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Reconciling the Biological and Transcriptional Variability of Hepatoblastoma with Its Mutational Uniformity

Prochownik, Edward V. (2021) Reconciling the Biological and Transcriptional Variability of Hepatoblastoma with Its Mutational Uniformity. Cancers, 13 (9). p. 1996. ISSN 2072-6694

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Hepatoblastoma (HB), the most common childhood liver cancer, is associated with seven distinct histologic subtypes and variable degrees of clinical aggressiveness and presentation. Yet it is among the least genomically altered tumors known, with about half of HBs showing mutation and/or dysregulation of the Wnt/β-catenin and Hippo pathways. This raises the question of how this mutational simplicity can generate such biological and histologic complexity. Recent work shows that the identity of the underlying β-catenin mutation is a major contributor. Mutation or over-expression of the NFE2L2/NRF2 transcription factor, previously thought only to promote anti-oxidant responses, has also recently been shown to accelerate the growth of HBs generated by mutations in the Wnt/β-catenin and Hippo pathways while imparting novel features such as the tumor-associated cysts and necrosis. Moreover, patient-associated NFE2L2 mutations are overtly transforming when co-expressed with either mutant β-catenin or a Hippo pathway effector. The finding that tumorigenesis can be driven by any two arms of the β-catenin/Hippo/NFE2L2 axis has permitted the identification of a small subset of coordinately regulated tumor-specific transcripts, some of whose levels correlate with inferior long-term outcomes in HB and other cancers. Collectively, these findings begin to provide for more refined and molecularly based classification, survival algorithms and design of chemotherapeutic regimens.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Prochownik, Edward V.evp4@pitt.eduevp4
Centers: Other Centers, Institutes, Offices, or Units > Hillman Cancer Center
Date: 21 April 2021
Date Type: Publication
Journal or Publication Title: Cancers
Volume: 13
Number: 9
Publisher: MDPI AG
Page Range: p. 1996
DOI or Unique Handle: 10.3390/cancers13091996
Schools and Programs: School of Medicine > Microbiology and Molecular Genetics
Refereed: Yes
Uncontrolled Keywords: β-catenin, hepatocellular carcinoma, Hippo pathway, liver cancer, NFE2L2, NRF2
ISSN: 2072-6694
Official URL:
Funders: National Institute of Health, Hyundai Hope on Wheels Scholar Award, V Foundation, The Richard King Mellon Foundation
Article Type: Review
Date Deposited: 29 Jun 2021 18:47
Last Modified: 29 Jun 2021 18:47


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