title: Deep targeted sequencing in pediatric acute lymphoblastic leukemia unveils distinct mutational patterns between genetic subtypes and novel relapse-associated genes.
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.
authors: Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: C Mårten
authors: CM
authors: Lindqvist
authors: Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Anders
authors: A
authors: Lundmark
authors: Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Jessica
authors: J
authors: Nordlund
authors: Cancer Pharmacology and Computational Medicine, Department of Medical Sciences, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Eva
authors: E
authors: Freyhult
authors: Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden.
authors: Diana
authors: D
authors: Ekman
authors: Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Jonas
authors: J
authors: Carlsson Almlöf
authors: Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Amanda
authors: A
authors: Raine
authors: Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Elin
authors: E
authors: Övernäs
authors: Department of Pediatrics, Queen Silvia Children's Hospital, Gothenburg, Sweden.|Nordic Society of Pediatric Hematology and Oncology.
authors: Jonas
authors: J
authors: Abrahamsson
authors: Department of Women's and Children's Health, University Children's Hospital, Uppsala, Sweden.|Nordic Society of Pediatric Hematology and Oncology.
authors: Britt-Marie
authors: BM
authors: Frost
authors: Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden.
authors: Dan
authors: D
authors: Grandér
authors: Childhood Cancer Research Unit, Department of Women and Child Health, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden.|Nordic Society of Pediatric Hematology and Oncology.
authors: Mats
authors: M
authors: Heyman
authors: Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.|Department of Women's and Children's Health, University Children's Hospital, Uppsala, Sweden.|Nordic Society of Pediatric Hematology and Oncology.
authors: Josefine
authors: J
authors: Palle
authors: Department of Medical Biosciences, University of Umeå, Umeå, Sweden.|Nordic Society of Pediatric Hematology and Oncology.
authors: Erik
authors: E
authors: Forestier
authors: Department of Women's and Children's Health, University Children's Hospital, Uppsala, Sweden.|Nordic Society of Pediatric Hematology and Oncology.
authors: Gudmar
authors: G
authors: Lönnerholm
authors: Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Eva C
authors: EC
authors: Berglund
authors: Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
authors: Ann-Christine
authors: AC
authors: Syvänen
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D004268:DNA-Binding Proteins; D050881:E1A-Associated p300 Protein / Q000235:genetics; D044127:Epigenesis, Genetic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D016130:Immunophenotyping; D007223:Infant; D047908:Intracellular Signaling Peptides and Proteins; D009154:Mutation; D009364:Neoplasm Recurrence, Local / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics; D015514:Oncogene Proteins, Fusion / Q000235:genetics; D015452:Precursor B-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics*; D054218:Precursor T-Cell Lymphoblastic Leukemia-Lymphoma / Q000235:genetics; D011506:Proteins / Q000235:genetics; D012008:Recurrence; D012074:Remission Induction; D017422:Sequence Analysis, DNA; D014157:Transcription Factors / Q000235:genetics; D014178:Translocation, Genetic
chemical_list: C112476:ARID1A protein, human; D048868:Adaptor Proteins, Signal Transducing; D004268:DNA-Binding Proteins; D047908:Intracellular Signaling Peptides and Proteins; D009687:Nuclear Proteins; D015514:Oncogene Proteins, Fusion; D011506:Proteins; C490778:SH2B3 protein, human; D014157:Transcription Factors; D050881:E1A-Associated p300 Protein; C494360:EP300 protein, human
keywords: acute lymphoblastic leukemia; clonal evolution; relapse; somatic mutation; targeted next generation sequencing