Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia.
Genomic and epigenomic landscapes of adult de novo acute myeloid leukemia.
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DOI：
10.1056/nejmoa1301689
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发表时间：
2013-05-30
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影响因子：
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通讯作者：
Eley G
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作者：
Cancer Genome Atlas Research Network;Ley TJ;Miller C;Ding L;Raphael BJ;Mungall AJ;Robertson A;Hoadley K;Triche TJ Jr;Laird PW;Baty JD;Fulton LL;Fulton R;Heath SE;Kalicki-Veizer J;Kandoth C;Klco JM;Koboldt DC;Kanchi KL;Kulkarni S;Lamprecht TL;Larson DE;Lin L;Lu C;McLellan MD;McMichael JF;Payton J;Schmidt H;Spencer DH;Tomasson MH;Wallis JW;Wartman LD;Watson MA;Welch J;Wendl MC;Ally A;Balasundaram M;Birol I;Butterfield Y;Chiu R;Chu A;Chuah E;Chun HJ;Corbett R;Dhalla N;Guin R;He A;Hirst C;Hirst M;Holt RA;Jones S;Karsan A;Lee D;Li HI;Marra MA;Mayo M;Moore RA;Mungall K;Parker J;Pleasance E;Plettner P;Schein J;Stoll D;Swanson L;Tam A;Thiessen N;Varhol R;Wye N;Zhao Y;Gabriel S;Getz G;Sougnez C;Zou L;Leiserson MD;Vandin F;Wu HT;Applebaum F;Baylin SB;Akbani R;Broom BM;Chen K;Motter TC;Nguyen K;Weinstein JN;Zhang N;Ferguson ML;Adams C;Black A;Bowen J;Gastier-Foster J;Grossman T;Lichtenberg T;Wise L;Davidsen T;Demchok JA;Shaw KR;Sheth M;Sofia HJ;Yang L;Downing JR;Eley G
导致急性髓细胞白血病（AML）发病的许多突变尚不明确。突变模式和表观遗传表型之间的关系尚不清楚。我们使用全基因组测序（50例）或全外显子组测序（150例），沿着RNA和microRNA测序以及DNA甲基化分析，分析了200例临床注释的成人初发AML病例的基因组。AML基因组的突变比大多数其他成人癌症少，平均只有13个基因突变。其中，平均5个是AML中复发突变的基因。共有23个基因发生了显著突变，另有237个基因在两个或更多样本中发生了突变。几乎所有的样本在九类基因中至少有一个非同义突变，这些基因几乎肯定与发病机制有关，包括转录因子融合（18%的病例），编码核磷酸蛋白（NPM 1）的基因（27%），肿瘤抑制基因（16%），DNA甲基化相关基因（44%），信号基因（59%），染色质修饰基因（30%），髓系转录因子基因（22%）、粘附素复合体基因（13%）和剪接体复合体基因（14%）。合作和相互排斥的模式表明了几个基因和类别之间的强大生物学关系。我们在几乎所有AML样本中发现了至少一种潜在的驱动突变，并发现遗传事件的复杂相互作用有助于个体患者的AML发病机制。本研究的数据库广泛可用，可作为进一步研究AML发病机制、分类和风险分层的基础。（由美国国立卫生研究院资助。
Many mutations that contribute to the pathogenesis of acute myeloid leukemia (AML) are undefined. The relationships between patterns of mutations and epigenetic phenotypes are not yet clear. We analyzed the genomes of 200 clinically annotated adult cases of de novo AML, using either whole-genome sequencing (50 cases) or whole-exome sequencing (150 cases), along with RNA and microRNA sequencing and DNA-methylation analysis. AML genomes have fewer mutations than most other adult cancers, with an average of only 13 mutations found in genes. Of these, an average of 5 are in genes that are recurrently mutated in AML. A total of 23 genes were significantly mutated, and another 237 were mutated in two or more samples. Nearly all samples had at least 1 nonsynonymous mutation in one of nine categories of genes that are almost certainly relevant for pathogenesis, including transcription-factor fusions (18% of cases), the gene encoding nucleophosmin (NPM1) (27%), tumor-suppressor genes (16%), DNA-methylation–related genes (44%), signaling genes (59%), chromatin-modifying genes (30%), myeloid transcription-factor genes (22%), cohesin-complex genes (13%), and spliceosome-complex genes (14%). Patterns of cooperation and mutual exclusivity suggested strong biologic relationships among several of the genes and categories. We identified at least one potential driver mutation in nearly all AML samples and found that a complex interplay of genetic events contributes to AML pathogenesis in individual patients. The databases from this study are widely available to serve as a foundation for further investigations of AML pathogenesis, classification, and risk stratification. (Funded by the National Institutes of Health.)