Methylation of BNIP3 and DAPK indicates lower response to chemotherapy and poor prognosis in gastric cancer[J]

Department of Surgical Oncology, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8519, Japan.
Oncology Reports (Impact Factor: 2.3). 02/2011; 25(2):513-8. DOI: 10.3892/or.2010.1085
Source: PubMed


Aberrant promoter hypermethylation (methylation) is an epigenetic change that silences the expression of crucial genes, thus inactivating the apoptotic pathway in various cancers. Inactivation of the apoptotic pathway has been considered to be associated with chemoresistance. The objective of the present study was to clarify the effect of the methylation of the apoptosis-related genes, Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) and death-associated protein kinase (DAPK), on the response to chemotherapy in metastatic or recurrent gastric cancers. Tumor samples were obtained from 80 gastric cancer patients who were treated with fluoropyrimidine-based chemotherapy for distant metastatic or recurrent disease, after surgical resection of the primary tumor. The methylation status of the apoptosis-related genes, BNIP3 and DAPK, was investigated by methylation-specific PCR. Methylation in BNIP3 was detected in 31 tumors (39%) and in DAPK in 33 tumors (41%). There was no correlation between the methylation status of BNIP3 and that of DAPK. The response rate was significantly lower in patients with methylation of DAPK, than in those without (21 vs. 49% p=0.012). Progression-free survival time (PFS) was shorter in patients with methylation of DAPK than in those without (p=0.007). The overall survival time (OS) was shorter in patients with methylation of BNIP3 than in those without (p=0.031). The response rate was significantly lower in patients with methylation of either DAPK or BNIP3, or both, than in those without methylation (p=0.003). PFS and OS were significantly shorter in patients with methylation of either or both of these genes than in those without (p=0.002, p=0.001). The methylation of BNIP3 and DAPK can predict lower response to chemotherapy and poor prognosis in gastric cancer.

Download full-text


Available from: Mikito Inokuchi, Mar 04, 2015
  • Source
    • "There is a growing body of evidence that gene methylation in cancerous gastric tissues is associated with differential sensitivity to chemotherapy. Methylation of the MLH1 gene is related to resistance to oxaliplatin-based chemotherapy[38], and patients with DAPK-1 methylation show a worse response to fluoropyrimidine-based chemotherapy[39]. We hope that our study will lead to better understanding of the different pathways of molecular carcinogenesis in different parts of the stomach. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Background There is considerable information on the methylation of the promoter regions of different genes involved in gastric carcinogenesis. However, there is a lack of information on how this epigenetic process differs in tumors originating at different sites in the stomach. The aim of this study is to assess the methylation profiles of the MLH1, MGMT, and DAPK-1 genes in cancerous tissues from different stomach sites. Methods Samples were acquired from 81 patients suffering stomach adenocarcinoma who underwent surgery for gastric cancer in the Lithuanian University of Health Sciences Hospital Kaunas Clinics in 2009–2012. Gene methylation was investigated with methylation-specific PCR. The study was approved by the Lithuanian Biomedical Research Ethics Committee. Results The frequencies of methylation in cancerous tissues from the upper, middle, and lower thirds of the stomach were 11.1, 23.1, and 45.4 %, respectively, for MLH1; 22.2, 30.8, and 57.6 %, respectively, for MGMT; and 44.4, 48.7, and 51.5 %, respectively, for DAPK-1. MLH1 and MGMT methylation was observed more often in the lower third of the stomach than in the upper third (p < 0.05). In the middle third, DAPK-1 promoter methylation was related to more-advanced disease in the lymph nodes (N2–3 compared with N0–1 [p = 0.02]) and advanced tumor stage (stage III rather than stages I–II [p = 0.05]). MLH1 and MGMT methylation correlated inversely when the tumor was located in the lower third of the stomach (coefficient, –0.48; p = 0.01). DAPK-1 and MLH1 methylation correlated inversely in tumors in the middle-third of the stomach (coefficient, –0.41; p = 0.01). Conclusion Gene promoter methylation depends on the gastric tumor location.
    Full-text · Article · Dec 2016 · BMC Cancer
  • Source
    • "DAPK1 is a positive regulator of cell apoptosis, and has been found to correlate with poorly differentiated tumors and lymph node metastasis. The frequency and specificity of DAPK1 were 30.9–83.2 and 57.8–100%, respectively (12,15,24–26). No significant correlation has been identified between SFRP2, a candidate tumor-suppressor gene, and clinical outcomes. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Oct 2014 · Oncology letters
  • Source
    • "Epigenetic silencing of DAPK was found in the majority of sporadic chronic lymphocytic leukemia (CLL) (Raval et al., 2007). These results were supported by DAPK1 promoter methylation in a wide range of human tumor types in which DAPK silencing correlated with tumor progression, histo-pathological staging, increased metastasis and high tumor recurrence (Bialik and Kimchi, 2004; Chaopatchayakul et al., 2010; Christoph et al., 2006b; Raval et al., 2007; Sugita et al., 2011; Tada et al., 2002; Toyooka et al., 2003; Voso et al., 2010). However, in AML and MDS the extent of DAPK promoter methylation is a matter of debate since some studies identified this as a very rare event, contradicting previous studies (Claus et al., 2011; Voso et al., 2010). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Resistance of cancer cells to chemotherapeutics and emerging targeted drugs is a devastating problem in the treatment of cancer patients. Multiple mechanisms contribute to drug resistance such as increased drug efflux, altered drug metabolism, secondary mutations in drug targets, and activation of downstream or parallel signal transduction pathways. The rapid kinetics, the reversibility of acquired drug resistance and the absence of genetic mutations suggest an epigenetic basis for drug insensitivity. Similar to the cellular variance seen in the human body, epigenetic mechanisms, through reversible histone modifications and DNA methylation patterns, generate a variety of transcriptional states resulting in a dynamic heterogeneous tumor cell population. Consequently, epigenomes favoring survival in the presence of a drug by aberrant transcription of drug transporters, DNA-repair enzymes and pro-apoptotic factors render cytotoxic and targeted drugs ineffective and allow selection of rare drug-resistant tumor cells. Recent advances in charting cancer genomes indeed strongly indicate a role for epigenetic regulators in driving cancer, which may result in the acquisition of additional (epi)genetic modifications leading to drug resistance. These observations have important clinical consequences as they provide an opportunity for "epigenetic drugs" to change reversible drug-resistance-associated epigenomes to prevent or reverse non-responsiveness to anti-cancer drugs.
    Full-text · Article · Feb 2012 · Drug resistance updates: reviews and commentaries in antimicrobial and anticancer chemotherapy
Show more