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Genome-wide mapping of ASCL2 and CTNNB1 in hepatoblastoma cell lines

ABSTRACT: Hepatoblastoma (HB) is the most common pediatric liver malignancy; however, hereditary predisposition and acquired molecular aberrations related to HB clinicopathological diversity are not well understood. We performed an integrative genomic profiling of 163 pediatric liver tumors (154 HB and 9 hepatocellular carcinoma) based on data acquired from a cohort study (JPLT-2). The total number of somatic mutations was found to be extremely low (0.52 /Mb on exonic regions) but correlated with age at diagnosis. TERT promoter mutations are prevalent in the tween HBs, selective in the transitional liver cell tumor (TLCT, > 8 years old). DNA methylation profiling revealed that classical HBs are characterized by the specific hypomethylated enhancers, which are enriched with binding sites for ASCL2, a regulatory transcription factor for definitive endoderm in Wnt-pathway. Prolonged upregulation of ASCL2, as well as fetal-liver-like methylation patterns of IGF2 promoters, suggests their “cell of origin” derived from the premature hepatoblast, similar to intestinal epithelial cells, which are highly proliferative. Systematic molecular profiling of HB is a promising approach to understanding the epigenetic drivers of hepatoblast carcinogenesis and clues for risk stratification.

ORGANISM(S): Homo sapiens

PROVIDER: GSE169566 | GEO | 2021/06/01

REPOSITORIES: GEO

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Mouse hepatoblastoma models with expression of mutant β-catenin and/or c-Myc for therapeutic target identification of childhood liver cancer

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| phs001433 | dbGaP

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Project description:Wnt signals control three functions of intestinal crypts: maintenance of Lgr5 stem cells, proliferation of transit-amplifying daughters and formation of Paneth cells. Here, we study how the Wnt effector Î²-catenin/Tcf4 cooperates with the Wnt-activated transcription factor Ascl2 to control a stem cell transcription program. DNA elements that are co-occupied and synergistically regulated by Ascl2 and Tcf4 specifically map to stem cell genes. In vitro, Tcf4-/- mini-guts are rescued by Ascl2 expression, while Ascl2-/- organoids are rescued by Wnt signaling. A direct auto-activatory loop leads to an on/off expression pattern of Ascl2 with a threshold that depends on the previous state. Wnt/R-spondin1 activates this loop. This mechanism interprets Wnt levels in crypts and translates this continuous signal into a discrete Ascl2 âonâ or âoffâ decision. In turn Ascl2, together with Î²-catenin/Tcf, activates stem cell genes. Thus, Ascl2 forms a transcriptional 'stemness switch' that is both Wnt-responsive and Wnt-dependent Examination of Tcf4, B-catenin and Ascl2 DNA occupancy in murine intestinal organoids and human colorectal cancer cell lines *** Original raw files unavailable due to loss during backup ***

2016-07-15 | E-GEOD-84456 | biostudies-arrayexpress

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2021-03-01 | GSE154350 | GEO

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