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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.    Electronic supplementary material  The online version of this article (doi:10.1186/1471-2407-14-891) contains supplementary material, which is available to authorized users.

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