Mutational spectrum and risk stratification of intermediate-risk acute myeloid leukemia patients based on next-generation sequencing

Abstract

Intermediate-risk acute myeloid leukemia (IR-AML), which accounts for a substantial number of AML cases, is highly heterogeneous. Although several mutations have been identified, the heterogeneity of AML is uncertain because novel mutations have yet to be discovered. Here we applied next generation sequencing (NGS) platform to screen mutational hotspots in 410 genes relevant to hematological malignancy. IR-AML samples (N=95) were sequenced by Illumina Hiseq and mutations in 101 genes were identified. Only seven genes (CEBPA, NPM1, DNMT3A, FLT3-ITD, NRAS, IDH2 and WT1) were mutated in more than 10% of patients. Genetic interaction analysis identified several cooperative and exclusive patterns of overlapping mutations. Mutational analysis indicated some correlation between genotype and phenotype. FLT3-ITD mutations were identified as independent factors of poor prognosis, while CEBPA mutations were independent favorable factors. Co-occurrence of FLT3-ITD, NPM1 and DNMT3A mutations was identified with associated with specific clinical AML features and poor outcomes. Furthermore, by integrating multiple mutations in the survival analysis, 95 IR-AML patients could be stratified into three distinct risk groups allowing reductions in IR-AML by one-third. Our study offers deep insights into the molecular pathogenesis and biology of AML and indicated that the prognosis of IR-AML could be further stratified by different mutation combinations which may direct future treatment intervention.

Mutation profile and associated clinical features in Chinese patients with cytogenetically normal acute myeloid leukemia

“…About 86.8% (132 cases) of our patients were assigned to M2/M4/M5 subtypes, and five genes including NPM1 , CEBPAbi , GATA2 , RUNX1 , and DNMT3A exhibited a specificity in mutation distribution in regard to FAB subtypes (Figure a and b). NPM1 and DNMT3A mutations were mostly involved in the M4 and M5 subtypes (31.7%, 32/101 and 28.7%, 29/101), and this trend was consistent with the Western and Asian reports (20.3% to 56.0% for NPM1 mut and 20.3% to 43.0% for DNMT3A mut ) . However, the high mutation rates of CEBPAbi (58.1%) and GATA2 (35.5%) genes constituted the specific feature in M2 subtype in our cohort, which was not reported before.…”

“…Differences in mutation frequencies between particular genes and in cytomorphology were also observed. DNMT3A and NPM1 mutations were more involved in M4 and M5 subtypes as in the most reports in literature . However, the specific feature of high mutation rates of CEBPA and GATA2 genes in M2 subtype, which may also characterize Chinese CN‐AML, was first noted in our study.…”

“…The comparison of most driver mutation frequencies among our cohort and several large‐scale Asian and Western reports is listed in Table …”

Mutation profiling of 19 candidate genes in acute myeloid leukemia suggests significance ofDNMT3Amutations

“…Wang et al [36] reported high mutation rates (>10%) in CEBPA, NPM1, DNMT3A, FLT3-ITD, NRAS, IDH2 and WT1 . Kihara et al [37] reported high mutation rates of FLT3, NPM1, CEBPA, DNMT3A and KIT mutations in Japanese patients with AML.…”

Favourable/Intermediate ELN-Risk Acute Myeloid Leukemia to Transplant or Not to Transplant First-Line?

“…The opportunity to screen mutational hotspots in different target genes by target re-sequencing is biologically meaningful and reveals new evidences regarding the risk stratification of the patients. In this regard, it was observed that the genomic profile of leukemic clones may significantly change from diagnosis to relapse showing the emergence of clones that are more difficult to eradicate [5][6][7]. In the next future, these technologies will be commonly available, but currently the great majority of hematological centers do not have the opportunity of adopting them into clinical practice.…”