骨髓增生异常综合征患者FHIT基因启动子甲基化改变

Alteration of methylation status of fragile histidine triad gene promoter in patients with myelmiysplasfic syndrome

目的研究骨髓增生异常综合征 （ myelodysplastic syndrome, MDS） 患者中脆性组氨酸三联基因（fragile histidine triad, FHIT）启动子的甲基化状况及其临床相关性。方法应用甲基化特异性PCR（methylation-specific PCR, MSP）技术对54例不同阶段MDS患者骨髓标本FHIT基因甲基化状态进行检测。结果54例MDS患者中26例（48．1％）发生FHIT基因甲基化，FHIT基因甲基化改变与患者的性别、血象、染色体异常等结果均无相关性，但与患者年龄具有显著的相关性（R=-0．291，P=0．033）。FHIT基因甲基化频率在难治性贫血／伴有环形铁粒幼细胞的难治性贫血 （refractory anemia/refractory anemia with ringed sideroblasts, RA/RAS） （ 1/6,16.7% ）,伴多系病态造血的难治性血细胞减少症（refractory cytopenia with muhilineage dysplasia, RCMD） 和伴环形铁粒幼细胞的RCMD（refractory cytopenia with multilineage dysplasia with ringed blasts,RCMD-RS） （6/19,31.6%）,难治性贫血伴有原始细胞增多-1型（ refractory anemia with excess blasts- 1, RAEB- 1 ） （7／11，63．6％）、难治性贫血伴原始细胞增多2型（refractory anemia with excess blasts-2, RAEB-2） （4/7, 57.1% ）和难治性贫血伴有原始细胞增多转化型／急性髓性白血病（refractory anemia with excess blasts in transformation/acute myeloid leukemia, RAEBt/AML） （8/11,72.7 % ）之间的差异无统计学意义（X^2=8．417，P=0．077），但早期阶段（RA／RAS和RCMD）、晚期阶段（RAEB-1和RAEB-2）以及RAEBt／AML患者之间的差异具有统计学意义（X^2=7．938，P=0．019），并且FHIT基因甲基化频率与国际预后评分系统分组预后危险程度也具有显著的正相关性（X^2=10．110，P=0．018）。结论FHTI基因甲基化可能是促进MDS疾病进展的分子事件之一。

Objective To study the methylation status of fragile histidine triad （FHIT） gene promoter in patients with myelodysplastic syndrome （MDS） and its clinical relevance. Methods Methylation-specific PCR （MSP） was used to detect FHIT promoter methylation in bone marrow samples from 54 MDS cases. Results Hypermethylation of FHIT promoter was detected in 26 cases （48.1% ）. Association was not found between FHIT gene hypermethylation and sex, hematologic parameters and chromosomal abnormalities of MDS patients, but found between FHIT gene hypermethylation and age of the MDS cases. Although significant difference was not observed in the frequencies of FHIT gene hypermethylation among patients with refractory anemia/refractory anemia with ringed sideroblasts （RA/RAS） （1/6, 16.7% ）, refractory anemia/refractory anemia with ringed sideroblasts （RCMD） and refractory cytopenia with multilineage dysplasia with ringed blasts （RCMD-RS） （6/19, 31.6%）, refractory anemia with excess blasts-1 （RAEB-1） （7/ 11, 63.6%）, refractory anemia with excess blasts-2 （RAEB-2） （4/7, 57.1%） and refractory anemia with excess blasts in transformation/acute myeloid leukemia （RAEBt/AML） （8/11, 72.7% ）（X^2 = 8.417, P =0.077）, it was observed in patients in early stages （RA/RAS and RCMD） （7/25, 28.0%）, advanced stages （RAEB-1 and RAEB-2） （11/18, 61.1%） and RAEBt/AML （8/11, 72.7%） （X^2 = 7.938, P = 0.019）. Furthermore, there was a positive correlation between the frequency of FHIT gene hypermethylation and different IPSS groups （X^2 = 10.110, P = 0.018）. Conclusion FHIT gene hypermethylation might be one of the molecular events involved in the disease progression of MDS.