Oncotarget

Research Papers:

Deep targeted sequencing in pediatric acute lymphoblastic leukemia unveils distinct mutational patterns between genetic subtypes and novel relapse-associated genes

C. Mårten Lindqvist, Anders Lundmark, Jessica Nordlund, Eva Freyhult, Diana Ekman, Jonas Carlsson Almlöf, Amanda Raine, Elin Övernäs, Jonas Abrahamsson, Britt-Marie Frost, Dan Grandér, Mats Heyman, Josefine Palle, Erik Forestier, Gudmar Lönnerholm, Eva C. Berglund and Ann-Christine Syvänen _

PDF  |  HTML  |  Supplementary Files  |  How to cite

Oncotarget. 2016; 7:64071-64088. https://doi.org/10.18632/oncotarget.11773

Metrics: PDF 2558 views  |   HTML 4928 views  |   ?  


Abstract

C. Mårten Lindqvist1, Anders Lundmark1, Jessica Nordlund1, Eva Freyhult2, Diana Ekman3, Jonas Carlsson Almlöf1, Amanda Raine1, Elin Övernäs1, Jonas Abrahamsson4,9, Britt-Marie Frost5,9, Dan Grandér6, Mats Heyman7,9, Josefine Palle1,5,9, Erik Forestier8,9, Gudmar Lönnerholm5,9, Eva C. Berglund1,*, Ann-Christine Syvänen1,*

1Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden

2Cancer Pharmacology and Computational Medicine, Department of Medical Sciences, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden

3Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden

4Department of Pediatrics, Queen Silvia Children’s Hospital, Gothenburg, Sweden

5Department of Women’s and Children’s Health, University Children’s Hospital, Uppsala, Sweden

6Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden

7Childhood Cancer Research Unit, Department of Women and Child Health, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden

8Department of Medical Biosciences, University of Umeå, Umeå, Sweden

9Nordic Society of Pediatric Hematology and Oncology

*These authors contributed equally to this work

Correspondence to:

Ann-Christine Syvänen, email: [email protected]

Keywords: acute lymphoblastic leukemia, targeted next generation sequencing, somatic mutation, relapse, clonal evolution

Received: June 25, 2016     Accepted: August 25, 2016     Published: August 31, 2016

ABSTRACT

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.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 4.0 License.
PII: 11773