methylator phenotype-negative LD cancers, Key Wnt negative regulator genes were differentially expressed between LD/ligand-independent (LI) tumors. AXIN2 mRNA expression was utilized as a differentiating molecular biomarker to discriminate LD/LI tumors. Hence, in conclusion, epigenetic suppression of relevant Wnt negative feedback loops is particularly beneficial in LD tumors and differential AXIN2 expression in LD/LI lesions could be exploited as a molecular biomarker. Differentiating between LD/LI tumor types is necessary. Moreover, individuals with LD tumors preserve sensitivity to Wnt ligand inhibition and could be stratified at diagnosis to clinical examinations of Porcupine inhibitors.