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

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

*Corresponding author for this work

Research output: Contribution to journalArticle

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.
Original languageEnglish
Pages (from-to)1092-1103
Number of pages12
JournalGut
Volume69
Early online date28 Sep 2019
DOIs
Publication statusPublished - 2020

Keywords

  • AXIN2
  • colorectal cancer
  • molecular biomarker
  • stratification
  • Wnt signalling
  • RNF43
  • COLON
  • FUSIONS
  • MUTATIONS
  • TUMORS

ASJC Scopus subject areas

  • Gastroenterology

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    Kleeman, S. O., Koelzer, V. H., Jones, H. J. S., Vazquez, E. G., Davis, H., East, J. E., Arnold, R., Koppens, M. A. J., Blake, A., Domingo, E., Cunningham, C., Beggs, A. D., Pestinger, V., Loughrey, M. B., Wang, L-M., Lannagan, T. R. M., Woods, S. L., Worthley, D., The S:CORT Consortium, ... Leedham, S. J. (2020). Exploiting differential Wnt target gene expression to generate a molecular biomarker for colorectal cancer stratification. Gut, 69, 1092-1103. https://doi.org/10.1136/gutjnl-2019-319126