Research Article: Prognostic significance of DAPK promoter methylation in lymphoma: A meta-analysis

Date Published: January 25, 2019

Publisher: Public Library of Science

Author(s): Hong Wang, Lin-Yu Zhou, Ze-Bing Guan, Wen-Bin Zeng, Lan-Lan Zhou, Ya-Nan Liu, Xue-Yi Pan, Masaru Katoh.


We aimed to characterize the clinical significance of epigenetic loss of death-associated protein kinase (DAPK) gene function through promoter methylation in the development and prognosis of lymphoma. PubMed, Web of Science and ProQuest databases were searched for relevant studies. Twelve studies involving 709 patients with lymphoma were identified. The prognostic value of DAPK methylation was expressed as risk ratio (RR) and its corresponding 95% confidence interval (CI), while the associations between DAPK methylation and the clinical characteristics of patients with lymphoma were expressed as odd ratios (ORs) and their corresponding 95% CIs. Meta-analysis showed that the 5-year survival rate was significantly lower in lymphoma patients with hypermethylated DAPK (RR = 0.85, 95% CI (0.73, 0.98), P = 0.025). Sensitivity analysis demonstrated consistent result. However, no associations were found between DAPK methylation and clinicopathological features of lymphoma, in relation to gender (OR = 1.07, 95% CI (0.72, 1.59), P = 0.751), age (OR = 1.01, 95% CI (0.66, 1.55), P = 0.974), international prognostic index (OR = 1.20, 95% CI (0.63, 2.27), P = 0.575), B symptoms (OR = 0.76, 95% CI (0.38, 1.51), P = 0.452), serum lactate dehydrogenase (OR = 1.13, 95% CI (0.62, 2.05), P = 0.683), and BCL-2 expression (OR = 1.55, 95% CI (0.91, 2.66), P = 0.106). Lymphoma patients with hypermethylated DAPK are at risk for poorer 5-year survival rate. DAPK methylation may serve as a negative prognostic biomarker among lymphoma patients, although it may not be associated with the progression of lymphoma.

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Lymphoma accounts for about 3.6% of all cancer-related deaths in the developed countries [1]. It is a highly heterogeneous hematological malignancy that arises from the lymphatic system. Lymphoma patients exhibit wide range of responses to treatments and clinical outcomes [2–4]. At present, the international prognostic index (IPI) based on clinical parameters is widely applied to predict clinical outcomes. However, the variability observed in the patients’ outcome with similar clinical presentations undermines its prognostic value. However, the variability observed in the patients’ outcome with similar clinical presentations undermines the prognostic value of these factors in lymphoma [2–4]. Therefore, in order to improve the outcome prediction and indicate the requirement for aggressive therapy in patients with lymphoma, it is essential to identify effective prognostic biomarkers.

This study was conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) [26] guidelines. All analyses were based on previous published studies. No ethical approval or informed consent is required.

Six studies [18, 20–24] analyzed the association of DAPK methylation with 5-year mortality in patients with lymphoma. Our result shows that lymphoma patients with DAPK promoter methylation have poorer 5-year survival rates compared to those without methylation. Moderate but statistically insignificant heterogeneity was observed despite including studies involving various types of lymphoma, including DLBCL [18, 20, 22, 24], MALT lymphoma [21], and follicular lymphoma [23]. Sensitivity analyses showed consistent results, indicating that no individual study significantly affected the pooled result. Our result, therefore, suggested that DAPK hypermethylation could be a general pathological event in lymphoma and that it might be used as a prognostic biomarker among lymphoma patients.

Lymphoma patients with hypermethylated DAPK are at higher risk of death within 5 years. However, our results did not support the association of DAPK methylation with increased 5-year mortality rate in DLBCL patients. Our analyses were limited by the number of studies, variability in methylation detection methods and our results were pooled using unadjusted data. Future high quality studies are warranted. Our results also showed that DAPK methylation is not associated with gender, age, IPI score, B symptoms, serum LDH, or BCL-2 expression. Our findings indicate that methylation of DAPK in lymphoma may serve as a prognostic biomarker in lymphoma, but not as an indicator for disease progression.




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