DNA methylation of SFRP1, SFRP2, and WIF1 and prognosis of postoperative colorectal cancer patients

Abstract

BackgroundAs biomarkers, DNA methylation is used to detect colorectal cancer (CRC) and make assessment of CRC prognosis. The published findings showed the association between the methylation of SFRP1, SFRP2, and WIF1, located in the Wnt signaling pathway, and the prognosis of CRC were not consistent. Our study aimed to explore the potential possibility of SFRP1, SFRP2, and WIF1 concomitant promoter methylation as prognostic biomarkers of postoperative CRC patients.MethodsAs a total of 307 sporadic postoperative CRC patients were followed up, we detected SFRP1, SFRP2, and WIF1 methylation obtained from tumor tissues and adjacent non-tumor tissues respectively on the basis of methylation-sensitive high resolution melting analysis. Univariate and multivariate Cox regressions were carried out so as to assess the potential possibility of SFRP1, SFRP2, and WIF1 promoter methylation as predictors of prognosis. Confounders in our study were controlled by Propensity Score (PS) analysis.ResultsThe SFRP1, SFRP2, and WIF1 methylation levels in tumor tissues were significantly higher than that in adjacent non-tumor tissues (P < 0.001). SFRP2 hypermethylation was significantly associated with a favorable clinical outcome at the hazard ratio (HR) of 0.343 [95% confidence intervals (CI): 0.164–0.718, P = 0.005] and 0.410 (95% CI: 0.200–0.842, P = 0.015) in multivariate Cox regression and PS analysis, respectively. Co-hypermethylation of SFRP1 and SFRP2 was significantly associated with a favorable clinical outcome at the HR of 0.333 (95% CI: 0.159–0.694, P = 0.003) and 0.398 (95% CI: 0.192–0.821, P = 0.013) in multivariate Cox regression and PS analysis, respectively. Co-hypermethylation of SFRP1, SFRP2 and WIF1 was significantly associated with a favorable clinical outcome at the HR of 0.326 (95% CI: 0.117–0.908, P = 0.032) and 0.401 (95% CI: 0.146–1.106, P = 0.077) in multivariate Cox regression and PS analysis, respectively.ConclusionsSFRP1, SFRP2, and WIF1 were frequently hypermethylated in CRC tumor tissues. It was apparent that the promoter hypermethylation of SFRP2 and co-hypermethylation of SFRP1 and SFRP2 might be considered as independent prognostic predictors for survival advantage of postoperative CRC patients.

Epigenetics of SFRP1: The Dual Roles in Human Cancers

“…The majority of CRC samples in this study are methylated at SFRP1 with 72.2% methylation frequency [99]. On the contrary, Liu and colleagues postulated that the co-hypermethylation of SFRP1 and SFRP2 were suggested as independent prognostic predictors of survival advantage in postoperative CRC patients [100], whereby silencing of SFRP1 and SFRP2 by hypermethylation lead to a better prognosis. Meanwhile, in an in vivo study to correlate gut microbiota with epigenetic signature, CRC-associated microbiota induced higher numbers of hypermethylated genes in the murine colonic mucosa, among which SFRP1 was also hypermethylated [101].…”

DNA methyltransferase expression is associated with cell proliferation in salivary mucoepidermoid carcinoma

“…A number of tumor suppressor genes have been described methylated in MEC, including RUNX3, SFRP1, p16INK4a, and E‐cadherin 5,11,13,27 . RUNX3, SRFP1, and E‐cadherin are related to WNT/beta‐catenin pathway, and the methylation is related to proliferation and lymph node metastasis, poor prognosis, and tumor stage 28–30 . p16INK4a inhibits cyclin‐dependent kinases (CDK) CDK4 and CDK6, and thereby preventing G1‐to‐S cell‐cycle phase progression; thus, the methylation of p16INK4a is reported cell‐cycle progression 31 .…”

“…p16INK4a inhibits cyclin‐dependent kinases (CDK) CDK4 and CDK6, and thereby preventing G1‐to‐S cell‐cycle phase progression; thus, the methylation of p16INK4a is reported cell‐cycle progression 31 . As well as, the inhibition of DNMT1 leads to the activation of p16, RUNX3, SFRP1, and E‐cadherin 29,32–34 . It shows that DNMT could influence the proliferation by leading methylation of suppressor genes that act directly or indirectly in cell cycle.…”

Integration Analysis of Differential Expressed Genes Regulated by Differential Methylated Regions for Predicting Prognosis in Human Colon Cancer

“…For colon cancer, DNA methylation alters are found in many patients, for example, SST1 pericentromeric repeats existed hypomethylation, which resulted in the mutation of TP53, and the mutated TP53 associated with genome damage, which related to the tumorigenesis and development of colon cancer (16). Similarly, hypermethylation appeared in the promoter of antioncogenes SFPR1, SFPR2 and WIF1, leaded to downregulation expression of genes, inhibition of gene function, action of Wnt/β-catenin signal pathway and promotion of colon cancer (17); ADHFEI is also an antioncogene, the hypermethylation of ADHFEI promotes proliferation of the colon cancer cell via regulating cell cycle progression (18). The abnormal methylation of the genes above predicted poor prognosis of colon cancer.…”