p15、DAPK、SOCS1和FHIT 4基因甲基化联合检测在骨髓增生异常综合征早期诊断及预后评估中的价值
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摘要
目的:探讨p15、DAPK、SOCS1和FHIT 4基因甲基化联合检测在骨髓增生异常综合征(MDS)早期诊断与预后评估中的价值。方法:应用甲基化特异性PCR(MSP)对67例MDS患者骨髓进行上述4种基因甲基化检测,分析4个基因联检在MDS患者早期诊断及预后评估中的价值。结果:67例MDS患者p15、DAPK、SOCS1和FHIT 4个基因甲基化率分别为37.3%、35.8%、47.8%和52.2%,较对照组显著增高(P<0.05),4个基因单检诊断MDS的阳性符合率分别为37.3%、35.8%、47.8%和52.2%,而4个基因联合检测诊断MDS的阳性符合率为82.1%,较单一基因检查阳性符合率明显增高(P<0.001);相对高危组中≥2个基因甲基化共表达明显高于相对低危组(P<0.05)。MDS患者中位生存时间18(13.3,22.7)个月,相对低危组患者中位生存时间明显长于相对高危组[27(20.3,33.7)vs 9(5.9,12.1)个月](P<0.05)。在不同危险度患者中,随着表达基因数的增多,患者的生存时间呈明显缩短趋势(P<0.05)。结论:p15、DAPK、SOCS1和FHIT 4种基因联合检测有利于提高MDS患者的早期诊断和预后判断。
Objective: To investigate the value of p15,DAPK,SOCS1 and FHIT genes combined detection in the early diagnosis and prognosis evaluation of patients with myelodysplastic syndrome( MDS). Methods: The methylation-specific PCR( MSP) was used to detect the methylation of the above-mentioned 4 genes in 67 patients with MDS. The value of 4 gene combined detection in the early diagnosis and prognosis evaluation of patients with MDS was compared and anazlyzed.Results: The methylation rates of p15,DAPK,SOCS1 and FHIT genes in 67 patients with MDS were 37. 3%,35. 8%,47. 8% and 52. 2%,respectively,which were significantly higher than those in control group( P < 0. 05). The accordance rates of p15,DAPK,SOCS1 and FHIT single detection for diagnosis of MDS were 37. 3%,35. 8%,47. 8% and 52. 2%,respectively,meanswhile the accordance rate of above-mentioned 4 gene combined detection for diagnosis of MDS was 82.1%,which was significantly higher than that of single gene detection( P < 0. 001). The methylation of ≥2 genes in relatively high risk group was significantly higher than that in relatively low risk group( P < 0. 05). The median survival time of MDS patients was 18( 13. 3,22. 7) months; the median survival time in relatively low risk group was significantly longer than that in relatively high risk group [27( 20. 3,33. 7) months vs 9( 5. 9,12. 1) months]( P < 0. 05). The survival time of MDS patients with different risks displayed the trend of shorting feature along with increasing of methylated genes( P < 0.05). Conclusion: The combined detection of above menthioned 4 genes can improve the accuracy of early diagnosis and prognosis evaluation for MDS patients.
Objective: To investigate the value of p15,DAPK,SOCS1 and FHIT genes combined detection in the early diagnosis and prognosis evaluation of patients with myelodysplastic syndrome( MDS). Methods: The methylation-specific PCR( MSP) was used to detect the methylation of the above-mentioned 4 genes in 67 patients with MDS. The value of 4 gene combined detection in the early diagnosis and prognosis evaluation of patients with MDS was compared and anazlyzed.Results: The methylation rates of p15,DAPK,SOCS1 and FHIT genes in 67 patients with MDS were 37. 3%,35. 8%,47. 8% and 52. 2%,respectively,which were significantly higher than those in control group( P < 0. 05). The accordance rates of p15,DAPK,SOCS1 and FHIT single detection for diagnosis of MDS were 37. 3%,35. 8%,47. 8% and 52. 2%,respectively,meanswhile the accordance rate of above-mentioned 4 gene combined detection for diagnosis of MDS was 82.1%,which was significantly higher than that of single gene detection( P < 0. 001). The methylation of ≥2 genes in relatively high risk group was significantly higher than that in relatively low risk group( P < 0. 05). The median survival time of MDS patients was 18( 13. 3,22. 7) months; the median survival time in relatively low risk group was significantly longer than that in relatively high risk group [27( 20. 3,33. 7) months vs 9( 5. 9,12. 1) months]( P < 0. 05). The survival time of MDS patients with different risks displayed the trend of shorting feature along with increasing of methylated genes( P < 0.05). Conclusion: The combined detection of above menthioned 4 genes can improve the accuracy of early diagnosis and prognosis evaluation for MDS patients.
