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BMC Cancer
Published in: BMC Cancer 1/2014

Open Access 01-12-2014 | Research article

Boosting Wnt activity during colorectal cancer progression through selective hypermethylation of Wnt signaling antagonists

Authors: Ana-Luisa Silva, Sarah N Dawson, Mark J Arends, Kiran Guttula, Nigel Hall, Ewen A Cameron, Tim H-M Huang, James D Brenton, Simon Tavaré, Mariann Bienz, Ashraf EK Ibrahim

Published in: BMC Cancer | Issue 1/2014

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Abstract

Background

There is emerging evidence that Wnt pathway activity may increase during the progression from colorectal adenoma to carcinoma and that this increase is potentially an important step towards the invasive stage. Here, we investigated whether epigenetic silencing of Wnt antagonists is the biological driver for this increased Wnt activity in human tissues and how these methylation changes correlate with MSI (Microsatelite Instability) and CIMP (CpG Island Methylator Phenotype) statuses as well as known mutations in genes driving colorectal neoplasia.

Methods

We conducted a systematic analysis by pyrosequencing, to determine the promoter methylation of CpG islands associated with 17 Wnt signaling component genes. Methylation levels were correlated with MSI and CIMP statuses and known mutations within the APC, BRAF and KRAS genes in 264 matched samples representing the progression from normal to pre-invasive adenoma to colorectal carcinoma.

Results

We discovered widespread hypermethylation of the Wnt antagonists SFRP1, SFRP2, SFRP5, DKK2, WIF1 and SOX17 in the transition from normal to adenoma with only the Wnt antagonists SFRP1, SFRP2, DKK2 and WIF1 showing further significant increase in methylation from adenoma to carcinoma. We show this to be accompanied by loss of expression of these Wnt antagonists, and by an increase in nuclear Wnt pathway activity. Mixed effects models revealed that mutations in APC, BRAF and KRAS occur at the transition from normal to adenoma stages whilst the hypermethylation of the Wnt antagonists continued to accumulate during the transitions from adenoma to carcinoma stages.

Conclusion

Our study provides strong evidence for a correlation between progressive hypermethylation and silencing of several Wnt antagonists with stepping-up in Wnt pathway activity beyond the APC loss associated tumour-initiating Wnt signalling levels.
Appendix
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Metadata
Title
Boosting Wnt activity during colorectal cancer progression through selective hypermethylation of Wnt signaling antagonists
Authors
Ana-Luisa Silva
Sarah N Dawson
Mark J Arends
Kiran Guttula
Nigel Hall
Ewen A Cameron
Tim H-M Huang
James D Brenton
Simon Tavaré
Mariann Bienz
Ashraf EK Ibrahim
Publication date
01-12-2014
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2014
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/1471-2407-14-891

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