The Diagnostic Value of DNA Methylation in Leukemia: A Systematic Review and Meta-Analysis

Jiang, Danjie; Hong, Qingxiao; Shen, Yusheng; Xu, Yan; Zhu, Huarui; Li, Yirun; Xu, Cai; Ouyang, Guifang; Duan, Shiwei

doi:10.1371/journal.pone.0096822

Cited by 45 publications

(31 citation statements)

References 41 publications

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“…Two alternatively spliced transcript variants of this gene, which encode distinct proteins, have been reported (provided by RefSeq, Jul 2008). Methylation of CDKN2B has been found in several cancer types including laryngeal squamous cell carcinoma, acute myeloid leukemia, and in ovarian cancer, where the presence of methylation in the CDKN2B gene was present mainly in clear cell carcinoma [34][35][36] . MUS81 (Structure-Specific Endonuclease Subunit) is a protein coding gene.…”

Section: Discussionmentioning

confidence: 99%

Methylation status as a predictor of intravesical Bacillus Calmette-Guérin (BCG) immunotherapy response of high grade non-muscle invasive bladder tumor

Hušek¹,

Pacovský²,

Chmelařová³

et al. 2017

BIOMED PAP

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, Milos Brodak aBackground and Aims. Genetic and epigenetic alterations play an important role in urothelial cancer pathogenesis. Deeper understanding of these processes could help us achieve better diagnosis and management of this life-threatening disease. The aim of this research was to evaluate the methylation status of selected tumor suppressor genes for predicting BCG response in patients with high grade non-muscle-invasive bladder tumor (NMIBC). Materials and Methods. We retrospectively evaluated 82 patients with high grade non-muscle-invasive bladder tumor (stage Ta, T1, CIS) who had undergone BCG instillation therapy. We compared epigenetic methylation status in BCGresponsive and BCG-failure groups. We used the MS-MLPA (Methylation-Specific Multiplex Ligation-Dependent Probe Amplification probe sets ME001 and ME004. The control group was 13 specimens of normal urotel (bladder tissue)). Results. Newly identified methylations in high grade NMIBC were found in MUS81a, NTRK1 and PCCA. The methylation status of CDKN2B (P=0.00312 ** ) and MUS81a (P=0.0191 * ) is associated with clinical outcomes of BCG instillation therapy response. CDKN2B and MUS81a unmethylation was found in BCG failure patients. Conclusion.The results show that the methylation status of selected tumor suppressor genes (TSGs) has the potential for predicting BCG response in patients with NMIBC high grade tumors. Tumor suppressor genes such as CDKN2b, MUS81a, PFM-1, MSH6 and THBS1 are very promising for future research.

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Section: Discussionmentioning

confidence: 99%

Methylation status as a predictor of intravesical Bacillus Calmette-Guérin (BCG) immunotherapy response of high grade non-muscle invasive bladder tumor

Hušek¹,

Pacovský²,

Chmelařová³

et al. 2017

BIOMED PAP

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“…Accumulating studies have indicated that DNA methylation changes are associated with an increased risk of CHD (27)(28)(29). CDKN2A and CDKN2B genes have been previously reported as hypermethylated tumor suppressor genes in leukemia (30), parathyroid tumor (31) and breast cancer (32), suggesting a potential epigenetic regulation on cell proliferation and apoptosis. Using pyrosequencing and MethyLight methods, Zhuang et al (23) demonstrated that p15…”

