Exploiting differential Wnt target gene expression to generate a molecular biomarker for colorectal cancer stratification

Sam O Kleeman, Viktor H Koelzer, Helen Js Jones, Ester Gil Vazquez, Hayley Davis, James E East, Roland Arnold, Martijn Aj Koppens, Andrew Blake, Enric Domingo, Chris Cunningham, Andrew D Beggs, Valerie Pestinger, Maurice B Loughrey, Lai-Mun Wang, Tamsin Rm Lannagan, Susan L Woods, Daniel Worthley, S Cort Consortium, Ian TomlinsonPhilip D Dunne, Timothy Maughan, Simon J Leedham

Research output: Contribution to journalArticlepeer-review

16 Citations (Scopus)
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OBJECTIVE: Pathological Wnt pathway activation is a conserved hallmark of colorectal cancer. Wnt-activating mutations can be divided into: i) ligand-independent (LI) alterations in intracellular signal transduction proteins (Adenomatous polyposis coli, β-catenin), causing constitutive pathway activation and ii) ligand-dependent (LD) mutations affecting the synergistic R-Spondin axis (RNF43, RSPO-fusions) acting through amplification of endogenous Wnt signal transmembrane transduction. Our aim was to exploit differential Wnt target gene expression to generate a mutation-agnostic biomarker for LD tumours.

DESIGN: We undertook harmonised multi-omic analysis of discovery (n=684) and validation cohorts (n=578) of colorectal tumours collated from publicly available data and the Stratification in Colorectal Cancer Consortium. We used mutation data to establish molecular ground truth and subdivide lesions into LI/LD tumour subsets. We contrasted transcriptional, methylation, morphological and clinical characteristics between groups.

RESULTS: Wnt disrupting mutations were mutually exclusive. Desmoplastic stromal upregulation of RSPO may compensate for absence of epithelial mutation in a subset of stromal-rich tumours. Key Wnt negative regulator genes were differentially expressed between LD/LI tumours, with targeted hypermethylation of some genes (AXIN2, NKD1) occurring even in CIMP-negative LD cancers. AXIN2 mRNA expression was used as a discriminatory molecular biomarker to distinguish LD/LI tumours (area under the curve >0.93).

CONCLUSIONS: Epigenetic suppression of appropriate Wnt negative feedback loops is selectively advantageous in LD tumours and differential AXIN2 expression in LD/LI lesions can be exploited as a molecular biomarker. Distinguishing between LD/LI tumour types is important; patients with LD tumours retain sensitivity to Wnt ligand inhibition and may be stratified at diagnosis to clinical trials of Porcupine inhibitors.

Original languageEnglish
Pages (from-to)1092-1103
Issue number6
Publication statusPublished - 28 Sept 2019


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