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Deep targeted sequencing in pediatric acute lymphoblastic leukemia unveils distinct mutational patterns between genetic subtypes and novel relapse-associated genes
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.ORCID iD: 0000-0003-3887-9519
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Molecular Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Cell and Molecular Biology, The Linnaeus Centre for Bioinformatics.
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2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 39, p. 64071-64088Article in journal (Refereed) Published
Abstract [en]

To characterize the mutational patterns of acute lymphoblastic leukemia (ALL) we performed deep next generation sequencing of 872 cancer genes in 172 diagnostic and 24 relapse samples from 172 pediatric ALL patients. We found an overall greater mutational burden and more driver mutations in T-cell ALL (T-ALL) patients compared to B-cell precursor ALL (BCP-ALL) patients. In addition, the majority of the mutations in T-ALL had occurred in the original leukemic clone, while most of the mutations in BCP-ALL were subclonal. BCP-ALL patients carrying any of the recurrent translocations ETV6-RUNX1, BCR-ABL or TCF3-PBX1 harbored few mutations in driver genes compared to other BCP-ALL patients. Specifically in BCP-ALL, we identified ATRX as a novel putative driver gene and uncovered an association between somatic mutations in the Notch signaling pathway at ALL diagnosis and increased risk of relapse. Furthermore, we identified EP300, ARID1A and SH2B3 as relapse-associated genes. The genes highlighted in our study were frequently involved in epigenetic regulation, associated with germline susceptibility to ALL, and present in minor subclones at diagnosis that became dominant at relapse. We observed a high degree of clonal heterogeneity and evolution between diagnosis and relapse in both BCP-ALL and T-ALL, which could have implications for the treatment efficiency.

Place, publisher, year, edition, pages
2016. Vol. 7, no 39, p. 64071-64088
Keyword [en]
acute lymphoblastic leukemia, targeted next generation sequencing, somatic mutation, relapse, clonal evolution
National Category
Cancer and Oncology Cell and Molecular Biology
Identifiers
URN: urn:nbn:se:uu:diva-310028DOI: 10.18632/oncotarget.11773ISI: 000387167800099PubMedID: 27590521OAI: oai:DiVA.org:uu-310028DiVA: diva2:1055264
Funder
Swedish Foundation for Strategic Research , RBc08-08Swedish Cancer Society, CAN 2013/504Swedish Childhood Cancer Foundation, PR2014-0100Swedish Research Council, C0524801Knut and Alice Wallenberg Foundation
Available from: 2016-12-12 Created: 2016-12-09 Last updated: 2018-01-13Bibliographically approved

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Lindqvist, C. MårtenLundmark, AndersNordlund, JessicaFreyhult, EvaAlmlöf, Jonas CarlssonRaine, AmandaÖvernäs, ElinPalle, JosefineLönnerholm, GudmarBerglund, Eva C.Syvänen, Ann-Christine

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Lindqvist, C. MårtenLundmark, AndersNordlund, JessicaFreyhult, EvaAlmlöf, Jonas CarlssonRaine, AmandaÖvernäs, ElinPalle, JosefineLönnerholm, GudmarBerglund, Eva C.Syvänen, Ann-Christine
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Molecular MedicineScience for Life Laboratory, SciLifeLabCancer Pharmacology and Computational MedicineThe Linnaeus Centre for BioinformaticsPediatrics
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