title: Next-generation-sequencing of recurrent childhood high hyperdiploid acute lymphoblastic leukemia reveals mutations typically associated with high risk patients.
abstract: 20% of children suffering from high hyperdiploid acute lymphoblastic leukemia develop recurrent disease. The molecular mechanisms are largely unknown. Here, we analyzed the genetic landscape of five patients at relapse, who developed recurrent disease without prior high-risk indication using whole-exome- and whole-genome-sequencing. Oncogenic mutations of RAS pathway genes (NRAS, KRAS, FLT3, n=4) and deactivating mutations of major epigenetic regulators (CREBBP, EP300, each n=2 and ARID4B, EZH2, MACROD2, MLL2, each n=1) were prominent in these cases and virtually absent in non-recurrent cases (n=6) or other pediatric acute lymphoblastic leukemia cases (n=18). In relapse nucleotide variations were detected in cell fate determining transcription factors (GLIS1, AKNA). Structural genomic alterations affected genes regulating B-cell development (IKZF1, PBX1, RUNX1). Eleven novel translocations involved the genes ART4, C12orf60, MACROD2, TBL1XR1, LRRN4, KIAA1467, and ELMO1/MIR1200. Typically, patients harbored only single structural variations, except for one patient who displayed massive rearrangements in the context of a germline tumor suppressor TP53 mutation and a Li-Fraumeni syndrome-like family history. Another patient harbored a germline mutation in the DNA repair factor ATM. In summary, the relapse patients of our cohort were characterized by somatic mutations affecting the RAS pathway, epigenetic and developmental programs and germline mutations in DNA repair pathways.
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany; Fujian Institute of Hematology, Fujian Medical University Union Hospital, Fuzhou, China.
authors.forename: Cai
authors.initials: C
authors.lastname: Chen
authors.affiliation: Institute of Medical Informatics, University of Münster, Münster, Germany.
authors.forename: Christoph
authors.initials: C
authors.lastname: Bartenhagen
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Gombert
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Okpanyi
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Vera
authors.initials: V
authors.lastname: Binder
authors.affiliation: Oncogenetic Laboratory, Department of Pediatric Hematology and Oncology, Justus Liebig University, Giessen, Germany.
authors.forename: Silja
authors.initials: S
authors.lastname: Röttgers
authors.affiliation: Oncogenetic Laboratory, Department of Pediatric Hematology and Oncology, Justus Liebig University, Giessen, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Bradtke
authors.affiliation: Oncogenetic Laboratory, Department of Pediatric Hematology and Oncology, Justus Liebig University, Giessen, Germany.
authors.forename: Andrea
authors.initials: A
authors.lastname: Teigler-Schlegel
authors.affiliation: Oncogenetic Laboratory, Department of Pediatric Hematology and Oncology, Justus Liebig University, Giessen, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Harbott
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany; Department of Computer Science, Bonn-Rhine-Sieg University of Applied Sciences, Sankt Augustin, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Ginzel
authors.affiliation: Department of Computer Science, Bonn-Rhine-Sieg University of Applied Sciences, Sankt Augustin, Germany.
authors.forename: Ralf
authors.initials: R
authors.lastname: Thiele
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Husemann
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Pina F I
authors.initials: PF
authors.lastname: Krell
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Borkhardt
authors.affiliation: Institute of Medical Informatics, University of Münster, Münster, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Dugas
authors.affiliation: Fujian Institute of Hematology, Fujian Medical University Union Hospital, Fuzhou, China. Electronic address: jdhu@medmail.com.cn.
authors.forename: Jianda
authors.initials: J
authors.lastname: Hu
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany. Electronic address: ute.fischer@med.uni-duesseldorf.de.
authors.forename: Ute
authors.initials: U
authors.lastname: Fischer
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D051017:Apoptosis Regulatory Proteins / Q000235:genetics*; D001483:Base Sequence; D002675:Child, Preschool; D004260:DNA Repair / Q000235:genetics; D044127:Epigenesis, Genetic; D005260:Female; D015973:Gene Expression Regulation, Leukemic; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D059785:Karyotype; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D011003:Ploidies; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D011518:Proto-Oncogene Proteins / Q000235:genetics*; D012008:Recurrence; D012307:Risk Factors; D015398:Signal Transduction; D014157:Transcription Factors / Q000235:genetics*
chemical_list: D000970:Antineoplastic Agents; D051017:Apoptosis Regulatory Proteins; D011518:Proto-Oncogene Proteins; D014157:Transcription Factors
keywords: Acute lymphoblastic leukemia; CREBBP; High hyperdiploidy; Ikaros; RAS; Relapse; TP53