Tomasson Michael H, Xiang Zhifu, Walgren Richard, Zhao Yu, Kasai Yumi, Miner Tracie, Ries Rhonda E, Lubman Olga, Fremont Daved H, McLellan Michael D, Payton Jacqueline E, Westervelt Peter, DiPersio John F, Link Daniel C, Walter Matthew J, Graubert Timothy A, Watson Mark, Baty Jack, Heath Sharon, Shannon William D, Nagarajan Rakesh, Bloomfield Clara D, Mardis Elaine R, Wilson Richard K, Ley Timothy J
Division of Oncology, Department of Medicine, Washington University School of Medicine, St Louis, MO 63110, USA.
Blood. 2008 May 1;111(9):4797-808. doi: 10.1182/blood-2007-09-113027. Epub 2008 Feb 12.
Activating mutations in tyrosine kinase (TK) genes (eg, FLT3 and 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 germline 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.
超过30%的初发急性髓系白血病（AML）患者中可发现酪氨酸激酶（TK）基因（如FLT3和KIT）的激活突变；许多研究团队推测，其余70%的患者中可能存在其他TK基因的突变。我们使用来自94例初发AML患者骨髓（肿瘤）的基因组DNA以及匹配的皮肤活检样本（“种系”），对大多数AML患者中表达的26个TK基因（11个受体TK；15个细胞质TK）的激酶结构域进行了高通量重测序；在另外94个AML肿瘤样本中验证了序列变异（共获得并分析了1430万个碱基对的序列）。我们在FLT3、KIT和JAK2 TK基因中以预期频率鉴定出已知的体细胞突变，并发现了4个新的体细胞突变，分别为JAK1（V623A）、JAK1（T478S）、DDR1（A803V）和NTRK1（S677N），在188例检测患者中各有1例。我们还在14个TK基因中鉴定出编码氨基酸替代的新种系序列变化（即非同义变化），其中TYK2的非同义序列变异数量最多（共检测到11个）。需要进一步研究来确定这些体细胞和种系TK基因变异在AML发病机制中的作用。
