[The Mutated Gene Sequenced by NGS and the Correlation of Their Coexistent Mutual Exclusiveness in NPM1 Mutated Acute Myeloid Leukemia].

OBJECTIVE: To analyze the clinicobiological heterogeneity of NPM1 mutated (NPM1mut) acute myeloid leukemia (AML) detected by next generation sequencing (NGS) and their coexistence and mutual exclusivity relationship in the AML subtype. METHODS: The NGS data based on 112 genes related to blood disease in 238 newly diagnosed patients with NPM1mut were collected. The χ2 test and non-parametric test were used to analyze the distribution correlation between the genes in the mutational spectrum. RESULTS: Among all the patients, at least one co-mutation was detected out. The median number per case of the mutated genes, including NPM1mut was 4.5 (range 2－14), among them, there were 5.0 (range 2－10) for NPM1mut/FLT3-ITD+ and 4.0 (range 2－14) for NPM1mut/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 NPM1mut patients, of which 10 (4.2%) were missense mutations, and were all found in NPM1mut/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 NPM1mut 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. CONCLUSION: 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 NPM1mut AML provide a mechanism explaining biological diversity and clinical heterogeneity in this AML subset.

Prognostic significance of monosomal karyotype in myelodysplastic syndrome: a meta-analysis.

OBJECTIVES: In myelodysplastic syndrome (MDS), the prognostic role of monosomal karyotype (MK), defined as at least two autosomal monosomies or a single monosomy associated with at least one additional structural abnormality, remained controversial. Therefore, we conducted a meta-analysis to address this issue. METHODS: PubMed, Embase, Web of Science, Medline, and the Cochrane Library were retrieved. We extracted hazard ratios (HRs) and the corresponding 95% confidential intervals (CIs) for overall survival (OS) on patients with MK versus those without, as well as on MK patients with monosomies of chromosome 7 and/or 5 versus those without from the available studies. RESULTS: Seventeen studies covering 7500 patients were included this meta-analysis. The pooled HRs indicated MK had a negative impact on OS in MDS (pooled HR: 2.484, 95%CI: 2.033-3.036, P < .001), in MDS patients undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT) (pooled HR: 2.150, 95%CI: 1.861-2.48, P < .001), and in MDS with complex karyotype (CK) (pooled HR: 2.56, 95%CI: 2.032-3.036, P = .01). However, monosomies of chromosome 5 and/or 7 had no impact on OS in MDS with MK (pooled HR: 1.330, 95%CI: 0.827-2.139, P = .240). Meta-regression indicated that therapy was the origin of the heterogeneity (P = .012). DISCUSSION: Our meta-analysis indicated that MK has a negative impact on OS in MDS, in MDS patients undergoing allo-HSCT, and MDS with CK, but monosomies of chromosome 5 and/or 7 have no impact on OS in MDS with MK. The heterogeneity reflected the biologic and therapeutic heterogeneity of MDS. CONCLUSION: MK is associated with poor prognosis in MDS, the underlying mechanism needs further exploring.