Section: Discussionmentioning

confidence: 99%

CDKN2A and CDKN2B methylation in coronary heart disease cases and controls

Zhong

Chen

et al. 2017

Exp Ther Med

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Abstract. The aim of the present study was to investigate the association between cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase inhibitor 2B (CDKN2B) methylation, and coronary heart disease (CHD), and to explore the interaction between methylation status and CHD clinical characteristics in Han Chinese patients. A total of 189 CHD (96 males, 93 females) and 190 well-matched non-CHD controls (96 males, 94 females) were recruited for the study. Methylation-specific polymerase chain reaction technology was used to examine gene promoter methylation status. Comparisons of methylation frequencies between CHD and non-CHD patients were carried out using the Chi-square test. Methylation levels of CDKN2A and CDKN2B genes were not found to be associated with the risk of CHD. However, the mean age of CDKN2A-hypermethylated participants was significantly lower than CDKN2A-unmethylated participants (58.73±5.88 vs. 62.62±5.36 years, adjusted P<0.001). Conversely, the mean age of CDKN2B-hypermethylated participants was significantly higher compared with CDKN2B-unmethylated participants (62.26±5.48 vs. 58.33±7.47 years, adjusted P=0.048). In addition, CDKN2B methylation frequencies were significantly increased in female participants compared with males (99.47 vs. 11.98%, P=0.032). In conclusion, the results indicated that CDKN2A and CDKN2B promoter methylation frequencies were significantly associated with age, and there was a gender dimorphism in CDKN2B methylation. IntroductionCoronary heart disease (CHD) is a complex chronic disease that is caused by an imbalance between blood supply and demand in myocardium. Various environmental and genetic factors are known to contribute to onset and development of CHD (1). As of 2010, CHD was the leading cause of mortality globally, resulting in over 7 million cases of mortality (2). Therefore, association studies for CHD biomarkers have been performed worldwide (3-5) for future forefront diagnostics for the early assessment of cardiac risks.The genetic locus at chromosome 9p21 has been demonstrated to be strongly associated with the risk of CHD (6,7). Cyclin-dependent kinase inhibitor 2A (CDKN2A) and cyclin-dependent kinase inhibitor 2B (CDKN2B) genes both encode putative regulators of cyclin-dependent kinases on chromosome 9p21. Genome-wide association studies have identified that some CDKN2A or CDKN2B genetic variants are susceptible to CHD (8-10). As recently reported, many human diseases, including cardiovascular disease, could be influenced by aberrant DNA methylation modification (11). Aberrant methylation of cytosine-phosphate-guanine (CpG) islands in gene promoters is associated with transcription silencing and activity (3). However, the exact role of CDKN2A and CDKN2B methylation in cardiovascular system has not yet been fully elucidated.CDKN2A gene is involved in the regulation of cell proliferation, cell aging and apoptosis (12). However, a bidirectional role of CDKN2A gene expression has been reported in previous studies. Knösel et al (13) reported...

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“…Based on our previous study (18), a further subgroup meta-analysis by ethnicity was performed for CDKN2A and CDKN2B methylation. Hypermethylation of CDKN2A and CDKN2B was associated with an increased risk of leukemia in Chinese populations (P<0.00001), while only CDKN2B was associated with leukemia in Europeans (P=0.007) (Figs.…”

Section: Meta-analysis Of the Association Between Cyclin-dependentmentioning

confidence: 99%

“…Although a recent meta-analysis by our group identified significant associations between a number of aberrantly methylated genes and leukemia (18), the majority of the studies published in the Chinese language are overlooked. Thus, the aim of the present study was to focus on the association of aberrant DNA methylation and leukemia susceptibility in the Chinese population and to investigate ethnic differences in DNA methylation using subgroup meta-analyses.…”

Section: Introductionmentioning

confidence: 98%

DNA methylation and leukemia susceptibility in China: Evidence from an updated meta-analysis

Jiang

Hong

et al. 2016

Molecular and Clinical Oncology

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Abstract. Mounting evidence supports a role for DNA methylation in the pathogenesis of leukemia; however, there no overview of these results in the Chinese population. The present study performed a comprehensive meta-analysis to establish candidate genes with an altered methylation status in Chinese leukemia patients. Eligible studies were identified through searching the National Center of Biotechnology Information PubMed and Wanfang databases. Studies were pooled and overall odds ratios with corresponding confidence intervals were calculated. A total of 4,325 leukemia patients and 2,010 controls from 94 studies on 53 genes were included in this meta-analysis, and 47 genes were found to be aberrantly methylated in leukemia patients. A further subgroup meta-analysis by leukemia subtype demonstrated that hypermethylation of 5 genes, namely cyclin-dependent kinase (CDKN)2A, DNA-binding protein inhibitor-4, CDKN2B, glioma pathogenesis-related protein 1 and p73, contributed to the risk of various subtypes of leukemia. In addition, a strong association between CDKN2A and leukemia was identified in Chinese (P<0.00001) but not in European patients. The aberrantly methylated genes identified in the present meta-analysis may help elucidate the mechanisms underlying the development of leukemia in Chinese patients.

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The Diagnostic Value of DNA Methylation in Leukemia: A Systematic Review and Meta-Analysis

Cited by 45 publications

References 41 publications

Methylation status as a predictor of intravesical Bacillus Calmette-Guérin (BCG) immunotherapy response of high grade non-muscle invasive bladder tumor

Methylation status as a predictor of intravesical Bacillus Calmette-Guérin (BCG) immunotherapy response of high grade non-muscle invasive bladder tumor

CDKN2A and CDKN2B methylation in coronary heart disease cases and controls

DNA methylation and leukemia susceptibility in China: Evidence from an updated meta-analysis

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