PMID- 27590521 OWN - NLM STAT- MEDLINE DCOM- 20180522 LR - 20210122 IS - 1949-2553 (Electronic) IS - 1949-2553 (Linking) VI - 7 IP - 39 DP - 2016 Sep 27 TI - Deep targeted sequencing in pediatric acute lymphoblastic leukemia unveils distinct mutational patterns between genetic subtypes and novel relapse-associated genes. PG - 64071-64088 LID - 10.18632/oncotarget.11773 [doi] AB - 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. FAU - Lindqvist, C Marten AU - Lindqvist CM AD - Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. FAU - Lundmark, Anders AU - Lundmark A AD - Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. FAU - Nordlund, Jessica AU - Nordlund J AD - Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. FAU - Freyhult, Eva AU - Freyhult E AD - Cancer Pharmacology and Computational Medicine, Department of Medical Sciences, National Bioinformatics Infrastructure Sweden, Science for Life Laboratory, Uppsala University, Uppsala, Sweden. FAU - Ekman, Diana AU - Ekman D AD - Science for Life Laboratory, Department of Biochemistry and Biophysics, Stockholm University, Stockholm, Sweden. FAU - Carlsson Almlof, Jonas AU - Carlsson Almlof J AD - Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. FAU - Raine, Amanda AU - Raine A AD - Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. FAU - Overnas, Elin AU - Overnas E AD - Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. FAU - Abrahamsson, Jonas AU - Abrahamsson J AD - Department of Pediatrics, Queen Silvia Children's Hospital, Gothenburg, Sweden. AD - Nordic Society of Pediatric Hematology and Oncology. FAU - Frost, Britt-Marie AU - Frost BM AD - Department of Women's and Children's Health, University Children's Hospital, Uppsala, Sweden. AD - Nordic Society of Pediatric Hematology and Oncology. FAU - Grander, Dan AU - Grander D AD - Department of Oncology-Pathology, Karolinska Institute, Stockholm, Sweden. FAU - Heyman, Mats AU - Heyman M AD - Childhood Cancer Research Unit, Department of Women and Child Health, Astrid Lindgren Children's Hospital, Karolinska University Hospital, Stockholm, Sweden. AD - Nordic Society of Pediatric Hematology and Oncology. FAU - Palle, Josefine AU - Palle J AD - Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. AD - Department of Women's and Children's Health, University Children's Hospital, Uppsala, Sweden. AD - Nordic Society of Pediatric Hematology and Oncology. FAU - Forestier, Erik AU - Forestier E AD - Department of Medical Biosciences, University of Umea, Umea, Sweden. AD - Nordic Society of Pediatric Hematology and Oncology. FAU - Lonnerholm, Gudmar AU - Lonnerholm G AD - Department of Women's and Children's Health, University Children's Hospital, Uppsala, Sweden. AD - Nordic Society of Pediatric Hematology and Oncology. FAU - Berglund, Eva C AU - Berglund EC AD - Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. FAU - Syvanen, Ann-Christine AU - Syvanen AC AD - Department of Medical Sciences, Molecular Medicine and Science for Life Laboratory, Uppsala University, Uppsala, Sweden. LA - eng PT - Journal Article PL - United States TA - Oncotarget JT - Oncotarget JID - 101532965 RN - 0 (ARID1A protein, human) RN - 0 (Adaptor Proteins, Signal Transducing) RN - 0 (DNA-Binding Proteins) RN - 0 (Intracellular Signaling Peptides and Proteins) RN - 0 (Nuclear Proteins) RN - 0 (Oncogene Proteins, Fusion) RN - 0 (Proteins) RN - 0 (SH2B3 protein, human) RN - 0 (Transcription Factors) RN - EC 2.3.1.48 (E1A-Associated p300 Protein) RN - EC 2.3.1.48 (EP300 protein, human) SB - IM MH - Adaptor Proteins, Signal Transducing MH - Child MH - Child, Preschool MH - Cohort Studies MH - DNA Mutational Analysis MH - DNA-Binding Proteins MH - E1A-Associated p300 Protein/genetics MH - Epigenesis, Genetic MH - *High-Throughput Nucleotide Sequencing MH - Humans MH - Immunophenotyping MH - Infant MH - Intracellular Signaling Peptides and Proteins MH - *Mutation MH - Neoplasm Recurrence, Local/*genetics MH - Nuclear Proteins/genetics MH - Oncogene Proteins, Fusion/genetics MH - Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics MH - Precursor Cell Lymphoblastic Leukemia-Lymphoma/*genetics MH - Precursor T-Cell Lymphoblastic Leukemia-Lymphoma/genetics MH - Proteins/genetics MH - Recurrence MH - Remission Induction MH - Sequence Analysis, DNA MH - Transcription Factors/genetics MH - Translocation, Genetic PMC - PMC5325426 OTO - NOTNLM OT - acute lymphoblastic leukemia OT - clonal evolution OT - relapse OT - somatic mutation OT - targeted next generation sequencing COIS- CONFLICTS OF INTEREST No conflicts to disclose. EDAT- 2016/09/04 06:00 MHDA- 2018/05/23 06:00 PMCR- 2016/09/27 CRDT- 2016/09/04 06:00 PHST- 2016/06/25 00:00 [received] PHST- 2016/08/25 00:00 [accepted] PHST- 2016/09/04 06:00 [pubmed] PHST- 2018/05/23 06:00 [medline] PHST- 2016/09/04 06:00 [entrez] PHST- 2016/09/27 00:00 [pmc-release] AID - 11773 [pii] AID - 10.18632/oncotarget.11773 [doi] PST - ppublish SO - Oncotarget. 2016 Sep 27;7(39):64071-64088. doi: 10.18632/oncotarget.11773.