Detection of aberrant promoter methylation of RNF180, DAPK1 and SFRP2 in plasma DNA of patients with gastric cancer

Abstract

Gastric cancer (GC) is one of the most frequently diagnosed malignancies in East Asia, particularly in China, and remains the second leading cause of cancer-associated mortality worldwide. However, no effective plasma biomarkers have been identified for the diagnosis of patients with GC. The aim of this study was to investigate the DNA methylation status of the ring finger protein 180 (RNF180), secreted frizzled-related protein 2 (SFRP2) and death-associated protein kinase 1 (DAPK1) genes in the plasma samples of 57 GC patients and 42 control individuals with no malignant disease, and to evaluate the clinical utility of these makers. A significantly higher level of methylation was observed in the plasma DNA of GC patients when compared with that of controls for the three genes investigated (RNF180, 57.89% vs. 23.81%; DAPK1, 49.12% vs. 28.57%; and SFRP2, 71.93% vs. 42.86%). No association was identified between the DAPK1 or SFRP2 methylation level in the plasma DNA and the clinicopathological parameters of patients. Notably, RNF180 methylation was found to positively correlate with tumor size (P=0.018), histological type (P=0.025), TNM stage (P=0.002), lymph node metastasis (P=0.008) and distant metastasis (P=0.018). Overall, 50 cancer patients (87.72%) exhibited methylation of at least one of the three markers, while 26 normal subjects presented methylation in plasma DNA [specificity, 38.1%; odds ratio (OR), 4.4]. The combined use of RNF180 and SFRP2 as methylation markers appeared to be the most preferable predictor with regard to predictive power and cost-performance (OR, 5.57; P=0.0002). The results of the present study indicate that aberrant promoter methylation of genes in the plasma may be detected in a substantial proportion of GC patients and thus, these genes must be evaluated in the screening and surveillance of GC.

Clinical effect of DAPK promoter methylation in gastric cancer

“…Ultimately, 22 eligible studies [ 24–45 ] involving 1606 GC patients and 1508 nonmalignant controls were included in the current meta-analysis based on our inclusion criteria (Fig. 1).…”

“…Of the included studies, methylation detection methods included 1 study of combined bisulphite restriction analysis (COBRA) [43] and 21 studies of methylation-specific polymerase chain reaction (MSP). [ 24–42 44 45 ] Eighteen studies including 1133 cases and 1508 controls assessed the DAPK promoter methylation status in gastric cancer and noncancerous samples. [ 24–27 29 30 33–36 38–45 ] Fifteen studies comprising 813 male and 391 female GC patients investigated the relationship between DAPK promoter methylation and gender status.…”

“…[ 24–42 44 45 ] Eighteen studies including 1133 cases and 1508 controls assessed the DAPK promoter methylation status in gastric cancer and noncancerous samples. [ 24–27 29 30 33–36 38–45 ] Fifteen studies comprising 813 male and 391 female GC patients investigated the relationship between DAPK promoter methylation and gender status. [ 24 25 27–29 31 32 34 36–38 40–42 44 ] Nine studies comprising 235 early GC patients and 468 advanced GC patients investigated the association between DAPK promoter methylation and tumor stage.…”

“…[ 24–27 29 30 33–36 38–45 ] Fifteen studies comprising 813 male and 391 female GC patients investigated the relationship between DAPK promoter methylation and gender status. [ 24 25 27–29 31 32 34 36–38 40–42 44 ] Nine studies comprising 235 early GC patients and 468 advanced GC patients investigated the association between DAPK promoter methylation and tumor stage. [ 24 27–29 31 32 36 38 44 ] Twelve studies involving 607 lymph node-positive patients and 301 lymph node-negative patients investigated the association between DAPK promoter methylation and lymph node status.…”

“…[ 24 25 27–29 31 32 34 36–38 40–42 44 ] Nine studies comprising 235 early GC patients and 468 advanced GC patients investigated the association between DAPK promoter methylation and tumor stage. [ 24 27–29 31 32 36 38 44 ] Twelve studies involving 607 lymph node-positive patients and 301 lymph node-negative patients investigated the association between DAPK promoter methylation and lymph node status. [ 24 25 27 29 32 36–38 40–42 44 ] Nine studies involving 438 intestinal gastric cancer patients and 356 nonintestinal gastric cancer patients investigated the association between DAPK promoter methylation and tumor histology.…”