摘要
背景:原发性血小板增多症是骨髓增殖性肿瘤的一个亚型。以往的研究发现JAK2,CALR和MPL突变与骨髓增殖性肿瘤的发病密切相关。所有这些突变都有助于JAK2/STAT通路的超活化。然而,一小部分原发性血小板增多症患者不存在这样的突变。三阴性原发性血小板增多症形式的发病机制尚不清楚。目的:探讨三阳性血小板增多症的临床特点及相关的突变基因。方法:为了探究与三阴性原发性血小板增多症相关的突变,本研究用二代测序对来自68名患者的样品中的360个基因进行靶向测序。结果:所有患者和所有基因均至少检测到一个错义突变。在筛选数据后,观察到具有10个最高突变计数的基因:FLT3,SH2B3,ASXL1,ADAMTS1,TET2,TP53,EG FR,CUX1,G ATA2和MPL。当只考虑罕见基因突变(即千人基因组项目中亚洲人群频率低于5%)时,发现突变频率最高的基因有TET2(33.82%),SH2B3(29.41%)和ASXL1(23.53%)。本研究发现了一些以前没有报道的突变。虽然需要进一步进行功能验证,但突变频率较高可能表明与原发性血小板增多症发病机制的相关性较高。本研究检测到的一些突变在先前也已有报道,而且在本研究中占有很大的比例。结论:全外显子测序可以提供更准确的基因突变分析,并有助于确定导致原发性血小板增多症发病的突变。
Background： Essential thrombocythemia is a subgroup of myeloproliferative neoplasms. Previous studies identified mutations of JAK2,CALR,and MPL that are closely related with the pathogenesis of myeloproliferative neoplasms. All these mutations contribute to the hyperactivation of JAK2/STAT pathway. However,a small proportion of essential thrombocythemia patients does not display such mutations. The pathogenesis of ＂ triple-negative＂ form of essential thrombocythemia remains unknown. Objective： To investigate the clinical characteristics of triple-negative essential thrombocythemia and related mutation genes. Methods： To identify the mutations associated with triple-negative essential thrombocythemia,next-generation sequencing was used to conduct targeted sequencing of 360 genes in samples from 68 patients. Results： At least one missense mutation was detected in all the patients and all the detected genes.After screening the data,it was observed that 10 genes with the 10 highest mutation were follows： FLT3,SH2 B3,ASXL1,ADAMTS1,TET2,TP53,EGFR,CUX1,GATA2,and MPL. When only rare genes（ i. e.,with a frequency in Asian populations lower than 5%,as estimated by the 1000 Genomes Project） were analyzed,the most frequently mutated genes in the patients were TET2（ 33. 82%）,SH2 B3（ 29. 41%）,and ASXL1（ 23. 53%）. Our study identified some mutations that did not previously reported. Although all these mutations need further validation,high incidence rates may indicate relevance of the respective mutations to essential thrombocythemia pathogenesis. Some of the detected mutations have been previously reported; these mutations were also found in a large proportion of our subjects.Conclusion： whole-exon sequencing can provide a higher level of accuracy for gene mutation analysis and assist in identifying mutations that contribute to illustrate the pathogenesis of essential thrombocythemia.
作者
鞠满凯
付荣凤
李慧媛
刘晓帆
薛峰
陈云飞
黄月婷
张丽艳
杨仁池
张磊
JU Man-Kai;FU Rong-Feng;LI Hui-Yuan;LIU Xiao-Fan;XUE Feng;CHEN Yun-Fei;HUANG Yue-Ting;ZHANG Li-Yan;YANG Ren-Chi;ZHANG Lei(Institute of Hematology and Blood Disease Hospital,Chinese Academy of Medical Sciences ＆ Peking Union Medical College,Tianjin 300020,Chin)
出处
《中国实验血液学杂志》
CAS
CSCD
北大核心
2018年第4期1137-1145,共9页
Journal of Experimental Hematology
基金
国家自然科学基金(81470302
81600099)
天津市应用基础及前沿技术研究计划(15JCZDJC35800)
协和青年科研基金(2017320033)
关键词
三阴性血小板增多症
基因突变
靶向基因测序
triple-negative essential thrombocytosis
gene mutation
Targeted gene sequence
