Genomic Profiling of Pediatric Acute Myeloid Leukemia Reveals a Changing Mutational Landscape from Disease Diagnosis to Relapse.
Genomic Profiling of Pediatric Acute Myeloid Leukemia Reveals a Changing Mutational Landscape from Disease Diagnosis to Relapse.
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DOI：
10.1158/0008-5472.can-15-1015
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发表时间：
2016-04-15
期刊：
影响因子：
11.2
通讯作者：
Meshinchi S
中科院分区：
文献类型：
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作者：
Farrar JE;Schuback HL;Ries RE;Wai D;Hampton OA;Trevino LR;Alonzo TA;Guidry Auvil JM;Davidsen TM;Gesuwan P;Hermida L;Muzny DM;Dewal N;Rustagi N;Lewis LR;Gamis AS;Wheeler DA;Smith MA;Gerhard DS;Meshinchi S
用于开发和实施AML治疗方法的基因组和临床信息主要来自成人患者，并已推广至儿童AML患者。然而，年龄特异性的分子改变正变得越来越明显，可能意味着需要对治疗方案进行年龄分层。NCI/COG TARGET-AML计划采用全外显子组捕获测序（WXS）来询问匹配的三重基因组的基因组图谱，这些三重基因组代表了从20例新发儿童AML病例中在诊断、缓解和复发时收集的标本。通过正交方法鉴定并验证了诊断时的145个体细胞变异（每例患者中位6个突变）和复发时的149个变异（中位6.5个突变）。鉴定了10种基因（FLT 3、NRAS、PTPN 11、WT 1、TET 2、DHX 15、DHX 30、KIT、ETV 6、KRAS）的复发性体细胞变体（在{大于或等于}2名患者中），在复发时具有可变的持续性。用于测量体细胞突变患病率的变异等位基因分数（VAF）在诊断时变化很大。与复发时消退的突变相比，从诊断到复发持续存在的突变具有显著更高的诊断VAF（中位数VAF 0.43 vs. 0.24，P<0.001）。进一步分析显示，90%的VAF >0.4的诊断变异持续复发，而VAF <0.2的诊断变异持续复发的比例为28%（P<0.001）。本研究表明，从诊断到复发，儿童AML的突变谱和克隆演变存在显著差异。此外，在诊断时具有高VAF的突变，代表白血病克隆结构中共有的变体，可能会限制复发时的基因组景观，并有助于确定治疗靶向的关键途径。
The genomic and clinical information used to develop and implement therapeutic approaches for AML originated primarily from adult patients and has been generalized to patients with pediatric AML. However, age-specific molecular alterations are becoming more evident and may signify the need to age-stratify treatment regimens. The NCI/COG TARGET-AML initiative employed whole exome capture sequencing (WXS) to interrogate the genomic landscape of matched trios representing specimens collected upon diagnosis, remission, and relapse from 20 cases of de novo childhood AML. One hundred forty-five somatic variants at diagnosis (median 6 mutations per patient) and 149 variants at relapse (median 6.5 mutations) were identified and verified by orthogonal methodologies. Recurrent somatic variants (in {greater than or equal to}2 patients) were identified for 10 genes (FLT3, NRAS, PTPN11, WT1, TET2, DHX15, DHX30, KIT, ETV6, KRAS), with variable persistence at relapse. The variant allele fraction (VAF), used to measure the prevalence of somatic mutations, varied widely at diagnosis. Mutations that persisted from diagnosis to relapse had a significantly higher diagnostic VAF compared to those that resolved at relapse (median VAF 0.43 vs. 0.24, P<0.001). Further analysis revealed that 90% of the diagnostic variants with VAF >0.4 persisted to relapse compared to 28% with VAF <0.2 (P<0.001). This study demonstrates significant variability in the mutational profile and clonal evolution of pediatric AML from diagnosis to relapse. Furthermore, mutations with high VAF at diagnosis, representing variants shared across a leukemic clonal structure, may constrain the genomic landscape at relapse and help to define key pathways for therapeutic targeting.