title: Promoter methylation of Wnt antagonists DKK1 and SFRP1 is associated with opposing tumor subtypes in two large populations of colorectal cancer patients.
abstract: Aberrant activation of canonical Wnt signaling is a hallmark event in colorectal carcinogenesis. The Dickkopf-1 (DKK1) and Secreted Frizzled Related Protein 1 (SFRP1) genes encode extracellular inhibitors of Wnt signaling that are frequently silenced by promoter hypermethylation in colorectal cancer (CRC). These methylation events have been identified as prognostic markers of patient outcome and tumor subtype in several cancers but similar roles in CRC have not been comprehensively examined. In CRC, the microsatellite instability (MSI) subtype associates with favorable disease outcome but the molecular events that are responsible remain poorly understood. Consequently, we quantified promoter methylation status of the Wnt antagonist genes DKK1 and SFRP1 in a large population-based cohort of CRCs from Ontario (n = 549) and Newfoundland (n = 696) stratified by MSI status. We examined the association between methylation status and clinicopathological features including tumor MSI status and patient survival. DKK1 and SFRP1 were methylated in 13 and 95% of CRCs, respectively. In Ontario, DKK1 methylation was strongly associated with MSI tumors after adjustment for age, sex and tumor location [odds ratio (OR) = 13.7, 95% confidence interval (CI) = 7.8-24.2, P < 0.001]. Conversely, SFRP1 methylation was inversely associated with MSI tumors after these adjustments (OR = 0.3, 95% CI = 0.1-0.9, P = 0.009). Similar results were obtained in Newfoundland. There were no independent associations with recurrence-free survival. This is the first large study to identify associations between Wnt antagonist promoter hypermethylation and CRC MSI subtype. These events provide insight into subtype-specific epigenetic mediation of Wnt signaling in CRC.
authors.affiliation: Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
authors.forename: James B
authors.initials: JB
authors.lastname: Rawson
authors.forename: Michael
authors.initials: M
authors.lastname: Manno
authors.forename: Miralem
authors.initials: M
authors.lastname: Mrkonjic
authors.forename: Darshana
authors.initials: D
authors.lastname: Daftary
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Dicks
authors.forename: Daniel D
authors.initials: DD
authors.lastname: Buchanan
authors.forename: H Banfield
authors.initials: HB
authors.lastname: Younghusband
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Parfrey
authors.forename: Joanne P
authors.initials: JP
authors.lastname: Young
authors.forename: Aaron
authors.initials: A
authors.lastname: Pollett
authors.forename: Roger C
authors.initials: RC
authors.lastname: Green
authors.forename: Steven
authors.initials: S
authors.lastname: Gallinger
authors.forename: John R
authors.initials: JR
authors.lastname: McLaughlin
authors.forename: Julia A
authors.initials: JA
authors.lastname: Knight
authors.forename: Bharati
authors.initials: B
authors.lastname: Bapat
mesh_terms: D015179:Colorectal Neoplasms / Q000453:epidemiology / Q000235:genetics* / Q000473:pathology; D019175:DNA Methylation; D005260:Female; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics*; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D053842:Microsatellite Instability; D018895:Microsatellite Repeats; D008875:Middle Aged; D009523:Newfoundland and Labrador / Q000453:epidemiology; D009864:Ontario / Q000453:epidemiology; D011379:Prognosis; D011401:Promoter Regions, Genetic / Q000235:genetics*; D015996:Survival Rate; D051153:Wnt Proteins / Q000037:antagonists & inhibitors*; D000094742:Secreted Frizzled-Related Proteins
chemical_list: D036341:Intercellular Signaling Peptides and Proteins; D008565:Membrane Proteins; D051153:Wnt Proteins; C501126:DKK1 protein, human; C117636:SFRP1 protein, human; D000094742:Secreted Frizzled-Related Proteins