Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia
Somatic mutations and germline sequence variants in the expressed tyrosine kinase genes of patients with de novo acute myeloid leukemia
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DOI：
10.1182/blood-2007-09-113027
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发表时间：
2008-05-01
期刊：
影响因子：
20.3
通讯作者：
Ley, Timothy J.
中科院分区：
文献类型：
--
作者：
Tomasson, Michael H.;Xiang, Zhifu;Ley, Timothy J.
在超过30%的原发急性髓细胞白血病（AML）患者中发现酪氨酸激酶（TK）基因（如FLT 3和KIT）的激活突变;许多研究小组推测，在其余70%的患者中可能存在其他TK基因的突变。我们对26个TK基因的激酶结构域进行了高通量重测序使用来自骨髓（肿瘤）和匹配的皮肤活检样本的基因组DNA，在大多数AML患者中表达（11种受体TK; 15种细胞质TK）（“生殖系”）;在另外94个AML肿瘤样品中验证了序列变体（获得并分析了1430万个碱基对的序列）。我们以预期的频率鉴定了FLT 3、KIT和JAK 2 TK基因中已知的体细胞突变，并在188例受试患者中的4例中发现了4种新的体细胞突变，JAK 1（V623 A）、JAK 1（T478 S）、DDR 1（A803 V）和NTRK 1（S677 N）。我们还确定了14个TK基因中编码氨基酸取代（即非同义变化）的新种系序列变化，包括TYK 2，其非同义序列变体数量最多（共检测到11个）。需要进一步的研究来确定这些体细胞和生殖系TK基因变异在AML发病机制中的作用。
Activating mutations in tyrosine kinase (TK)genes(eg, FLT3and KIT)are found in more than 30% of patients with de novo acute myeloid leukemia (AML); many groups have speculated that mutations in other TK genes may be present in the remaining 70%. We performed high-throughput resequencing of the kinase domains of 26 TK genes (11 receptor TK; 15 cytoplasmic TK) expressed in most AML patients using genomic DNA from the bone marrow (tumor) and matched skin biopsy samples ("germline") from 94 patients with de novo AML; sequence variants were validated in an additional 94 AML tumor samples (14.3 million base pairs of sequence were obtained and analyzed). We identified known somatic mutations in FLT3, KIT, and JAK2 TK genes at the expected frequencies and found 4 novel somatic mutations, JAK1(V623A), JAK1(T478S), DDR1(A803V), and NTRK1(S677N), once each in 4 respective patients of 188 tested. We also identified novel germ line sequence changes encoding amino acid substitutions (ie, nonsynonymous changes) in 14 TK genes, including TYK2, which had the largest number of nonsynonymous sequence variants (11 total detected). Additional studies will be required to define the roles that these somatic and germline TK gene variants play in AML pathogenesis.