Integrative analysis of type-I and type-II aberrations underscores the genetic heterogeneity of pediatric acute myeloid leukemia
Integrative analysis of type-I and type-II aberrations underscores the genetic heterogeneity of pediatric acute myeloid leukemia
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DOI：
10.3324/haematol.2010.038976
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发表时间：
2011-10-01
期刊：
影响因子：
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通讯作者：
van den Heuvel-Eibrink, Marry M.
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文献类型：
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作者：
Balgobind, Brian V.;Hollink, Iris H. I. M.;van den Heuvel-Eibrink, Marry M.
研究背景几项关于儿童急性髓系白血病的研究描述了各种I型或II型畸变及其与临床预后的关系。然而，最近一直没有这些遗传畸变在一个大的儿科急性髓性白血病cohol.Design和MethodsWe研究了不同的遗传畸变，他们的协会和他们对预后的影响在一个大的儿科急性髓性白血病系列（n=506）的全面概述。研究核型，并筛选NPM 1、CEPBA、MLL、WT 1、FLT 3、N-RAS、K-RAS、PTPN 11和KIT热点区域的突变。分别在330例和263例病例中获得了所有I型和II型畸变的突变状态。生存分析进行了连续急性髓细胞白血病柏林-法兰克福-明斯特研究组和荷兰儿童肿瘤组治疗protocols.ResultsGenetic畸变与特定的临床特征，例如，在一个子集（n=385）治疗。G. ML重排、WT 1突变和FLT 3-ITD阳性急性髓性白血病的诊断性白色细胞计数显著更高。此外，有一个显着的差异，这些畸变的分布之间的儿童低于和超过2岁。非随机关联，e。G.分别观察到KIT突变伴核心结合因子急性髓性白血病和FLT 3-ITD突变伴t（15;17）（q22;q21）、NPM 1和WT 1突变的急性髓性白血病。多变量分析显示“有利核型”，即t（15;17）（q22;q21）、t（8;21）（q22;q22）和inv（16）（p13 q22）/t（16;16）（p13;q22）。NPM 1和CEBPA双突变是有利的无事件生存的独立因素。WT 1突变联合FLT 3-ITD显示了5年总生存期的最差结局（22 +/- 14%）和5年无事件生存率（20 +/- 13%），虽然它不是一个独立的因素，在多变量analysis.ConclusionsIntegrative分析I型和II型畸变提供了一个深入了解的频率，非随机协会和预后影响的各种畸变，反映了小儿急性髓细胞白血病的异质性。这些畸变可能指导儿童急性髓性白血病的分层，并可能指导靶向治疗的发展。
BackgroundSeveral studies of pediatric acute myeloid leukemia have described the various type-I or type-II aberrations and their relationship with clinical outcome. However, there has been no recent comprehensive overview of these genetic aberrations in one large pediatric acute myeloid leukemia cohort.Design and MethodsWe studied the different genetic aberrations, their associations and their impact on prognosis in a large pediatric acute myeloid leukemia series (n=506). Karyotypes were studied, and hotspot regions of NPM1, CEPBA, MLL, WT1, FLT3, N-RAS, K-RAS, PTPN11 and KIT were screened for mutations of available samples. The mutational status of all type-I and type-II aberrations was available in 330 and 263 cases, respectively. Survival analysis was performed in a subset (n=385) treated on consecutive acute myeloid leukemia Berlin-Frankfurt-Munster Study Group and Dutch Childhood Oncology Group treatment protocols.ResultsGenetic aberrations were associated with specific clinical characteristics, e. g. significantly higher diagnostic white blood cell counts in MLL-rearranged, WT1-mutated and FLT3-ITD-positive acute myeloid leukemia. Furthermore, there was a significant difference in the distribution of these aberrations between children below and above the age of two years. Non-random associations, e. g. KIT mutations with core-binding factor acute myeloid leukemia, and FLT3-ITD with t(15;17)(q22;q21), NPM1- and WT1-mutated acute myeloid leukemia, respectively, were observed. Multivariate analysis revealed a 'favorable karyotype', i.e. t(15;17)(q22;q21), t(8;21)(q22;q22) and inv(16)(p13q22)/t(16;16)(p13;q22). NPM1 and CEBPA double mutations were independent factors for favorable event-free survival. WT1 mutations combined with FLT3-ITD showed the worst outcome for 5-year overall survival (22 +/- 14%) and 5-year event-free survival (20 +/- 13%), although it was not an independent factor in multivariate analysis.ConclusionsIntegrative analysis of type-I and type-II aberrations provides an insight into the frequencies, non-random associations and prognostic impact of the various aberrations, reflecting the heterogeneity of pediatric acute myeloid leukemia. These aberrations are likely to guide the stratification of pediatric acute myeloid leukemia and may direct the development of targeted therapies.