背景:7号染色体的缺失和部分缺失(chr7)在急性髓细胞性白血病(AML)中很常见,并且与预后不良有关。然而,伴随遗传畸变的基因组景观和预后影响仍未完全了解。
方法:为了发现患有7号染色体畸变[abn(7)]的成年AML患者的遗传病变,在探索队列中通过全外显子组测序研究了60个配对的诊断/缓解样品。随后,我们设计了一个包括66个基因和一个用于拷贝数变异检测的SNP骨架的基因组,并将其应用于验证队列的其余样本.总的来说,对519名患者进行了调查,其中415人接受了强化诱导治疗,通常含有阿糖胞苷和蒽环类药物的组合。
结果:在探索队列中,最常见的突变基因是TP53(33%),其次是表观遗传调节因子(DNMT3A,KMT2C,IDH2)和信号基因(NRAS,PTPN11)。519例患者中有30%在chr7常见缺失区域的基因中存在≥1个突变,最常影响KMT2C(16%)和EZH2(10%)。KMT2C突变通常是亚克隆的,并且在del(7q)患者中富集,从头或核心结合因子AML(45%)。癌细胞分数分析和突变获取的重建确定TP53突变主要是疾病起始事件,而del(7q)或-7在三分之一的病例中作为亚克隆事件出现。多变量分析确定了在强化治疗的ABNAML患者中具有显著预后影响的5个遗传性病变(7)。TP53和PTPN11的突变(11%)显示出与较差的总体生存率(OS,TP53:危险比[HR],2.53[95%CI1.66-3.86];P<0.001;PTPN11:HR,2.24[95%CI1.56-3.22];P<0.001)和无复发生存率(RFS,TP53:HR,2.3[95%CI1.25-4.26];P=0.008;PTPN11:HR,2.32[95%CI1.33-4.04];P=0.003)。相比之下,IDH2突变患者(9%)表现出延长的OS(HR,0.51[95%CI0.30-0.88];P=0.0015)和持久反应(RFS:HR,0.5[95%CI0.26-0.96];P=0.036)。
结论:这项工作揭示了以前被低估的遗传病变,并全面概述了复发基因突变的谱及其在患有ABN的AML中的临床相关性(7)。KMT2C突变是该异质性AML亚组中最常见的基因突变之一,需要进一步的功能研究。
BACKGROUND: Deletions and partial losses of chromosome 7 (chr7) are frequent in acute myeloid leukemia (AML) and are linked to dismal outcome. However, the genomic landscape and prognostic impact of concomitant genetic aberrations remain incompletely understood.
METHODS: To discover genetic lesions in adult AML patients with aberrations of chromosome 7 [abn(7)], 60 paired diagnostic/remission samples were investigated by whole-exome sequencing in the exploration cohort. Subsequently, a gene panel including 66 genes and a SNP backbone for copy-number variation detection was designed and applied to the remaining samples of the validation cohort. In total, 519 patients were investigated, of which 415 received intensive induction treatment, typically containing a combination of cytarabine and anthracyclines.
RESULTS: In the exploration cohort, the most frequently mutated gene was TP53 (33%), followed by epigenetic regulators (DNMT3A, KMT2C, IDH2) and signaling genes (NRAS, PTPN11). Thirty percent of 519 patients harbored ≥ 1 mutation in genes located in commonly deleted regions of chr7-most frequently affecting KMT2C (16%) and EZH2 (10%). KMT2C mutations were often subclonal and enriched in patients with del(7q), de novo or core-binding factor AML (45%). Cancer cell fraction analysis and reconstruction of mutation acquisition identified TP53 mutations as mainly disease-initiating events, while del(7q) or -7 appeared as subclonal events in one-third of cases. Multivariable analysis identified five genetic lesions with significant prognostic impact in intensively treated AML patients with abn(7). Mutations in TP53 and PTPN11 (11%) showed the strongest association with worse overall survival (OS, TP53: hazard ratio [HR], 2.53 [95% CI 1.66-3.86]; P < 0.001; PTPN11: HR, 2.24 [95% CI 1.56-3.22]; P < 0.001) and relapse-free survival (RFS, TP53: HR, 2.3 [95% CI 1.25-4.26]; P = 0.008; PTPN11: HR, 2.32 [95% CI 1.33-4.04]; P = 0.003). By contrast, IDH2-mutated patients (9%) displayed prolonged OS (HR, 0.51 [95% CI 0.30-0.88]; P = 0.0015) and durable responses (RFS: HR, 0.5 [95% CI 0.26-0.96]; P = 0.036).
CONCLUSIONS: This work unraveled formerly underestimated genetic lesions and provides a comprehensive overview of the spectrum of recurrent gene mutations and their clinical relevance in AML with abn(7). KMT2C mutations are among the most frequent gene mutations in this heterogeneous AML subgroup and warrant further functional investigation.