scholarly journals Gene mutation profile and risk stratification in AML1‑ETO‑positive acute myeloid leukemia based on next‑generation sequencing

2019 ◽  
Author(s):  
Guopan Yu ◽  
Changxin Yin ◽  
Fuqun Wu ◽  
Ling Jiang ◽  
Zhongxin Zheng ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Next Generation Sequencing ◽  
Risk Stratification ◽  
Gene Mutation ◽  
Myeloid Leukemia ◽  
Next Generation ◽  
Mutation Profile ◽  
Generation Sequencing ◽  
Acute Myeloid

scholarly journals Gene Mutation Profile and Risk Stratification in AML1-ETO-Positive Acute Myeloid Leukemia Based on Next-Generation Sequencing

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5249-5249
Author(s):  
Guopan Yu ◽  
Changxin Yin ◽  
Fuqun Wu ◽  
Ling Jiang ◽  
Zhongxin Zheng ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Next Generation Sequencing ◽  
Gene Mutation ◽  
Myeloid Leukemia ◽  
Tp53 Mutation ◽  
Gene Mutations ◽  
Kit Mutation ◽  
Mutation Profile ◽  
Generation Sequencing ◽  
Acute Myeloid

Abstract Gene mutations play a critical role in leukemogenesis of AML1-ETO-positive acute myeloid leukemia (AE-AML). Nevertheless, gene mutation profile in this subtype leukemia remains unclear, and their clinical effect might be underestimated. In this study, we detested gene mutations at diagnosis and relapse with next-generation sequencing in 64 newly diagnosed AE-AML patients, and verified the results with Sanger sequencing at the same time. Our results showed that 68.8% patients presented recurrent mutations at diagnosis and 6/11 cases underwent genetic alterations at relapse. C-KIT mutation was the most common event at diagnosis, with an incidence of 42.2%, followed by ASXL1 (15.6%), MET (12.5%), MLH1 (9.4%) , TET2 (7.8%), and FBXW7, TP53 and DNMT3A (7.8%), etc. Also, C-KIT mutation was the most common molecular event associated with relapse (7/11, 63.6%). No significant difference in the clinical characteristic between the gene mutation and wild type (WT) groups was observed, except of higher incidence of additional cytogenetic abnormalities (ACAs) (P=0.025) in TP53 mutation patients. C-KIT (exon 8, 17) mutation but not exon 10 adversely affected on survival. Also ASXL1 and TP53 mutation were poor for the RFS (P<0.05), and ASXL1, MET, FBXW7 and TP53 mutation negatively impacted on the OS (P<0.05). Multivariate analysis showed C-KIT (exon 8, 17) and ASXL1 mutations were the independent adverse factors for survival. Further, co-mutation of these two genes showed even worse effect on survival. Taking together, additional gene mutations are critical in the development and progression of AE-AML. C-KIT and ASXL1 mutations are the two most common molecular events in this subtype leukemia. Single mutation of C-KIT (exon 8, 17) or ASXL1 poorly affects on survival, even worse in the co-mutation. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

scholarly journals Clinical Utility of Multiple-Gene Mutation Testing By Next-Generation Sequencing in Acute Myeloid Leukemia in Community Hospital Setting

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4004-4004
Author(s):  
Jingxin Sun ◽  
Luwei Tao ◽  
Rushang D. Patel ◽  
Shahram Mori ◽  
Jeff Chang
Keyword(s):  
Acute Myeloid Leukemia ◽  
Next Generation Sequencing ◽  
Risk Stratification ◽  
Gene Mutation ◽  
Myeloid Leukemia ◽  
Clinical Utility ◽  
Community Hospital ◽  
Hospital Setting ◽  
Generation Sequencing ◽  
Acute Myeloid

