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.

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Available from: Mikito Inokuchi, Mar 04, 2015
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    • "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. "
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    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.
    Oncology letters 10/2014; 8(4):1745-1750. DOI:10.3892/ol.2014.2410 · 1.55 Impact Factor
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    • "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). "
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    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.
    Drug resistance updates: reviews and commentaries in antimicrobial and anticancer chemotherapy 02/2012; 15(1-2):21-38. DOI:10.1016/j.drup.2012.01.008 · 9.12 Impact Factor
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    • "Two apoptosis effectors , Bcl-2/adenovirus E1B 19 kDa-interacting protein 3 (BNIP3) and death-associated protein kinase (DAPK), are frequently methylated in gastrointestinal tumors, including colorectal cancer (Van Engeland et al., 2011). It has been shown that BNIP3 and DAPK methylation predicts lower response rates in gastric cancer patients treated with fluoropyrimidine-based chemotherapy (Sugita et al., 2011), probably due to increased resistance to chemotherapyinduced apoptosis. "
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    ABSTRACT: Colorectal cancer is the second leading cause of cancer-related deaths in the world. Despite many therapeutic opportunities, prognosis remains dismal for patients with metastatic disease, and a significant portion of early-stage patients develop recurrence after chemotherapy. Epigenetic gene regulation is a major mechanism of cancer initiation and progression, through the inactivation of several tumor suppressor genes. Emerging evidence indicates that epigenetics may also play a key role in the development of chemoresistance. In the present review, we summarize epigenetic mechanisms triggering resistance to three commonly used agents in colorectal cancer: 5-fluorouracil, irinotecan and oxaliplatin. Those epigenetic biomarkers may help stratify colorectal cancer patients and develop a tailored therapeutic approach. In addition, epigenetic modifications are reversible through specific drugs: histone-deacetylase and DNA-methyl-transferase inhibitors. Preclinical studies suggest that these drugs may reverse chemoresistance in colorectal tumors. In conclusion, an epigenetic approach to colorectal cancer chemoresistance may pave the way to personalized treatment and to innovative therapeutic strategies.
    Drug resistance updates: reviews and commentaries in antimicrobial and anticancer chemotherapy 09/2011; 14(6):280-96. DOI:10.1016/j.drup.2011.08.001 · 9.12 Impact Factor
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