Guo Hong, Zhang Ting-Juan, Wen Xiang-Mei, Zhou Jing-Dong, Ma Ji-Chun, An Cui, Zhang Wei, Xu Zi-Jun, Lin Jiang, Qian Jun
Laboratory Center, Affiliated People's Hospital of Jiangsu University.
The Key Lab of Precision Diagnosis and Treatment of Zhenjiang City.
Onco Targets Ther. 2017 Jul 20;10:3635-3644. doi: 10.2147/OTT.S136502. eCollection 2017.
Secreted frizzled-related proteins (SFRPs) as Wnt signaling antagonists have been found to be dysregulated by promoter hypermethylation in several cancers including acute myeloid leukemia (AML). This study aimed to investigate the methylated status of SFRPs promoter region and its clinical relevance in Chinese non-M3 AML patients.
SFRPs methylation in 139 primary non-M3 AML patients was determined using methylation-specific real-time quantitative polymerase chain reaction.
The frequency of aberrant methylation was as follows: 30.2% for SFRP1, 27.3% for SFRP2, 5.0% for SFRP4, and 1.4% for SFRP5. Hypermethylation of at least one SFRP gene occurred in 51.8% (72/139) of non-M3 AML patient samples, which was significantly higher compared to normal control (0/21) (<0.001). Hypermethylation of SFRP1 was potentially associated with / mutations (=0.043), and the frequency of SFRPs methylation was higher in patients ≥50 years compared to those <50 years, especially for SFRP2 (<0.05). Furthermore, both whole cohort and cytogenetically normal (CN) patients with high SFRPs-methylated group showed a shorter overall survival (OS) compared to those with low group (=0.036 and =0.035, respectively). Moreover, Cox regression multivariate analysis revealed that SFRPs hypermethylation acts as an independent prognostic biomarker among both whole cohort (hazard ratio =1.804, =0.026) and CN (hazard ratio =2.477, =0.023) patients. In leukemic cell line HL60 treated with 5-aza-2'-deoxycytidine, the alteration of SFRP1/2 expression inversely correlated with change in SFRP1/2 methylation (=-0.975, =0.005 and =-0.975, =0.005, respectively). A tendency of negative correlation was observed between SFRP1 expression and its promoter methylation in AML patients (=-0.334, =0.038).
These findings suggested that hypermethylation of SFRP1/2 was a frequent event and silenced SFRP1/2 expression in AML. Moreover, hypermethylation of SFRPs promoter was an adverse risk factor for OS in Chinese non-M3 AML patients.
分泌型卷曲相关蛋白（SFRPs）作为Wnt信号拮抗剂，已发现在包括急性髓系白血病（AML）在内的多种癌症中因启动子高甲基化而失调。本研究旨在调查中国非M3型AML患者中SFRPs启动子区域的甲基化状态及其临床相关性。
采用甲基化特异性实时定量聚合酶链反应测定139例原发性非M3型AML患者的SFRPs甲基化情况。
异常甲基化频率如下：SFRP1为30.2%，SFRP2为27.3%，SFRP4为5.0%，SFRP5为1.4%。51.8%（72/139）的非M3型AML患者样本中至少有一个SFRP基因发生高甲基化，与正常对照（0/21）相比显著更高（<0.001）。SFRP1的高甲基化可能与/突变相关（=0.043），≥50岁患者的SFRPs甲基化频率高于<50岁患者，尤其是SFRP2（<0.05）。此外，与低甲基化组相比，整个队列以及细胞遗传学正常（CN）的高SFRPs甲基化组患者的总生存期（OS）均较短（分别为=0.036和=0.035）。此外，Cox回归多变量分析显示，SFRPs高甲基化在整个队列（风险比=1.804，=0.026）和CN患者（风险比=2.477，=0.023）中均为独立的预后生物标志物。在用5-氮杂-2'-脱氧胞苷处理的白血病细胞系HL60中，SFRP1/2表达的改变与SFRP1/2甲基化的变化呈负相关（分别为=-0.975，=0.005和=-0.975，=0.005）。在AML患者中观察到SFRP1表达与其启动子甲基化之间存在负相关趋势（=-0.334，=0.038）。
这些发现表明，SFRP1/2的高甲基化在AML中是常见事件，并使SFRP1/2表达沉默。此外，SFRPs启动子的高甲基化是中国非M3型AML患者OS的不良危险因素。
