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Type: Journal article
Title: Exploiting differential Wnt target gene expression to generate a molecular biomarker for colorectal cancer stratification
Author: Kleeman, S.O.
Koelzer, V.H.
Jones, H.J.
Vazquez, E.G.
Davis, H.
East, J.E.
Arnold, R.
Koppens, M.A.
Blake, A.
Domingo, E.
Cunningham, C.
Beggs, A.D.
Pestinger, V.
Loughrey, M.B.
Wang, L.-M.
Lannagan, T.R.
Woods, S.L.
Worthley, D.
Consortium, S.C.
Tomlinson, I.
et al.
Citation: Gut, 2019; 69(6):1092-1103
Publisher: BMJ
Issue Date: 2019
ISSN: 0017-5749
Statement of
Sam O. Kleeman, Viktor H. Koelzer, Helen J.S. Jones ... Susan Woods ... Daniel Worthley ... Tamsin Lannagan ... et al.
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.
Keywords: AXIN2
Wnt signalling
colorectal cancer
molecular biomarker
Rights: © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ. This is an open access article distributed in accordance with the Creative Commons Attribution 4.0 Unported (CC BY 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. See: https:// creativecommons. org/ licenses/ by/ 4. 0/.
DOI: 10.1136/gutjnl-2019-319126
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