Abstract Clinical Utility of Multiple-Gene Mutation Testing by Next-Generation Sequencing in Acute Myeloid Leukemia in Community Hospital Setting Introduction The WHO 2016 classification system and the 2017 European LeukemiaNet (ELN) genetic risk stratification system incorporate cytogenetic aberrations and mutations of specific genes to classify acute myeloid leukemia (AML) and stratify prognosis of AML patients. Next-generation sequencing (NGS) of multiple genes associated with AML has been shown to be an important tool in studying AML in research and academic center settings. Our goal is to evaluate the clinical application of NGS in a community hospital setting which has not been well documented leading to rejection of coverage by some insurers. Methodology This retrospective study included 109 patients (52 females and 57 males with mean age of 58.7) from November, 2016 to June, 2018 with various races/ethnicities background and confirmed diagnosis of AML at Florida Hospital (FH). DNA was extracted from the peripheral blood/bone marrow for NGS analysis. A total of 54 hematopoietic tumor associated genes were studied: ABL1, ASXL1, ATM, BCOR, BIRC3, BRAF, CALR, CBL, CEBPA, CREBBP, CSF1R, CSF3R, DNMT3A, EP300, ETV6, EZH2, FBXW7, FGFR4, FLT3, GATA1, GATA2, GATA3, IDH1, IDH2, IL7R, JAK2, JAK3, KDM6A, KIT, KMT2A, KRAS, MPL, NF1, NOTCH1, NOTCH2, NPM1, NRAS, NSD1, PAX5, PDGFRA, PDGFRB, PTPN11, RUNX1, SETBP1, SF3B1, SRSF2, STAG2, TERT, TET1, TET2, TP53, TSLP,U2AF1 and ZRSR2. The sequencing was performed at Genomics and Pathology Services laboratory at Washington University in St. Louis and initial informatics analysis was performed by PierianDX using Clinical Genome Working platform. The initial analysis results were delivered to the pathologists at FH to do final interpretation with integration of the results of morphology/flow cytometry/karyotyping studies. The clinical utility of NGS was evaluated by: 1) comparing the AML classification and ELN genetic risk stratification of each patient with and without NGS data, 2) identifying gene mutations for targeted therapy and 3) other clinical impacts. Results NGS results changed ELN risk stratification in 45 cases (41.3%) and WHO AML classification in 37 cases (33.9%) out of 109 cases after considering the mutation status of NPM1, FLT3, RUNX1, ASXL1 and TP53. Among the 45 cases that had changes of ELN risk, 25 cases (55%) were downgraded to favorable risk group all because of mutations in NPM1 gene. While, the rest 20 cases (45%) were upgraded to adverse risk group due to the following mutations (RUNX1 in 7, TP53 in 5, ASXL1 in 4, RUNX1 and ASXL1 in 4). The change of WHO classification was caused by mutations in NPM1 (n=26) or RUNX1 (n=11). Additionally, NGS identified 8 cases with either GATA2 or CEBPA gene mutation, which are considered to increase the risk of myeloid neoplasms with germline predisposition based on WHO classification. Finally, NGS identified 42 patients (38.5%) carrying FLT3-ITD (n=17), FLT3-TKD (n=8) and/or IDH1/IDH2 (n=16) mutations. These mutations are known to have approved targeted therapies (FLT3 inhibitors and IDH2 inhibitors) or ongoing clinical trials (IDH1 inhibitors). Overall, NGS results led to clinically significant impacts in 62/109 (56.9%) patients by changing the AML classification/risk stratification, finding potential germline mutation and/or targeted therapies. Discussion Our results indicate that NGS findings provide important information for classification, risk stratification, genetic predisposition, and treatment options in the majority (62/109, 56.9%) of AML patients in a community hospital setting. How the information exactly changes the clinical management by community practicing hematologists is currently ongoing and will provide further insights in regards to the clinical utilities of NGS. In addition, NGS of multiple genes is more cost- and labor-effective than single gene sequencing. Taken together, the insurers should accept NGS testing as a standard of care for AML patients. Disclosures No relevant conflicts of interest to declare.

scholarly journals Molecular Risk Stratification using Next-generation Sequencing in Acute Myeloid Leukemia

2021 ◽  
Vol 96 (6) ◽  
pp. 493-500
Author(s):  
Jae-Sook Ahn
Keyword(s):  
Acute Myeloid Leukemia ◽  
Next Generation Sequencing ◽  
Risk Stratification ◽  
Myeloid Leukemia ◽  
Chromosomal Abnormalities ◽  
Residual Disease ◽  
Next Generation ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Acute Myeloid

Chromosomal abnormalities are an important prognostic factor in cases of acute myeloid leukemia (AML). Molecular mutations have been reported to contribute to the pathogenesis and prognosis of AML. Next-generation sequencing (NGS) has revolutionized the speed and cost of genomic sequencing and enables the parallel analysis of many genes for molecular risk stratification. The molecular mutations currently included in risk stratification at AML diagnosis are c-kit, FLT3-ITD, NPM1, CEBPA (biallelic), RUNX1, ASLX1, and TP53. The importance of screening for mutations has been further emphasized by introducing novel therapeutic targets for molecular mutations, such as FLT3-TKD, IDH1, and IDH2. Molecular mutations are also used to evaluate measurable residual disease during treatment and to select the intensity of the treatment during consolidation and follow-up. Pretreatment leukemic marrow and blood should be stored at a biobank to perform NGS analysis in cases of AML at diagnosis. Samples from various time points during and after treatment should be obtained and stored under appropriate conditions.

Mutational profiling of acute myeloid leukemia with normal cytogenetics in Brazilian patients: the value of next-generation sequencing for genomic classification

2017 ◽  
Vol 65 (8) ◽  
pp. 1155-1158 ◽  
Author(s):  
Thiago Rodrigo de Noronha ◽  
Miguel Mitne-Neto ◽  
Maria de Lourdes Chauffaille
Keyword(s):  
Acute Myeloid Leukemia ◽  
Next Generation Sequencing ◽  
Myeloid Leukemia ◽  
Regulation Of Gene Expression ◽  
Uniparental Disomy ◽  
Driver Mutations ◽  
Next Generation ◽  
Normal Cytogenetics ◽  
Generation Sequencing ◽  
Acute Myeloid

Karyotype (KT) aberrations are important prognostic factors for acute myeloid leukemia (AML); however, around 50% of cases present normal results. Single nucleotide polymorphism array can detect chromosomal gains, losses or uniparental disomy that are invisible to KT, thus improving patients’ risk assessment. However, when both tests are normal, important driver mutations can be detected by the use of next-generation sequencing (NGS). Fourteen adult patients with AML with normal cytogenetics were investigated by NGS for 19 AML-related genes. Every patient presented at least one mutation:DNMT3Ain nine patients;IDH2in six;IDH1in three;NRASandNPM1in two; andTET2,ASXL1,PTPN11, andRUNX1in one patient. No mutations were found inFLT3,KIT,JAK2,CEBPA,GATA2,TP53,BRAF,CBL,KRAS,andWT1genes. Twelve patients (86%) had at least one mutation in genes related with DNA methylation (DNMT3A,IDH1,IDH2,andTET2), which is involved in regulation of gene expression and genomic stability. All patients could be reclassified based on genomic status and nine had their prognosis modified. In summary, NGS offers insights into the molecular pathogenesis and biology of cytogenetically normal AML in Brazilian patients, indicating that the prognosis could be further stratified by different mutation combinations. This study shows a different frequency of mutations in Brazilian population that should be confirmed.

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