基于二代测序的基因突变分析及其在骨髓增生异常肿瘤患者中的临床意义：一项来自中国的多中心研究。
Gene mutation analysis using next-generation sequencing and its clinical significance in patients with myeloid neoplasm: A multi-center study from China.
机构信息
Department of Hematology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, People's Republic of China.
Department of Hematology, The First Affiliated Hospital of Army Medical University(Southwest Hospital), Chongqing, China.
出版信息
Cancer Med. 2023 Apr;12(8):9332-9350. doi: 10.1002/cam4.5690. Epub 2023 Feb 17.
BACKGROUND
Myeloid neoplasms (MN) tend to relapse and deteriorate. Exploring the genomic mutation landscape of MN using next-generation sequencing (NGS) is a great measure to clarify the mechanism of oncogenesis and progression of MN.
METHODS
This multicenter retrospective study investigated 303 patients with MN using NGS from 2019 to 2021. The characteristics of the mutation landscape in the MN subgroups and the clinical value of gene variants were analyzed.
RESULTS
At least one mutation was detected in 88.11% of the patients (267/303). TET2 was the most common mutation in the cohort, followed by GATA2, ASXL1, FLT3, DNMT3A, and TP53. Among patients with myeloid leukemia (ML), multivariate analysis showed that patients aged ≥60 years had lower overall survival (OS, p = 0.004). Further analysis showed TET2, NPM1, SRSF2, and IDH1 gene mutations, and epigenetic genes (p < 0.050) presented significantly higher frequency in older patients. In patients with myelodysplastic syndrome (MDS) and myelodysplastic neoplasms (MPN), univariate analysis showed that BCORL1 had a significant impact on OS (p = 0.040); however, in multivariate analysis, there were no factors significantly associated with OS. Differential analysis of genetic mutations showed FLT3, TP53, MUC16, SRSF2, and KDM5A mutated more frequently (p < 0.050) in secondary acute myeloid leukemia (s-AML) than in MDS and MPN. TP53, U2AF1, SRSF2, and KDM5A were mutated more frequently (p < 0.050) in s-AML than in primary AML. KDM5A was observed to be restricted to patients with s-AML in this study, and only co-occurred with MUC16 and TP53 (2/2, 100%). Another mutation was MUC16, and its co-occurrence pattern differed between s-AML and AML. MUC16 mutations co-occurred with KDM5A and TP53 in 66.7% (2/3) of patients with s-AML and co-occurred with CEBPA in 100% (4/4) of patients with AML.
CONCLUSIONS
Our results demonstrate different genomic mutation patterns in the MN subgroups and highlight the clinical value of genetic variants.
背景
髓系肿瘤（MN）往往会复发和恶化。使用下一代测序（NGS）探索 MN 的基因组突变景观是阐明 MN 致癌和进展机制的重要手段。
方法
本多中心回顾性研究采用 NGS 对 2019 年至 2021 年期间的 303 例 MN 患者进行了研究。分析了 MN 亚组中突变景观的特征和基因变异的临床价值。
结果
88.11%（267/303）的患者至少检测到一种突变。在该队列中，TET2 是最常见的突变，其次是 GATA2、ASXL1、FLT3、DNMT3A 和 TP53。在髓系白血病（ML）患者中，多变量分析显示，≥60 岁的患者总生存（OS）较低（p=0.004）。进一步分析显示，TET2、NPM1、SRSF2 和 IDH1 基因突变以及表观遗传基因（p<0.050）在老年患者中频率更高。在骨髓增生异常综合征（MDS）和骨髓增生性肿瘤（MPN）患者中，单变量分析表明 BCORL1 对 OS 有显著影响（p=0.040）；然而，多变量分析显示，与 OS 相关的因素无统计学意义。基因突变的差异分析显示，FLT3、TP53、MUC16、SRSF2 和 KDM5A 突变在继发性急性髓系白血病（s-AML）中比 MDS 和 MPN 更频繁（p<0.050）。TP53、U2AF1、SRSF2 和 KDM5A 在 s-AML 中比原发性 AML 更频繁突变（p<0.050）。在本研究中，KDM5A 仅在 s-AML 患者中观察到，并且仅与 MUC16 和 TP53 共同发生（2/2，100%）。另一个突变是 MUC16，其在 s-AML 和 AML 中的共同发生模式不同。在 66.7%（2/3）的 s-AML 患者中，MUC16 突变与 KDM5A 和 TP53 共同发生，在 100%（4/4）的 AML 患者中与 CEBPA 共同发生。
结论
我们的结果表明 MN 亚组存在不同的基因组突变模式，并强调了遗传变异的临床价值。
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