引文
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4 Gutiérrez MI,Siraj AK,Khaled H,et al.Cp G island methylation in Schistosoma-and non-Schistosoma-associated bladder cancer.Mod Pathol,2004;17(10):1268-1274.
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6 Kim M,Oh B,Kim SY,et al.p15INK4b methylation correlates with thrombocytopenia,blast percentage,and survival in myelodysplastic syndromes in a dose dependent manner:quantitation using pyrosequencing study.Leuk Res,2010;34(6):718-722.
7 Poloni A,Maurizi G,Mattiucci D,et al.Overexpression of CDKN2B(p15INK4B)and altered global DNA methylation status in mesenchymal stem cells of high-risk myelodysplastic syndromes.Leukemia,2014;28(11):2241-2244.
8 邓银芬,张磊,张秀群,等.骨髓增生异常综合征患者血浆DNA中FHIT基因启动子区甲基化状态及地西他滨的去甲基化作用.中国实验血液学杂志,2012;20(5):1144-1148.
9 Chaubey R,Sazawal S,Mahapatra M,et al.Prognostic relevance of aberrant SOCS-1 gene promoter methylation in myelodysplastic syndromes patients.Int J Lab Hematol,2015;37(2):265-271.
10 Zhao J,Zhao D,Poage GM,et al.Death-associated protein kinase 1promotes growth of p53-mutant cancers.J Clin Invest,2015;125(7):2707-2720.
2 Chan SM,Majeti R.Role of DNMT3A,TET2,and IDH1/2 mutations in pre-leukemic stem cells in acute myeloid leukemia.Int J Hematol,2013;98(6):648-657.
3 中华医学会血液学分会.骨髓增生异常综合征诊断与治疗专家共识.中华血液学杂志,2014;35(11):1042-1048.
4 Gutiérrez MI,Siraj AK,Khaled H,et al.Cp G island methylation in Schistosoma-and non-Schistosoma-associated bladder cancer.Mod Pathol,2004;17(10):1268-1274.
5 Gutiérrez MI,Siraj AK,Bhargava M,et al.Concurrent methylation of multiple genes in childhood ALL:Correlation with phenotype and molecular subgroup.Leukemia,2003;17(9):1845-1850.
6 Kim M,Oh B,Kim SY,et al.p15INK4b methylation correlates with thrombocytopenia,blast percentage,and survival in myelodysplastic syndromes in a dose dependent manner:quantitation using pyrosequencing study.Leuk Res,2010;34(6):718-722.
7 Poloni A,Maurizi G,Mattiucci D,et al.Overexpression of CDKN2B(p15INK4B)and altered global DNA methylation status in mesenchymal stem cells of high-risk myelodysplastic syndromes.Leukemia,2014;28(11):2241-2244.
8 邓银芬,张磊,张秀群,等.骨髓增生异常综合征患者血浆DNA中FHIT基因启动子区甲基化状态及地西他滨的去甲基化作用.中国实验血液学杂志,2012;20(5):1144-1148.
9 Chaubey R,Sazawal S,Mahapatra M,et al.Prognostic relevance of aberrant SOCS-1 gene promoter methylation in myelodysplastic syndromes patients.Int J Lab Hematol,2015;37(2):265-271.
10 Zhao J,Zhao D,Poage GM,et al.Death-associated protein kinase 1promotes growth of p53-mutant cancers.J Clin Invest,2015;125(7):2707-2720.