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

Ana Luisa Silva, Sarah N. Dawson, Mark J. Arends, Kiran Guttula, Nigel Hall, Ewen A. Cameron, Hui-ming Huang, James D. Brenton, Simon Tavaré, Mariann Bienz, Ashraf E K Ibrahim

Research output: Contribution to journalArticle

38 Citations (Scopus)

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.

Original languageEnglish (US)
Article number891
JournalBMC Cancer
Volume14
Issue number1
DOIs
StatePublished - Nov 29 2014
Externally publishedYes

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Adenoma
Colorectal Neoplasms
Methylation
CpG Islands
Wnt Signaling Pathway
Carcinoma
Mutation
Gene Components
Phenotype
Epigenomics
Human Activities
Genes
Neoplasms

ASJC Scopus subject areas

  • Oncology
  • Cancer Research
  • Genetics

Cite this

Silva, A. L., Dawson, S. N., Arends, M. J., Guttula, K., Hall, N., Cameron, E. A., ... Ibrahim, A. E. K. (2014). Boosting Wnt activity during colorectal cancer progression through selective hypermethylation of Wnt signaling antagonists. BMC Cancer, 14(1), [891]. https://doi.org/10.1186/1471-2407-14-891

Boosting Wnt activity during colorectal cancer progression through selective hypermethylation of Wnt signaling antagonists. / Silva, Ana Luisa; Dawson, Sarah N.; Arends, Mark J.; Guttula, Kiran; Hall, Nigel; Cameron, Ewen A.; Huang, Hui-ming; Brenton, James D.; Tavaré, Simon; Bienz, Mariann; Ibrahim, Ashraf E K.

In: BMC Cancer, Vol. 14, No. 1, 891, 29.11.2014.

Research output: Contribution to journalArticle

Silva, AL, Dawson, SN, Arends, MJ, Guttula, K, Hall, N, Cameron, EA, Huang, H, Brenton, JD, Tavaré, S, Bienz, M & Ibrahim, AEK 2014, 'Boosting Wnt activity during colorectal cancer progression through selective hypermethylation of Wnt signaling antagonists', BMC Cancer, vol. 14, no. 1, 891. https://doi.org/10.1186/1471-2407-14-891
Silva, Ana Luisa ; Dawson, Sarah N. ; Arends, Mark J. ; Guttula, Kiran ; Hall, Nigel ; Cameron, Ewen A. ; Huang, Hui-ming ; Brenton, James D. ; Tavaré, Simon ; Bienz, Mariann ; Ibrahim, Ashraf E K. / Boosting Wnt activity during colorectal cancer progression through selective hypermethylation of Wnt signaling antagonists. In: BMC Cancer. 2014 ; Vol. 14, No. 1.
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AU - Dawson, Sarah N.

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AU - Hall, Nigel

AU - Cameron, Ewen A.

AU - Huang, Hui-ming

AU - Brenton, James D.

AU - Tavaré, Simon

AU - Bienz, Mariann

AU - Ibrahim, Ashraf E K

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AB - 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.

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