Dai Li, Wang Zhi-Lin, Qiu Guo-Qiang, Wu Yi-Cun, Zhang Xiu-Wen, Xing Shan-Shan, Wang Biao
Department of Hematology, The Third Affiliated Hospital of Soochow University (Changzhou First People's Hospital), Changzhou 213000, Jiangsu Province, China.
Department of Hematology, Nanjing Medical University Affiliated Changzhou Second Hospital, Changzhou 213000, Jiangsu Province, China.
Zhongguo Shi Yan Xue Ye Xue Za Zhi. 2021 Dec;29(6):1733-1740. doi: 10.19746/j.cnki.issn.1009-2137.2021.06.007.
To analyze the clinicobiological heterogeneity of NPM1 mutated (NPM1) acute myeloid leukemia (AML) detected by next generation sequencing (NGS) and their coexistence and mutual exclusivity relationship in the AML subtype.
The NGS data based on 112 genes related to blood disease in 238 newly diagnosed patients with NPM1 were collected. The χ2 test and non-parametric test were used to analyze the distribution correlation between the genes in the mutational spectrum.
Among all the patients, at least one co-mutation was detected out. The median number per case of the mutated genes, including NPM1 was 4.5 (range 2－14), among them, there were 5.0 (range 2－10) for NPM1/FLT3-ITD and 4.0 (range 2－14) for NPM1/FLT3-ITD cases, but it was no significant difference between the two groups (P=0.378). A total of 240 NPM1 mutational events were detected out in entire 238 NPM1 patients, of which 10 (4.2%) were missense mutations, and were all found in NPM1/FLT3-ITD patients. Most (9/10, 90%) of these NPM1 missense mutations were accompanied by AML subtype-defining cytogenetic or molecular abnormalities, of which 7 patients were in low risk or 2 in high risk. The most common NPM1 coexisting mutations were DNMT3A (104, 43.7%), followed were FLT3-ITD (95, 39.9%) and FAT1 (57, 23.9%), FLT3-ITD and DNMT3A showed significant coexistence (P=0.005). FLT3-ITD showed significantly reciprocal exclusivity with FLT3-nonITD (P<0.001), NRAS (P<0.001), PTPN11 (P=0.017) and IDH1 (P=0.005), and showed an exclusivity inclination with KRAS (P=0.073). In addition, FLT3-nonITD along with KRAS (P=0.035), NRAS along with KRAS (P=0.008) and PTPN11 (P=0.039) coexisted significantly.
Prognoses of AML involving less common NPM1 missense mutations should be stated on a case by case basis. The mutational landscape and co-occurrence and mutual exclusivity correlations of NPM1 AML provide a mechanism explaining biological diversity and clinical heterogeneity in this AML subset.
分析通过下一代测序（NGS）检测到的NPM1突变（NPM1）急性髓系白血病（AML）的临床生物学异质性及其在AML亚型中的共存和相互排斥关系。
收集238例新诊断的NPM1患者基于112个血液疾病相关基因的NGS数据。采用χ2检验和非参数检验分析突变谱中基因之间的分布相关性。
在所有患者中，均检测到至少一种共突变。包括NPM1在内，每例患者突变基因的中位数为4.5（范围2 - 14），其中NPM1/FLT3-ITD患者为5.0（范围2 - 10），NPM1/非FLT3-ITD患者为4.0（范围2 - 14），但两组之间无显著差异（P = 0.378）。在全部238例NPM1患者中共检测到240个NPM1突变事件，其中10个（4.2%）为错义突变，均在NPM1/FLT3-ITD患者中发现。这些NPM1错义突变中的大多数（9/10，90%）伴有AML亚型定义的细胞遗传学或分子异常，其中7例患者为低风险，2例为高风险。最常见的NPM1共存突变是DNMT3A（104，43.7%），其次是FLT3-ITD（95，39.9%）和FAT1（57，23.9%），FLT3-ITD和DNMT3A显示出显著共存（P = 0.005）。FLT3-ITD与FLT3-非ITD（P < 0.001）、NRAS（P < 0.001）、PTPN11（P = 0.017）和IDH1（P = 0.005）显示出显著的相互排斥，与KRAS显示出排斥倾向（P = 0.073）。此外，FLT3-非ITD与KRAS（P = 0.035）、NRAS与KRAS（P = 0.008）以及PTPN11（P = 0.039）显著共存。
涉及较少见NPM1错义突变的AML预后应逐例说明。NPM1 AML的突变图谱以及共存和相互排斥相关性为解释该AML亚组中的生物学多样性和临床异质性提供了一种机制。
