Promoter methylation of Wnt antagonistsDKK1andSFRP1is 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.

Toward a comprehensive and systematic methylome signature in colorectal cancers

“…[23][24][25][26][27][28] Genome-wide analysis have cited Receptor Protein Tyrosine Phosphatase Delta gene (PTPRD) as hypermethylated in CRC and a predictor of poor prognosis, 12 an observation that was previously corroborated by our laboratory in Iranian and African American populations. 13 Additional Wnt signaling pathway genes, such as Secreted Frizzled Related Protein 1 (SFRP1), are frequently hypermethylated in CRC, [29][30][31] and high methylation of SFRP1 in normal rectal mucosa can be associated with aging, as per Worthley et al 32,33 Since SFRP1 can have high levels of methylation in normal colonic mucosa, and its promoter hypermethylation is convincingly involved in CRC pathogenesis, it will be important for future analysis to determine whether aberrant methylation of this gene is significantly different between cancer and normal adjacent tissue from individual CRC patients. RASSF1A, another Wnt pathway gene is often methylation-silenced in CRC.…”

Low SFRP1 Expression Correlates with Poor Prognosis and Promotes Cell Invasion by Activating the Wnt/β-Catenin Signaling Pathway in NPC

“…An SFRP family member, SFRP1, can block Wnt/b-catenin signaling by hindering Wnt-receptor interactions via an N-terminal cysteine-rich domain homologous to Frizzled proteins (33). SFRP1 is hypermethylated and downregulated in various cancers, including breast (34), colorectal (35), and ovarian cancer (36). SFRP1 hypermethylation and downregulation are also associated with poor prognosis in several tumors (34,37,38).…”

Role of the Wnt/β-catenin pathway in gastric cancer: An in-depth literature review

“…These Wnt-antagonists are initially upregulated in response to Wnt signaling activation, initiating a negative feedback loop [116] . However, in certain tumor cells, the epigenetic silencing of Dkk-1 by promoter hypermethylation or loss of heterozygosity, produces an imbalance of Wnt/Dkk negative feedback, therefore contributing to persistent activation of Wnt/ b-catenin signaling [117,118] . Moreover, recently it was reported that Polycomb group protein BMI1, which is transcriptionally regulated by the Wnt-target gene c-Myc, act as an activator of the Wnt pathway by repressing Dkk protein family (particularly Dkk-1) as part of positive feedback loop [119] .…”