Leukemic mutations in the methylation-associated genes DNMT3A and IDH2 are rare events in pediatric AML: a report from the Children's Oncology Group.
Leukemic mutations in the methylation-associated genes DNMT3A and IDH2 are rare events in pediatric AML: a report from the Children's Oncology Group.
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DOI：
10.1002/pbc.23179
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发表时间：
2011-08
影响因子：
3.2
通讯作者：
Meshinchi, Soheil
中科院分区：
文献类型：
--
作者：
Ho, Phoenix A.;Kutny, Matthew A.;Alonzo, Todd A.;Gerbing, Robert B.;Joaquin, Jason;Raimondi, Susana C.;Gamis, Alan S.;Meshinchi, Soheil
关键词：
DNMT 3A、TET 2、IDH 1和IDH 2基因的突变具有预后意义，并且经常发生在成人AML中。最近，所有四个基因的白血病突变都与异常DNA甲基化（肿瘤形成的标志）有关。我们之前报道了IDH 1突变不存在，而TET 2突变存在于6%的儿童AML患者中;在本研究中，我们确定了DNMT 3A和IDH 2突变在儿童AML中的患病率。我们通过对180名接受儿童肿瘤组临床试验AAML 03 P1治疗的儿童的诊断标本进行直接测序，筛查DNMT 3A和IDH 2突变。突变阳性患者的临床特征、其他白血病突变的存在和生存结局均被确定。未检测到疾病相关的DNMT 3A突变。在4/180例患者（2.2%）中检测到IDH 2突变，影响密码子R140（n=3）和R172（n=1）。2例IDH 2突变患者携带t（8;21），1例患者携带MLL易位，1例患者伴随NPM 1突变。在我们的研究中，FLT 3、CEBPA和WT 1突变没有与IDH 2突变一起发生。DNMT 3A和IDH 2突变在儿童AML中并不常见。在我们的研究中，甲基化相关突变的低患病率突出了儿童与成人AML在遗传以及潜在的表观遗传水平上的发病机制差异。AML的年龄特异性特征强调了平行研究儿童和成人形式白血病的分子生物学的重要性，因为新疗法的开发应该考虑这些生物学差异。
Mutations in the DNMT3A, TET2, IDH1, and IDH2 genes carry prognostic significance and occur frequently in adult AML. Leukemic mutations in all four genes have recently been implicated in aberrant DNA methylation, a hallmark of neoplasia. We previously reported that IDH1 mutations were absent whereas TET2 mutations were present in 6% of pediatric AML patients; in the present study we determined the prevalence of DNMT3A and IDH2 mutations in pediatric AML. We screened for DNMT3A and IDH2 mutations by direct sequencing of diagnostic specimens from 180 children treated on the Children’s Oncology Group clinical trial AAML03P1. Clinical characteristics, the presence of other leukemic mutations, and survival outcome was determined for mutation-positive patients. No disease-associated DNMT3A mutations were detected. IDH2 mutations were detected in 4/180 patients (2.2%), affecting codons R140 (n=3) and R172 (n=1). Two patients with IDH2 mutations harbored t(8;21), one patient harbored an MLL translocation, and one patient had a concomitant NPM1 mutation. FLT3, CEBPA, and WT1 mutations did not occur together with IDH2 mutations in our study. DNMT3A and IDH2 mutations are uncommon in pediatric AML. The low prevalence of methylation-associated mutations in our study highlights the differences in the pathogenesis of pediatric vs. adult AML, at the genetic as well as potentially the epigenetic level. The age-specific characteristics of AML underscore the importance of studying the molecular biology of both childhood and adult forms of this leukemia in parallel, as the development of novel therapeutics should account for these biologic differences.
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影响因子：
158.5
作者：
Falini, B;Mecucci, C;Martelli, MF
通讯作者：
Martelli, MF
影响因子：
50.3
作者：
Figueroa ME;Abdel-Wahab O;Lu C;Ward PS;Patel J;Shih A;Li Y;Bhagwat N;Vasanthakumar A;Fernandez HF;Tallman MS;Sun Z;Wolniak K;Peeters JK;Liu W;Choe SE;Fantin VR;Paietta E;Löwenberg B;Licht JD;Godley LA;Delwel R;Valk PJ;Thompson CB;Levine RL;Melnick A
通讯作者：
Melnick A
影响因子：
45.3
作者：
Paschka, Peter;Schlenk, Richard F.;Doehner, Konstanze
通讯作者：
Doehner, Konstanze
DOI：
10.1056/nejmoa1005143
发表时间：
2010-12-16
期刊：
The New England journal of medicine
影响因子：
--
作者：
Ley TJ;Ding L;Walter MJ;McLellan MD;Lamprecht T;Larson DE;Kandoth C;Payton JE;Baty J;Welch J;Harris CC;Lichti CF;Townsend RR;Fulton RS;Dooling DJ;Koboldt DC;Schmidt H;Zhang Q;Osborne JR;Lin L;O'Laughlin M;McMichael JF;Delehaunty KD;McGrath SD;Fulton LA;Magrini VJ;Vickery TL;Hundal J;Cook LL;Conyers JJ;Swift GW;Reed JP;Alldredge PA;Wylie T;Walker J;Kalicki J;Watson MA;Heath S;Shannon WD;Varghese N;Nagarajan R;Westervelt P;Tomasson MH;Link DC;Graubert TA;DiPersio JF;Mardis ER;Wilson RK
通讯作者：
Wilson RK
影响因子：
20.3
作者：
Pollard, Jessica A.;Alonzo, Todd A.;Meshinchi, Soheil
通讯作者：
Meshinchi, Soheil