The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias.
The landscape of somatic mutations in infant MLL-rearranged acute lymphoblastic leukemias.
复制标题
婴儿MLL重新培养急性淋巴细胞白血病中体细胞突变的景观。
DOI：
10.1038/ng.3230
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发表时间：
2015-04
期刊：
影响因子：
30.8
通讯作者：
St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project
中科院分区：
文献类型：
--
作者：
Andersson AK;Ma J;Wang J;Chen X;Gedman AL;Dang J;Nakitandwe J;Holmfeldt L;Parker M;Easton J;Huether R;Kriwacki R;Rusch M;Wu G;Li Y;Mulder H;Raimondi S;Pounds S;Kang G;Shi L;Becksfort J;Gupta P;Payne-Turner D;Vadodaria B;Boggs K;Yergeau D;Manne J;Song G;Edmonson M;Nagahawatte P;Wei L;Cheng C;Pei D;Sutton R;Venn NC;Chetcuti A;Rush A;Catchpoole D;Heldrup J;Fioretos T;Lu C;Ding L;Pui CH;Shurtleff S;Mullighan CG;Mardis ER;Wilson RK;Gruber TA;Zhang J;Downing JR;St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project
伴有MLL重排的婴儿急性淋巴细胞性白血病(ALL-R)是一种预后不良的独特白血病。为了确定其突变情况，我们对65名婴儿(47名MLL-R和18名非MLL-R)和20名年龄较大的白血病儿童(MLL-R病例)进行了全基因组、外显子组、RNA和靶向DNA测序。我们的数据显示，婴儿MLL-R ALL的体细胞突变频率是所有已测序癌症中最低的之一，主要的白血病克隆携带平均1.3个非沉默突变。尽管突变很少，但有47%的人检测到了激活的激酶/PI3K/RAS信号通路突变。然而，令人惊讶的是，这些突变往往是亚克隆的，并且经常在复发时丢失。与婴儿相比，年龄较大的儿童MLL-R白血病有更多的体细胞突变(平均6.5个/例比1.3个/例，P=7.15×10−5)，并含有频繁的表观遗传调控基因突变(45%)，这类基因在婴儿MLL-R ALL中很少发生突变。
Infant acute lymphoblastic leukemia (ALL) with MLL rearrangements (MLL-R) represents a distinct leukemia with a poor prognosis. To define its mutational landscape, we performed whole genome, exome, RNA and targeted DNA sequencing on 65 infants (47 MLL-R and 18 non-MLL-R) and 20 older children (MLL-R cases) with leukemia. Our data demonstrated infant MLL-R ALL to have one of the lowest frequencies of somatic mutations of any sequenced cancer, with the predominant leukemic clone carrying a mean of 1.3 non-silent mutations. Despite the paucity of mutations, activating mutations in kinase/PI3K/RAS signaling pathways were detected in 47%. Surprisingly, however, these mutations were often sub-clonal and frequently lost at relapse. In contrast to infant cases, MLL-R leukemia in older children had more somatic mutations (a mean of 6.5/case versus 1.3/case, P=7.15×10−5) and contained frequent mutations (45%) in epigenetic regulators, a category of genes that with the exception of MLL was rarely mutated in infant MLL-R ALL.