p15^INK4B甲基化与骨髓增生异常综合征患者预后及地西他滨疗效的关系

p15INK4B methylation on prognosis and response to decitabine in patients with MDS

目的通过检测初诊骨髓增生异常综合征（MDS）患者p15^INK4B甲基化水平，观察地西他滨治疗前、后p15^INK4B甲基化状态变化，探讨p15“啪甲基化水平与预后的关系及其对地西他滨疗效的影响。方法261例初诊MDS患者，其中男143例，女118例，中位年龄52（32—78）岁。低危组172例（低危104例、中危-168例），高危组89例（中危-252例、高危37例）。收集患者骨髓单个核细胞，采用甲基化特异性PCR（MSP）检测p15^INK4B甲基化水平，按p15^INK4B甲基化程度对患者进行生存分析。采用MSP方法分别检测58例MDS患者地西他滨治疗前及治疗2个疗程后骨髓p15^INK4B甲基化水平，分析p15^INK4B甲基化对地西他滨疗效的影响。结果低危组患者p15^INK4B甲基化水平明显低于高危组患者（117．22对157．63，P〈0．05）。p15^INK4B甲基化阳性患者2年预期生存（OS）率低于阴性患者（69．8％对91．8％，P〈0．05）；在低危组，p15^INK4B甲基化阳性患者2年预期OS率低于阴性患者（78．2％对92．0％，P〈0．05）；在高危组，p15^INK4B甲基化阳性患者OS率及中位0S时间与阴性患者比较差异无统计学意义[35．6％对38．5％，（17．0±9．3）个月对（18．0±5．7）个月，P〉0．05]。COX分析结果显示p15^INK4B甲基化水平是OS时间的独立预后因素。治疗前p15^INK4B甲基化阳性组患者地西他滨治疗的总反应率及完全缓解率与阴性组比较差异无统计学意义（65．9％对76．5％，22．0％对29．4％，P〉0．05）。地西他滨治疗有效组p15^INK4B甲基化水平在治疗前、后差异无统计学意义（P〉0．05）。结论初诊时p15^INK4B甲基化水平高的MDS患者生存时间更短，但p15^INK4B甲基化水平对地西他滨疗效无明显影响。

Objective To detect p15INK4B methylation levels and the kinetics of the methylation status before and after decitabine to explore its influences on prognosis and response to decitabine in myelodysplastic syndromes （MDS） patients. Methods We examined 261 MDS patients （ 143 male and 118 female） with the median age of 52 years （32-78）. Of them, 172 cases were low-risk group （low-risk 104 cases, intermediate-1 68 cases） , 89 cases high-risk group （intermediate-2 52 cases, high risk 37 cases）. Collections of bone marrow mononuclear cells of MDS patients and extracted the genomic DNA, the methylation status of p15INK4B was detected by methylation-specific PCR （MSP） method. Survival analysis was conducted according to the level of p15INK4B methylation in the cohort of patients. The kinetics of the methylation levels of p15INK4B in 58 MDS patients before and after 2 courses of decitabine have been assessed with the method of MSP. Results The methylation level of p15INK4B in low-risk group patients was significantly lower than that in high-risk group （ 117.22 vs 157.63, P 〈0.05 ）. The expected 2-year survival rate of p15INKaB methylation positive patients was lower than that of negative ones （91.8% vs 69.8%, P 〈 0.05 ） ; the expected 2-year survival rate of p15tNK4s methylation positive patients was shorter than that of negative ones in low-risk group （78.2% vs 92.0% , P 〈 0.05 ）, meanwhile there was no significant difference in terms of expected 2-year survival rate and median expected survival between p15tNK4s methylation positive and negative patients in high-risk group [ 35.6% vs 38.5%, （ 17.0 ± 9.3） month vs （ 18.0 ± 5.7） month, P 〉 0.05 ]. Multivariate analysis showed p15INK4B methylation degree was an independent prognostic factor for overall survival. No statistical difference of overall response （OR） rates were found between p15INK4B methylation positive patients and negative patients before decitabine（65.9% vs 76.5%, P 〉 0.05）, and complete remission （CR） rates between these two groups also showed no statistical difference（22.0% vs 29.4% , P 〉 0.05 ）. p15INK4B methylation levels had no obvious change before and after treatment in decitabine responders （ P 〉 0.05 ）. Conclusion The survival of newly diagnosed MDS patients with positive p15INK4B methylation was comparatively shorter, but p15INK4B methylation had no influence on response to decitabine.