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Open Access Green möglich sobald Postprint bei der ZB eingereicht worden ist.
The genomic landscape of hepatoblastoma and their progenies with HCC-like features.
J. Hepatol. 61, 1312-1320 (2014)
BACKGROUND & AIMS: 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 the genetically most simple tumor ever described (2.9 mutations per tumor) with recurrent mutations in CTNNB1 (12/15 cases) and 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 TERT promoter mutations. Targeted genotyping of 33 primary tumors 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 signaling. Clinically, overexpression of the NFE2L2 target gene NQO1 in tumors 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.
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Publikationstyp
Artikel: Journalartikel
Dokumenttyp
Wissenschaftlicher Artikel
Schlagwörter
Beta Catenin ; Exome ; Hepatoblastoma ; Hepatocellular Carcinoma ; Mutation ; Nfe2l2 ; Pediatric ; Telomerase
ISSN (print) / ISBN
0168-8278
e-ISSN
1600-0641
Zeitschrift
Journal of Hepatology
Quellenangaben
Band: 61,
Heft: 6,
Seiten: 1312-1320
Verlag
Elsevier
Nichtpatentliteratur
Publikationen
Begutachtungsstatus
Peer reviewed
Institut(e)
Institute of Human Genetics (IHG)