title: The genomic landscape of hepatoblastoma and their progenies with HCC-like features.
abstract: OBJECTIVE
  Hepatoblastoma (HB) is the most common childhood liver cancer and occasionally presents with histological and clinical features reminiscent of hepatocellular carcinoma (HCC). Identification of molecular mechanisms that drive the neoplastic continuation towards more aggressive HCC phenotypes may help to guide the new stage of targeted therapies.
  
  
  METHODS
  We performed comprehensive studies on genetic and chromosomal alterations as well as candidate gene function and their clinical relevance.
  
  
  RESULTS
  Whole-exome sequencing identified HB as a genetically very simple tumour (2.9 mutations per tumour) with recurrent mutations in ß-catenin (CTNNB1) (12/15 cases) and the transcription factor NFE2L2 (2/15 cases). Their HCC-like progenies share the common CTNNB1 mutation, but additionally exhibit a significantly increased mutation number and chromosomal instability due to deletions of the genome guardians RAD17 and TP53, accompanied by telomerase reverse-transcriptase (TERT) promoter mutations. Targeted genotyping of 33 primary tumours and cell lines revealed CTNNB1, NFE2L2, and TERT mutations in 72.5%, 9.8%, and 5.9% of cases, respectively. All NFE2L2 mutations affected residues of the NFE2L2 protein that are recognized by the KEAP1/CUL3 complex for proteasomal degradation. Consequently, cells transfected with mutant NFE2L2 were insensitive to KEAP1-mediated downregulation of NFE2L2 signalling. Clinically, overexpression of the NFE2L2 target gene NQO1 in tumours was significantly associated with metastasis, vascular invasion, the adverse prognostic C2 gene signature, as well as poor outcome.
  
  
  CONCLUSIONS
  Our study demonstrates the importance of CTNNB1 mutations and NFE2L2-KEAP1 pathway activation in HB development and defines loss of genomic stability and TERT promoter mutations as prominent characteristics of aggressive HB with HCC features.
authors.affiliation: Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Melanie
authors.initials: M
authors.lastname: Eichenmüller
authors.affiliation: Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Franziska
authors.initials: F
authors.lastname: Trippel
authors.affiliation: Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Michaela
authors.initials: M
authors.lastname: Kreuder
authors.affiliation: Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Alexander
authors.initials: A
authors.lastname: Beck
authors.affiliation: Institute of Human Genetics, Helmholtz Center Munich, Neuherberg, Germany; Institute of Human Genetics, Technical University Munich, Munich, Germany.
authors.forename: Thomas
authors.initials: T
authors.lastname: Schwarzmayr
authors.affiliation: Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Beate
authors.initials: B
authors.lastname: Häberle
authors.affiliation: XenTech, Evry, France.
authors.forename: Stefano
authors.initials: S
authors.lastname: Cairo
authors.affiliation: Institute of Paidopathology, Pediatric Tumor Registry, Christian-Albrechts-University Kiel, Kiel, Germany.
authors.forename: Ivo
authors.initials: I
authors.lastname: Leuschner
authors.affiliation: Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany.
authors.forename: Dietrich
authors.initials: D
authors.lastname: von Schweinitz
authors.affiliation: Institute of Human Genetics, Helmholtz Center Munich, Neuherberg, Germany; Institute of Human Genetics, Technical University Munich, Munich, Germany.
authors.forename: Tim M
authors.initials: TM
authors.lastname: Strom
authors.affiliation: Department of Pediatric Surgery, Dr. von Hauner Children's Hospital, Ludwig-Maximilians-University Munich, Munich, Germany; German Cancer Consortium (DKTK), Heidelberg, Germany; German Cancer Research Center (DKFZ), Heidelberg, Germany. Electronic address: roland.kappler@med.uni-muenchen.de.
authors.forename: Roland
authors.initials: R
authors.lastname: Kappler
mesh_terms: D000328:Adult; D001706:Biopsy; D006528:Carcinoma, Hepatocellular / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D002648:Child; D004273:DNA, Neoplasm / Q000235:genetics; D023281:Genomics; D018197:Hepatoblastoma / Q000235:genetics* / Q000473:pathology; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics; D000072019:Kelch-Like ECH-Associated Protein 1; D008113:Liver Neoplasms / Q000235:genetics* / Q000473:pathology; D009154:Mutation / Q000235:genetics; D051267:NF-E2-Related Factor 2 / Q000235:genetics; D012189:Retrospective Studies; D017422:Sequence Analysis, DNA; D019098:Telomerase / Q000235:genetics; D051176:beta Catenin / Q000235:genetics
chemical_list: C495270:CTNNB1 protein, human; D004273:DNA, Neoplasm; D047908:Intracellular Signaling Peptides and Proteins; C431364:KEAP1 protein, human; D000072019:Kelch-Like ECH-Associated Protein 1; D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D051176:beta Catenin; C509186:TERT protein, human; D019098:Telomerase
keywords: Beta catenin; Exome; Hepatoblastoma; Hepatocellular carcinoma; Mutation; NFE2L2; Paediatric; Telomerase reverse-transcriptase