Recurring mutations found by sequencing an acute myeloid leukemia genome.
Recurring mutations found by sequencing an acute myeloid leukemia genome.
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DOI：
10.1056/nejmoa0903840
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发表时间：
2009-09-10
期刊：
影响因子：
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通讯作者：
Ley TJ
中科院分区：
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作者：
Mardis ER;Ding L;Dooling DJ;Larson DE;McLellan MD;Chen K;Koboldt DC;Fulton RS;Delehaunty KD;McGrath SD;Fulton LA;Locke DP;Magrini VJ;Abbott RM;Vickery TL;Reed JS;Robinson JS;Wylie T;Smith SM;Carmichael L;Eldred JM;Harris CC;Walker J;Peck JB;Du F;Dukes AF;Sanderson GE;Brummett AM;Clark E;McMichael JF;Meyer RJ;Schindler JK;Pohl CS;Wallis JW;Shi X;Lin L;Schmidt H;Tang Y;Haipek C;Wiechert ME;Ivy JV;Kalicki J;Elliott G;Ries RE;Payton JE;Westervelt P;Tomasson MH;Watson MA;Baty J;Heath S;Shannon WD;Nagarajan R;Link DC;Walter MJ;Graubert TA;DiPersio JF;Wilson RK;Ley TJ
负责急性髓性白血病（AML）发病机制的DNA突变的完整补充尚不清楚。我们使用大规模平行DNA测序获得了一个非常高水平的覆盖率（约98%）的初级，细胞遗传学正常，从头基因组的AML与最低限度的成熟（AML-M1）和匹配的正常皮肤基因组。我们确定了12个获得性（体细胞）基因编码序列内的突变和52个体细胞基因组的保守或调控部分的点突变。所有突变似乎都是杂合的，并且存在于肿瘤样品中的几乎所有细胞中。64个突变中的4个发生在188个检测样本中至少1个额外的AML样本中。NRAS和NPM 1的突变先前已在AML患者中发现，但其他两种突变尚未发现。这些突变之一，在IDH 1基因中，存在于187个额外的AML基因组中的15个，并且与正常的细胞遗传学状态密切相关;它存在于80个细胞遗传学正常的样本中的13个（16%）。另一个是在高等哺乳动物中具有调控潜力和保守性的基因组区域中的非基因突变;我们在另一个AML肿瘤中检测到它。我们测序的AML基因组包含大约750个点突变，其中只有一小部分可能与发病机制相关。通过比较AML-M1患者的肿瘤和皮肤基因组序列，我们已经确定了可能与发病机制相关的复发突变。
The full complement of DNA mutations that are responsible for the pathogenesis of acute myeloid leukemia (AML) is not yet known. We used massively parallel DNA sequencing to obtain a very high level of coverage (approximately 98%) of a primary, cytogenetically normal, de novo genome for AML with minimal maturation (AML-M1) and a matched normal skin genome. We identified 12 acquired (somatic) mutations within the coding sequences of genes and 52 somatic point mutations in conserved or regulatory portions of the genome. All mutations appeared to be heterozygous and present in nearly all cells in the tumor sample. Four of the 64 mutations occurred in at least 1 additional AML sample in 188 samples that were tested. Mutations in NRAS and NPM1 had been identified previously in patients with AML, but two other mutations had not been identified. One of these mutations, in the IDH1 gene, was present in 15 of 187 additional AML genomes tested and was strongly associated with normal cytogenetic status; it was present in 13 of 80 cytogenetically normal samples (16%). The other was a nongenic mutation in a genomic region with regulatory potential and conservation in higher mammals; we detected it in one additional AML tumor. The AML genome that we sequenced contains approximately 750 point mutations, of which only a small fraction are likely to be relevant to pathogenesis. By comparing the sequences of tumor and skin genomes of a patient with AML-M1, we have identified recurring mutations that may be relevant for pathogenesis.