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The molecular landscape of pediatric acute myeloid leukemia reveals recurrent structural alterations and age-specific mutational interactions.
Nature Medicine ( IF 82.9 ) Pub Date : 2017-12-11 , DOI: 10.1038/nm.4439 Hamid Bolouri 1 , Jason E Farrar 2 , Timothy Triche 3 , Rhonda E Ries 4 , Emilia L Lim 5 , Todd A Alonzo 6, 7 , Yussanne Ma 5 , Richard Moore 5 , Andrew J Mungall 5 , Marco A Marra 5 , Jinghui Zhang 8 , Xiaotu Ma 8 , Yu Liu 8 , Yanling Liu 8 , Jaime M Guidry Auvil 9 , Tanja M Davidsen 9 , Patee Gesuwan 9 , Leandro C Hermida 9 , Bodour Salhia 10 , Stephen Capone 3 , Giridharan Ramsingh 3 , Christian Michel Zwaan 11 , Sanne Noort 11 , Stephen R Piccolo 12, 13 , E Anders Kolb 14 , Alan S Gamis 15 , Malcolm A Smith 16 , Daniela S Gerhard 9 , Soheil Meshinchi 4
Nature Medicine ( IF 82.9 ) Pub Date : 2017-12-11 , DOI: 10.1038/nm.4439 Hamid Bolouri 1 , Jason E Farrar 2 , Timothy Triche 3 , Rhonda E Ries 4 , Emilia L Lim 5 , Todd A Alonzo 6, 7 , Yussanne Ma 5 , Richard Moore 5 , Andrew J Mungall 5 , Marco A Marra 5 , Jinghui Zhang 8 , Xiaotu Ma 8 , Yu Liu 8 , Yanling Liu 8 , Jaime M Guidry Auvil 9 , Tanja M Davidsen 9 , Patee Gesuwan 9 , Leandro C Hermida 9 , Bodour Salhia 10 , Stephen Capone 3 , Giridharan Ramsingh 3 , Christian Michel Zwaan 11 , Sanne Noort 11 , Stephen R Piccolo 12, 13 , E Anders Kolb 14 , Alan S Gamis 15 , Malcolm A Smith 16 , Daniela S Gerhard 9 , Soheil Meshinchi 4
Affiliation
We present the molecular landscape of pediatric acute myeloid leukemia (AML) and characterize nearly 1,000 participants in Children's Oncology Group (COG) AML trials. The COG-National Cancer Institute (NCI) TARGET AML initiative assessed cases by whole-genome, targeted DNA, mRNA and microRNA sequencing and CpG methylation profiling. Validated DNA variants corresponded to diverse, infrequent mutations, with fewer than 40 genes mutated in >2% of cases. In contrast, somatic structural variants, including new gene fusions and focal deletions of MBNL1, ZEB2 and ELF1, were disproportionately prevalent in young individuals as compared to adults. Conversely, mutations in DNMT3A and TP53, which were common in adults, were conspicuously absent from virtually all pediatric cases. New mutations in GATA2, FLT3 and CBL and recurrent mutations in MYC-ITD, NRAS, KRAS and WT1 were frequent in pediatric AML. Deletions, mutations and promoter DNA hypermethylation convergently impacted Wnt signaling, Polycomb repression, innate immune cell interactions and a cluster of zinc finger-encoding genes associated with KMT2A rearrangements. These results highlight the need for and facilitate the development of age-tailored targeted therapies for the treatment of pediatric AML.
中文翻译:
小儿急性髓细胞性白血病的分子格局揭示了反复出现的结构改变和特定年龄的突变相互作用。
我们介绍了小儿急性髓细胞性白血病(AML)的分子格局,并表征了儿童肿瘤学组(COG)AML试验的近1,000名参与者。COG国家癌症研究所(NCI)的TARGET AML计划通过全基因组,靶向DNA,mRNA和microRNA测序以及CpG甲基化分析评估了病例。经验证的DNA变体对应于各种不常见的突变,在超过2%的病例中,少于40个基因发生了突变。相反,与成人相比,在年轻人中体细胞结构变异,包括新的基因融合和MBNL1,ZEB2和ELF1的局部缺失,不成比例地普遍存在。相反,实际上在所有儿科病例中均不存在成年人中常见的DNMT3A和TP53突变。GATA2,FLT3和CBL中的新突变以及MYC-ITD中的复发性突变,NRAS,KRAS和WT1在小儿AML中很常见。缺失,突变和启动子DNA高甲基化会聚在一起影响Wnt信号,Polycomb抑制,先天免疫细胞相互作用以及与KMT2A重排相关的锌指编码基因簇。这些结果强调了针对儿童AML的针对年龄的针对性治疗的需求并促进了其发展。
更新日期:2017-12-11
中文翻译:
小儿急性髓细胞性白血病的分子格局揭示了反复出现的结构改变和特定年龄的突变相互作用。
我们介绍了小儿急性髓细胞性白血病(AML)的分子格局,并表征了儿童肿瘤学组(COG)AML试验的近1,000名参与者。COG国家癌症研究所(NCI)的TARGET AML计划通过全基因组,靶向DNA,mRNA和microRNA测序以及CpG甲基化分析评估了病例。经验证的DNA变体对应于各种不常见的突变,在超过2%的病例中,少于40个基因发生了突变。相反,与成人相比,在年轻人中体细胞结构变异,包括新的基因融合和MBNL1,ZEB2和ELF1的局部缺失,不成比例地普遍存在。相反,实际上在所有儿科病例中均不存在成年人中常见的DNMT3A和TP53突变。GATA2,FLT3和CBL中的新突变以及MYC-ITD中的复发性突变,NRAS,KRAS和WT1在小儿AML中很常见。缺失,突变和启动子DNA高甲基化会聚在一起影响Wnt信号,Polycomb抑制,先天免疫细胞相互作用以及与KMT2A重排相关的锌指编码基因簇。这些结果强调了针对儿童AML的针对年龄的针对性治疗的需求并促进了其发展。