Exploiting differential Wnt target gene expression to generate a molecular biomarker for colorectal cancer stratification. Issue 6 (28th September 2019)

• Record Type: Journal Article
• Authors: Kleeman, Sam O; Koelzer, Viktor H; Jones, Helen JS; Vazquez, Ester Gil; Davis, Hayley; East, James E; Arnold, Roland; Koppens, Martijn AJ; Blake, Andrew; Domingo, Enric; Cunningham, Chris; Beggs, Andrew D; Pestinger, Valerie; Loughrey, Maurice B; Wang, Lai-Mun; Lannagan, Tamsin RM; Woods, Susan L; Worthley, Daniel; Tomlinson, Ian; Dunne, Philip D; Maughan, Timothy; Leedham, Simon J
• Other Names: collab.
• Is Part Of: Gut. Volume 69:Issue 6(2020)
• Page Start: 1092
• Page End: 1103
• Publication Date: 2019-09-28
• Subjects: colorectal cancer -- Wnt signalling -- stratification -- AXIN2 -- molecular biomarker; Gastroenterology -- Periodicals; 616.33
• DOI: 10.1136/gutjnl-2019-319126
• Languages: English
• ISSNs: 0017-5749

Abstract

Abstract : 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.