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Genomic landscape and clonal evolution of acute myeloid leukemia with t(8;21): an international study on 331 patients.
- Source :
-
Blood [Blood] 2019 Mar 07; Vol. 133 (10), pp. 1140-1151. Date of Electronic Publication: 2019 Jan 04. - Publication Year :
- 2019
-
Abstract
- Acute myeloid leukemia with t(8;21)(q22;q22) is characterized by considerable clinical and biological heterogeneity leading to relapse in up to 40% of patients. We sequenced coding regions or hotspot areas of 66 recurrently mutated genes in a cohort of 331 t(8;21) patients. At least 1 mutation, in addition to t(8;21), was identified in 95%, with a mean of 2.2 driver mutations per patient. Recurrent mutations occurred in genes related to RAS/RTK signaling (63.4%), epigenetic regulators (45%), cohesin complex (13.6%), MYC signaling (10.3%), and the spliceosome (7.9%). Our study identified mutations in previously unappreciated genes: GIGYF2 , DHX15 , and G2E3 Based on high mutant levels, pairwise precedence, and stability at relapse, epigenetic regulator mutations were likely to occur before signaling mutations. In 34% of RAS/RTK <superscript>mutated</superscript> patients, we identified multiple mutations in the same pathway. Deep sequencing (∼42 000×) of 126 mutations in 62 complete remission samples from 56 patients identified 16 persisting mutations in 12 patients, of whom 5 lacked RUNX1-RUNX1T1 in quantitative polymerase chain reaction analysis. KIT <superscript>high</superscript> mutations defined by a mutant level ≥25% were associated with inferior relapse-free survival (hazard ratio, 1.96; 95% confidence interval, 1.22-3.15; P = .005). Together with age and white blood cell counts, JAK2 , FLT3 -internal tandem duplication <superscript>high</superscript> , and KIT <superscript>high</superscript> mutations were identified as significant prognostic factors for overall survival in multivariate analysis. Whole-exome sequencing was performed on 19 paired diagnosis, remission, and relapse trios. Exome-wide analysis showed an average of 16 mutations with signs of substantial clonal evolution. Based on the resemblance of diagnosis and relapse pairs, genetically stable (n = 13) and unstable (n = 6) subgroups could be identified.<br /> (© 2019 by The American Society of Hematology.)
- Subjects :
- Adolescent
Adult
Aged
Aged, 80 and over
Alleles
Chromosomes, Human, Pair 21
Chromosomes, Human, Pair 8
DNA Mutational Analysis
Female
GTP Phosphohydrolases genetics
Genomics
Humans
Male
Membrane Proteins genetics
Middle Aged
Neoplasm Recurrence, Local
Prognosis
Proto-Oncogene Proteins p21(ras) genetics
Remission Induction
Signal Transduction
Young Adult
Clonal Evolution
Leukemia, Myeloid, Acute genetics
Mutation
Translocation, Genetic
Subjects
Details
- Language :
- English
- ISSN :
- 1528-0020
- Volume :
- 133
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Blood
- Publication Type :
- Academic Journal
- Accession number :
- 30610028
- Full Text :
- https://doi.org/10.1182/blood-2018-05-852822