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.

中文翻译：

---

7 号染色体畸变 AML 的基因组特征：519 例患者的多国队列


7 号染色体 （chr7） 缺失和部分缺失在急性髓系白血病 （AML） 中很常见，并且与不良结局有关。然而，伴随遗传畸变的基因组景观和预后影响仍不完全清楚。为了发现 7 号染色体畸变 [abn（7）] 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 个配对诊断/缓解样本。随后，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 骨架的基因面板，并将其应用于验证队列的其余样本。总共调查了 519 名患者，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，突变最频繁的基因是 TP53 （33%），其次是表观遗传调节因子 （DNMT3A 、 KMT2C 、 IDH2） 和信号转导基因 （NRAS 、 PTPN11）。519 名患者中有 30% ≥位于 chr7 常见缺失区域的基因携带 1 个突变，最常影响 KMT2C （16%） 和 EZH2 （10%）。KMT2C 突变通常是亚克隆的，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得重建确定 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显示为亚克隆事件。多变量分析确定了 5 个对 abn 强化治疗的 AML 患者具有显着预后的遗传病变 （7）。TP53 和 PTPN11 突变 （11%） 与较差的总生存期 （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） 和无复发生存期 （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%） 的 OS 延长 （HR，0.51 [95% CI 0.30-0.88];P = 0.0015）和持久反应 （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损伤，并全面概述了复发基因突变的范围及其在 abn 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。