CAJ | 학술논문

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IDH1 R132及IDH2 R140、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IDH2 R172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RAEB1,7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472 d.突变组中位生存时间较非突变组的短(512比740 d,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512 d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165 d,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.
목적 검측이저몽산탈경매(IDH)1화IDH2기인돌변재골수증생이상종합정(MDS)환자중적발생솔,평고기여MDS환자림상특정적관계,병탐토기대MDS환자예후적영향.방법 채집2006년1월지2012년8월절강대학의학원부속제일의원수치적108례초발MDS환자골수단개핵세포,제취기인조DNA,이용PCR기술확증환자IDH1、2기인제4호외현자,측서검측IDH1 R132급IDH2 R140、R172기인돌변정황,탐구MDS환자IDH기인돌변적림상의의.결과 108례MDS환자공측출IDH돌변11례(10.19％,11/108),균위잡합돌변.기중IDH1돌변6례(5.56％,6/108),균위p.R132C；IDH2돌변5례(4.63％,5/108),균위p.R140Q,미발현IDH2 R172기인돌변,야미발현IDH1화IDH2기인돌변공존우동일환자적현상.IDH돌변주요집중재난치성빈혈반원시세포증다(RAEB)아형(2례RAEB1,7례RAEB2).IDH돌변조초진시골수원시세포비례고우비돌변조(중위수12.5％비6.0％,P=0.013),이백세포계수、혈홍단백、혈소판등지표차이균무통계학의의(균P＞0.05).핵형정상여이상적환자중구유상사IDH돌변솔(7/66비4/40,P＞0.05).중위수방472 d.돌변조중위생존시간교비돌변조적단(512비740 d,P=0.017).재국제예후평분계통(IPSS)적중위-1조중,IDH기인돌변조총체생존시간비비돌변조단(중위수512 d비미체도,P=0.038).재11례IDH돌변적환자중,지서타빈치료조비비지서타빈치료조유교호적예후(중위생존시간623비165 d,P=0.049).결론 IDH기인돌변여MDS환자림상특정、예후존재일정적상관성,제시기위예후불량분자학표지,장지납입MDS예후평분중가이완선현유적예후평분계통.거갑기화치료시IDH돌변양성환자적일충유효치료수단.
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 cells 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.The frequencies 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 better risk stratification of MDS patients with and improving IPSS.Hypomethylating agents may be effective for treating IDH mutation positive patients.