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

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• 作者：Ana-Luisa Silva (44)
  Sarah N Dawson (45) (46)
  Mark J Arends (44) (47)
  Kiran Guttula (44)
  Nigel Hall (48)
  Ewen A Cameron (49)
  Tim H-M Huang (50)
  James D Brenton (46)
  Simon Tavar茅 (46)
  Mariann Bienz (51)
  Ashraf EK Ibrahim (44) (51)
  
  44. Department of Pathology ; Division of Molecular Histopathology ; University of Cambridge ; Addenbrooke鈥檚 Hospital ; Hills Road ; Cambridge ; CB2 2QQ ; UK
  45. Cambridge Clinical Trials Unit ; Cambridge University Hospitals NHS Foundation Trust ; Hills Road ; Cambridge ; CB2 0QQ ; UK
  46. Cancer Research UK Cambridge Institute ; Li Ka Shing Centre ; Robinson Way ; Cambridge ; CB2 0RE ; UK
  47. University of Edinburgh Division of Pathology ; Edinburgh Cancer Research Centre ; Institute of Genetics & Molecular Medicine ; Western General Hospital ; Crewe Road South ; Edinburgh ; EH4 2XR ; UK
  48. Cambridge Colorectal Unit ; Department of Surgery ; Addenbrooke鈥檚 Hospital ; Box 201 ; Hills Road ; Cambridge ; CB2 2QQ ; UK
  49. Gastroenterology ; Addenbrooke鈥檚 Hospital ; Hills Road ; Cambridge ; CB2 2QQ ; UK
  50. University of Texas Health Science Center ; 7979 Wurzbach Road ; San Antonio ; Texas ; 78229-3900 ; USA
  51. MRC ; Laboratory of Molecular Biology ; Hills Road ; Cambridge ; CB2 0QH ; UK
  
• 刊名：BMC Cancer
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：14
• 期：1
• 全文大小：1,655 KB
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  47. The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2407/14/891/prepub
  
• 刊物主题：Cancer Research; Oncology; Stem Cells; Animal Models; Internal Medicine;
• 出版者：BioMed Central
• ISSN：1471-2407

文摘

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.