7 号染色体 (chr7) 的缺失和部分丢失在急性髓系白血病 (AML) 中很常见，并且与不良结果相关。然而，伴随遗传畸变的基因组图谱和预后影响仍不完全清楚。为了发现具有 7 号染色体畸变的成人 AML 患者的遗传病变 [abn(7)]，通过全外显子组测序对 60 个配对的诊断/缓解样本进行了研究探索队列。随后，设计了包含 66 个基因和用于拷贝数变异检测的 SNP 主干的基因组，并将其应用于验证队列的其余样本。总共有 519 名患者接受了调查，其中 415 名接受了强化诱导治疗，通常包含阿糖胞苷和蒽环类药物的组合。 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 名患者中，有 30% 的基因位于 chr7 的常见缺失区域，其中有 30% 的基因存在突变，最常影响 KMT2C (16%) 和 EZH2 (10%)。 KMT2C 突变通常为亚克隆，并在 del(7q)、新发或核心结合因子 AML 患者中富集 (45%)。癌细胞分数分析和突变获取重建确定 TP53 突变是主要的疾病起始事件，而 del(7q) 或 -7 在三分之一的病例中作为亚克隆事件出现。多变量分析确定了对 abn 接受强化治疗的 AML 患者具有显着预后影响的 5 个遗传病变(7)。 TP53 和 PTPN11 突变 (11%) 显示与较差总生存期的相关性最强（OS、TP53：风险比 [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）和无复发生存（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）。相比之下，IDH2 突变患者 (9%) 表现出延长的 OS（HR，0.51 [95% CI 0.30-0.88]；P = 0.0015）和持久的缓解（RFS：HR，0.5 [95% CI 0.26-0.96]；P = 0.036)。这项工作揭示了以前被低估的遗传病变，并全面概述了复发性基因突变的范围及其与 abn(7) AML 的临床相关性。 KMT2C 突变是该异质性 AML 亚组中最常见的基因突变之一，值得进一步的功能研究。© 2024。作者。

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.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.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).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.© 2024. The Author(s).