SFRP基因甲基化在骨髓增生异常综合征中的预后价值

The prognostic value of methylation status of SFRP in patients with myelodysplastic syndrome

背景与目的:分泌型卷曲相关蛋白(secreted frizzled-related protein,SFRP)基因甲基化与许多实体瘤及白血病相关。本研究旨在探讨SFRP基因甲基化在骨髓增生异常综合征(myelodysplaticsyndrome,MDS)中的预后价值。方法:采用甲基化特异性PCR的方法检测144例原发性MDS患者骨髓标本中SFRP基因甲基化状态,评价其预后价值。结果:在MDS患者中,SFRP1、2、4、5均存在甲基化,甲基化阳性率分别为41%、89.6%、43.1%和50.7%。SFRP1和SFRP5阳性率在世界卫生组织(World Health Organization,WHO)不同的亚型中差异有统计学意义(P=0.006和P=0.002);同时随着国际预后积分系统(international prognosticscoring system,IPSS)积分的增加,SFRP1和SFRP5甲基化阳性率呈上升趋势,差异有统计学意义(P=0.038和P=0.011)。生存分析提示,SFRP1、SFRP4和SFRP5甲基化阳性患者与甲基化阴性患者相比,整体生存时间(overall survival,OS)明显缩短:SFRP1、SFRP4和SFRP5甲基化阳性患者的中位生存时间分别为14.1、18.5和13.2个月,而甲基化阴性患者的中位生存时间分别为31.8、31.7和31.8个月,差异有统计学意义(P=0.001,P=0.009和P=0.015)。此外,SFRP5甲基化阳性患者向白血病转化的风险显著高于SFRP5甲基化阴性患者,无白血病生存(leukemia free survival,LFS)时间缩短(P=0.018)。结论:SFRP1、SFRP4和SFRP5基因异常甲基化与MDS患者的OS相关;SFRP5甲基化与MDS患者向急性白血病的转化风险相关。

Background and purpose： Methylation status of secreted frizzled-related protein （SFRP） has been implicated in the pathogenesis of many tumors as well as in leukemia. The purpose of our study was to explore the possible relationship between the methylation status of SFRP and clinical variables, and to determine their prognostic value in patients with myelodysplatic syndrome （MDS）. Methods： We employed methylation-specific PCR to examine the methylation status of SFRP in 144 adult de novo MDS patients, and to determine their prognostic value in MDS. Results： Methylation of the gene promoters was observed in all 4 SFRP genes in 144 MDS patients. The methylation frequencies were as follows： 41% for SFRP1, 89.6% for SFRP2, 43.1% for SFRP4, and 50.7% for SFRP5. For SFRP1 and SFRP5, aberrant methylation was more frequent in advanced stages of World Health Organization （WHO） subtypes （P=0.006, P=-0.002）; In addition, the frequency of SFRP1 and SFRP5 methylation was significantly correlated with the international prognostic score system （IPSS） risk score （P=0.038, P=0.011）. Evaluation of the prognostic impact of epigenetic aberrations showed that SFRP1, SFRP4, and SFRP5 methylation had a significant impact onoverall survival （OS） （P=0.001, P=-0.009, P=-0.015, respectively）. The median survival of patients with SFRP1, SFRP4, and SFRP5 methylation were 14.1, 18.5, and 13.2 months, respectively, compared to 31.8, 31.7, and 31.8 months for patients without methylation. Patients with SFRP5 methylation had a higher risk of leukemia evolution than those without SFRP5 methylation, with shorter leukemia free survival （LFS） （P=-0.018）. Using the number of these 3 genes present in a patient, we could classify patients into four risk groups with significantly different prognoses （OS： P=-0.002, LFS： P=-0.048）. Conclusion： The methylation status of SFRP1, 4, and SFRP 5 was a useful prognostic marker and predicts poor prognosis in patients with MDS： methylation status of SFRP1, SFRP4, and SFRP5 was associated with poor OS in MDS and SFRP5 methvlation also predicted a high risk of leukemia evolution, with shorter LFS （P=0.018）.