DNMT3A mutations in acute myeloid leukemia.
DNMT3A mutations in acute myeloid leukemia.
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DOI：
10.1056/nejmoa1005143
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发表时间：
2010-12-16
期刊：
影响因子：
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通讯作者：
Wilson RK
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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
在大多数急性髓性白血病（AML）患者中，导致不良结局的遗传变异尚不清楚。使用大规模并行DNA测序，我们确定了DNMT 3A的体细胞突变，编码DNA甲基转移酶，在一个正常核型的AML患者的细胞基因组中。我们对另外280例新发AML患者的DNMT 3A外显子进行测序，以确定复发突变。281例患者中共有62例（22.1%）存在DNMT 3A突变，这些突变预计会影响翻译。我们确定了18种不同的错义突变，其中最常见的是预测影响氨基酸R882（在37例患者中）。我们还确定了六个移码，六个无义，和三个剪接位点突变和一个1.5-Mbp的缺失，包括DNMT 3A。这些突变在具有中等风险细胞遗传学特征的患者组中高度富集（166例患者中的56例，或33.7%），但在所有79例具有中等风险细胞遗传学特征的患者中均不存在（两种比较均为P<0.001）。DNMT 3A突变患者的中位总生存期显著短于无此类突变患者（12.3个月vs.41.1个月，P<0.001）。在具有中等风险细胞遗传学特征或FLT 3突变的患者中，DNMT 3A突变与不良结局相关，与年龄无关，并且在考克斯比例风险分析中与不良结局独立相关。DNMT 3A突变在具有中等风险细胞遗传学特征的新发AML患者中高度复发，并与不良结局独立相关。（由美国国立卫生研究院和其他机构资助。
The genetic alterations responsible for an adverse outcome in most patients with acute myeloid leukemia (AML) are unknown. Using massively parallel DNA sequencing, we identified a somatic mutation in DNMT3A, encoding a DNA methyltransferase, in the genome of cells from a patient with AML with a normal karyotype. We sequenced the exons of DNMT3A in 280 additional patients with de novo AML to define recurring mutations. A total of 62 of 281 patients (22.1%) had mutations in DNMT3A that were predicted to affect translation. We identified 18 different missense mutations, the most common of which was predicted to affect amino acid R882 (in 37 patients). We also identified six frameshift, six nonsense, and three splice-site mutations and a 1.5-Mbp deletion encompassing DNMT3A. These mutations were highly enriched in the group of patients with an intermediate-risk cytogenetic profile (56 of 166 patients, or 33.7%) but were absent in all 79 patients with a favorable-risk cytogenetic profile (P<0.001 for both comparisons). The median overall survival among patients with DNMT3A mutations was significantly shorter than that among patients without such mutations (12.3 months vs. 41.1 months, P<0.001). DNMT3A mutations were associated with adverse outcomes among patients with an intermediate-risk cytogenetic profile or FLT3 mutations, regardless of age, and were independently associated with a poor outcome in Cox proportional-hazards analysis. DNMT3A mutations are highly recurrent in patients with de novo AML with an intermediate-risk cytogenetic profile and are independently associated with a poor outcome. (Funded by the National Institutes of Health and others.)