EZH2 基因突变状态、拷贝数、蛋白表达与 AML/MDS 患者 H3K27 三甲基化的综合研究。

Integrative study of EZH2 mutational status, copy number, protein expression and H3K27 trimethylation in AML/MDS patients.

机构信息

Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Medical Center - University of Freiburg, Freiburg, Germany.

Clinical Trials Unit, Faculty of Medicine, Medical Center - University of Freiburg, Freiburg, Germany.

出版信息

Clin Epigenetics. 2021 Apr 12;13(1):77. doi: 10.1186/s13148-021-01052-2.

DOI:10.1186/s13148-021-01052-2

PMID:33845873

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC8043064/

Abstract

BACKGROUND

Mutations in the EZH2 gene are recurrently found in patients with myeloid neoplasms and are associated with a poor prognosis. We aimed to characterize genetic and epigenetic alterations of EZH2 in 58 patients (51 with acute myeloid leukemia and 7 with myelodysplastic or myeloproliferative neoplasms) by integrating data on EZH2 mutational status, co-occurring mutations, and EZH2 copy number status with EZH2 protein expression, histone H3K27 trimethylation, and EZH2 promoter methylation.

RESULTS

EZH2 was mutated in 6/51 acute myeloid leukemia patients (12%) and 7/7 patients with other myeloid neoplasms. EZH2 mutations were not overrepresented in patients with chromosome 7q deletions or losses. In acute myeloid leukemia patients, EZH2 mutations frequently co-occurred with CEBPA (67%), ASXL1 (50%), TET2 and RAD21 mutations (33% each). In EZH2-mutated patients with myelodysplastic or myeloproliferative neoplasms, the most common co-mutations were in ASXL1 (100%), NRAS, RUNX1, and STAG2 (29% each). EZH2 mutations were associated with a significant decrease in EZH2 expression (p = 0.0002), which was similar in patients with chromosome 7 aberrations and patients with intact chromosome 7. An association between EZH2 protein expression and H3K27 trimethylation was observed in EZH2-unmutated patients (R = 0.2, p = 0.01). The monoallelic state of EZH2 was not associated with EZH2 promoter hypermethylation. In multivariable analyses, EZH2 mutations were associated with a trend towards an increased risk of death (hazard ratio 2.51 [95% confidence interval 0.87-7.25], p = 0.09); similarly, low EZH2 expression was associated with elevated risk (hazard ratio 2.54 [95% confidence interval 1.07-6.04], p = 0.04).

CONCLUSIONS

Perturbations of EZH2 activity in AML/MDS occur on different, genetic and non-genetic levels. Both low EZH2 protein expression and, by trend, EZH2 gene mutations predicted inferior overall survival of AML patients receiving standard chemotherapy.

摘要

背景

EZH2 基因的突变在骨髓增生性肿瘤患者中经常发生，并与预后不良相关。我们旨在通过整合 EZH2 突变状态、共同发生的突变以及 EZH2 拷贝数状态与 EZH2 蛋白表达、组蛋白 H3K27 三甲基化和 EZH2 启动子甲基化的数据，来描绘 58 名患者（51 名急性髓系白血病患者和 7 名骨髓增生异常或骨髓增生性肿瘤患者）中 EZH2 的遗传和表观遗传改变。

结果

在 51 名急性髓系白血病患者中有 6 名（12%）和 7 名其他骨髓增生性肿瘤患者中有 7 名（100%）发生 EZH2 突变。EZH2 突变在存在 7q 染色体缺失或丢失的患者中并未过度表达。在急性髓系白血病患者中，EZH2 突变常与 CEBPA（67%）、ASXL1（50%）、TET2 和 RAD21 突变（各 33%）共同发生。在患有骨髓增生异常或骨髓增生性肿瘤的 EZH2 突变患者中，最常见的共同突变是在 ASXL1（100%）、NRAS、RUNX1 和 STAG2（各 29%）中。EZH2 突变与 EZH2 表达显著降低相关（p=0.0002），在存在 7 号染色体异常的患者和存在完整 7 号染色体的患者中相似。在 EZH2 未突变的患者中观察到 EZH2 蛋白表达与 H3K27 三甲基化之间存在关联（R=0.2，p=0.01）。EZH2 的单等位基因状态与 EZH2 启动子过度甲基化无关。在多变量分析中，EZH2 突变与死亡风险增加呈趋势相关（风险比 2.51[95%置信区间 0.87-7.25]，p=0.09）；同样，EZH2 表达水平低与风险升高相关（风险比 2.54[95%置信区间 1.07-6.04]，p=0.04）。