Genomic landscape and clonal evolution of acute myeloid leukemia with t(8;21): an international study on 331 patients

Item Type:	Article
Title:	Genomic landscape and clonal evolution of acute myeloid leukemia with t(8;21): an international study on 331 patients
Creators Name:	Christen, F. and Hoyer, K. and Yoshida, K. and Hou, H.A. and Waldhueter, N. and Heuser, M. and Hills, R.K. and Chan, W. and Hablesreiter, R. and Blau, O. and Ochi, Y. and Klement, P. and Chou, W.C. and Blau, I.W. and Tang, J.L. and Zemojtel, T. and Shiraishi, Y. and Shiozawa, Y. and Thol, F. and Ganser, A. and Löwenberg, B. and Linch, D.C. and Bullinger, L. and Valk, P.J.M. and Tien, H.F. and Gale, R.E. and Ogawa, S. and Damm, F.
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: , , and 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 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 in quantitative polymerase chain reaction analysis. 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; = .005). Together with age and white blood cell counts, , -internal tandem duplication, and 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.
Keywords:	flt3 Gene, Genes, Genome, Acute Myeloid Leukemia, Ms-Like Tyrosine Kinase 3, Mutation, runx1 Translocation Partner 1 Protein, Whole Exome Sequencing, Heterogeneity, Disease Remission
Source:	Blood
ISSN:	0006-4971
Publisher:	American Society of Hematology
Volume:	133
Number:	10
Page Range:	1140-1151
Date:	7 March 2019
Official Publication:	https://doi.org/10.1182/blood-2018-05-852822
PubMed:	View item in PubMed

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