骨髓增生异常综合征患者IDH1和IDH2基因突变的临床意义  

Relationship between clinical characteristics and myelodysplastic syndrome patients with isocitratedehydrogenase gene mutations

作　　者：佟红艳[1] 胡超[1] 余梦霞[1] 马秋玲 陈菲菲[1] 叶丽[1] 韦菊英[1] 许改香[1] 毛莉萍[1] 李颖[1] 金洁[1] 

机构地区：[1]浙江大学医学院附属第一医院血液科骨髓增生异常综合征中心浙江大学血液病研究所浙江省血液病重点实验室,杭州310009 [2]河南中医学院第二附属医院血液科

出　　处：《中华医学杂志》2013年第40期3180-3184,共5页National Medical Journal of China

基　　金：国家自然科学基金（30870914、81270582）;卫生行业科研专项（201202017）;浙江省自然科学杰出青年项目（LR12H08001）;浙江省重点科技创新团队项目（2011R50015）;浙江省重大科技专项（2013C13G2010036）;浙江省卫生厅支撑学科重点项目（201234445）

摘　　要：目的检测异柠檬酸脱氢酶（IDH）1和IDH2基因突变在骨髓增生异常综合征（MDS）患者中的发生率，评估其与MDS患者临床特征的关系，并探讨其对MDS患者预后的影响。方法采集2006年1月至2012年8月浙江大学医学院附属第一医院收治的108例初发MDS患者骨髓单个核细胞，提取基因组DNA，利用PCR技术扩增患者IDH1、2基因第4号外显子，测序检测IDH1R132及IDH2R140、R172基因突变情况，探究MDS患者IDH基因突变的临床意义。结果108例MDS患者共测出IDH突变11例（10．19％，11／108），均为杂合突变。其中IDH1突变6例（5．56％，6／108），均为P．R132C；IDH2突变5例（4．63％，5／108），均为P．R140Q，未发现IDH2R172基因突变，也未发现IDH1和IDH2基因突变共存于同一患者的现象。IDH突变主要集中在难治性贫血伴原始细胞增多（RAEB）亚型（2例RAEBI，7例RAEB2）。IDH突变组初诊时骨髓原始细胞比例高于非突变组（中位数12．5％比6．0％，P=0．013），而白细胞计数、血红蛋白、血小板等指标差异均无统计学意义（均P〉0．05）。核型正常与异常的患者中具有相似IDH突变率（7／66比4／40，P〉0．05）。中位随访472do突变组中位生存时间较非突变组的短（512比740d，P=0．017）。在国际预后评分系统（IPSS）的中危-1组中，IDH基因突变组总体生存时间比非突变组短（中位数512d比未达到，P=0．038）。在11例IDH突变的患者中，地西他滨治疗组比非地西他滨治疗组有较好的预后（中位生存时间623比165d，P=0．049）。结论IDH基因突变与MDS患者临床特征、预后存在一定的相关性，提示其为预后不良分子学标志，将之纳入MDS预后评分中可以完善现有的预后评分系统。去甲基化治疗是IDH突变阳性患者的一种有效治疗手段。Objective To assess the prevalence and clinical characteristics of isocitrate dehydrogenase 1 and 2 （IDH 1 and IDH2 ） gene mutations in myelodysplastic syndrome （MDS） patients. Methods Pretreatment bone marrow specimens were enriched for mononuclear ceils in 108 adult patients with de novo MDS from January 2006 to August 2012. Genomic DNA was extracted from mononuclear cells. And PCR and direct sequencing were performed to sequence exon 4 of IDH gene. Results IDH mutations were discovered in 11 MDS patients （10. 19%, 11/108） and all were heterozygous. Thefrequencies of IDH1 and IDH2 mutations were 5.56% （6/108） and 4. 63% （5/108） respectively. Only one type of IDH1 mutation （c. 394C→T, p. R132C） was identified in our cohort. All IDH2 mutations caused the changes of R140 （c. 419G→A, p. R140Q）. However IDH2 R172 mutation was not detected. The combined mutations of IDH1 and IDH2 were not simultaneously observed in the same patient. The prevalence of IDH mutation was higher in advanced-stage MDS than those early-stage MDS patients. Mutated and wild-type groups had significantly difference in bone marrow blast percentage （median 12. 5% vs 6. 0%, P = 0. 013） at diagnosis, but not in white blood cell count, hemoglobin level and platelet count, etc. In the normal karyotype group, the frequencies of IDH mutations were as similar as those in the abnormal karyotype group （ 10. 61% （7/66） vs 10. 00% （4/40）, P 〉 0. 05 ）. The median follow-up time was 472 d, our data indicated that IDH mutations were correlated with poor overall survival （median time 512 vs 740 d, P =0. 017）. IDH mutations were also an inferiorly predictive factor in the intermediate-1 group patients of International Prognostic Scoring System （IPSS） （median survival time 512 d vs not reached, P = 0. 038 ）. There was also better efficacies than other treatments in IDH mutation positive patients （ median survival time 623 vs 165 d,P = 0. 049）. Conclusions IDH mutation is a vital biomarker for bett

关 键 词：骨髓增生异常综合征 异柠檬酸脱氢酶 突变 预后 

分 类 号：R551.3[医药卫生—血液循环系统疾病]