{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,3]],"date-time":"2026-09-03T22:22:07Z","timestamp":1788474127670,"version":"build-2803163510"},"reference-count":66,"publisher":"MDPI AG","issue":"9","license":[{"start":{"date-parts":[[2021,4,21]],"date-time":"2021-04-21T00:00:00Z","timestamp":1618963200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["RO1 CA174713"],"award-info":[{"award-number":["RO1 CA174713"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>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\/\u03b2-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 \u03b2-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\/\u03b2-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 \u03b2-catenin or a Hippo pathway effector. The finding that tumorigenesis can be driven by any two arms of the \u03b2-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.<\/jats:p>","DOI":"10.3390\/cancers13091996","type":"journal-article","created":{"date-parts":[[2021,4,21]],"date-time":"2021-04-21T12:47:07Z","timestamp":1619009227000},"page":"1996","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":15,"title":["Reconciling the Biological and Transcriptional Variability of Hepatoblastoma with Its Mutational Uniformity"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9666-8205","authenticated-orcid":false,"given":"Edward V.","family":"Prochownik","sequence":"first","affiliation":[{"name":"Division of Hematology\/Oncology, UPMC Children\u2019s Hospital of Pittsburgh, Pittsburgh, PA 15224, USA"},{"name":"The Department of Microbiology and Molecular Genetics, The University of Pittsburgh School of Medicine, Pittsburgh, PA 15224, USA"},{"name":"The University of Pittsburgh Hillman Cancer Center, Pittsburgh, PA 15232, USA"},{"name":"The University of Pittsburgh Liver Research Center, Pittsburgh, PA 15213, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2021,4,21]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"741","DOI":"10.1111\/hpb.12112","article-title":"Predictors of survival and incidence of hepatoblastoma in the paediatric population","volume":"15","author":"Allan","year":"2013","journal-title":"HPB"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"141","DOI":"10.3727\/105221616X693639","article-title":"Novel Advances in Understanding of Molecular Pathogenesis of Hepatoblastoma: A Wnt\/\u03b2-Catenin Perspective","volume":"17","author":"Bell","year":"2017","journal-title":"Gene Expr."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"19","DOI":"10.1097\/MOP.0000000000000046","article-title":"Hepatoblastoma state of the art: Pathology, genetics, risk stratification, and chemotherapy","volume":"26","author":"Czauderna","year":"2014","journal-title":"Curr. 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