The genetic and epigenetic landscapes of hepatoblastomas

Aguiar, Talita Ferreira Marques; Carneiro, Thaise Nayane Ribeiro; Costa, Cecília Maria Lima da; Rosenberg, Carla; Cunha, Isabela Werneck da; Krepischi, Ana Cristina Victorino

doi:10.1186/s41241-017-0021-0

Cited by 8 publications

(14 citation statements)

References 76 publications

(82 reference statements)

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“…Characterizing HB by its genetic events has only limited significance when it comes to risk stratification and treatment selection. In addition, genetic mutations do not explain HB tumorigenesis sufficiently and previous studies made clear that epigenetic phenomena play a key role in HB development [ 10 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

Overexpression of UHRF1 promotes silencing of tumor suppressor genes and predicts outcome in hepatoblastoma

et al. 2018

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BackgroundHepatoblastoma (HB) is the most common liver tumor of childhood and occurs predominantly within the first 3 years of life. In accordance to its early manifestation, HB has been described to display an extremely low mutation rate. As substitute, epigenetic modifiers seem to play an exceptional role in its tumorigenesis, which holds promise to develop targeted therapies and establish biomarkers for patient risk stratification.ResultsWe examined the role of a newly described protein complex consisting of three epigenetic regulators, namely E3 ubiquitin-like containing PHD and RING finger domain 1 (UHRF1), ubiquitin-specific-processing protease 7 (USP7), and DNA methyltransferase 1 (DNMT1), in HB. We found the complex to be located on the promoter regions of the pivotal HB-associated tumor suppressor genes (TSGs) HHIP, IGFBP3, and SFRP1 in HB cells, thereby leading to strong repression through DNA methylation and histone modifications. Consequently, knockdown of UHRF1 led to DNA demethylation and loss of the repressive H3K9me2 histone mark at the TSG loci with their subsequent transcriptional reactivation. The observed growth impairment of HB cells upon UHRF1 knockdown could be attributed to reduced expression of genes involved in cell cycle progression, negative regulation of cell death, LIN28B signaling, and the adverse 16-gene signature, as revealed by global RNA sequencing. Clinically, overexpression of UHRF1 in primary tumor tissues was significantly associated with poor survival and the prognostic high-risk 16-gene signature.ConclusionThese findings suggest that UHRF1 is critical for aberrant TSG silencing and sustained growth signaling in HB and that UHRF1 overexpression levels might serve as a prognostic biomarker and potential molecular target for HB patients.Electronic supplementary materialThe online version of this article (10.1186/s13148-018-0462-7) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

Overexpression of UHRF1 promotes silencing of tumor suppressor genes and predicts outcome in hepatoblastoma

et al. 2018

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“…HB is a disease mainly caused by the activation of the WNT pathway, which involves the activating mutation/deletion of exon 3 of the catenin β1 ( CTNNB1 ) gene ( 10 ). Certain rare gene mutations lead to the activation of the WNT pathway, such as those occurring in the genes axis inhibition protein 1 ( AXIN1 ), axis inhibition protein 2 ( AXIN2 ) and adenomatous polyposis coli ( APC ) (can only be observed in cases associated with familial adenomatous polyposis) ( 11 ).…”

Section: Introductionmentioning

confidence: 99%

Genotypic Characteristics of Hepatoblastoma as Detected by Next Generation Sequencing and Their Correlation With Clinical Efficacy

Zhang

Zhi

et al. 2021

Front. Oncol.

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BackgroundHepatoblastoma (HB) is the most common malignant embryonic liver tumor type in children under 3 years of age. In the present study, the next generation sequencing (NGS) method was used to detect the genotype characteristics of HB and summarize the correlation between the common mutation genotypes noted in this disease and the clinical treatment and prognosis. The results may aid clinical prognosis and the successful application of targeted drugs.MethodsInitially, DNA was extracted from tumor tissue specimens and peripheral blood derived from 19 pediatric patients with HB. Subsequently, DNA panel and NGS methods were used to detect tumor diagnosis and the expression levels of treatment-associated genes, followed by the summary of genotype characteristics. In addition, in order to further assess the application of immunotherapy in HB, immunohistochemical detection of programmed cell death 1 ligand 1 (PDL1) was performed in combination with tumor mutation burden (TMB) and DNA mismatch repair status analysis. Furthermore, the clinical treatment effect and prognosis of the pediatric patients were statistically analyzed according to the characteristics of the genotype. Overall prognosis and prognostic analyses in different groups were performed by Kaplan-Meier and log-rank tests, respectively. Finally, expression validation and diagnostic analysis of commonly reported genes were performed in the GSE75271 dataset, which was obtained from the Gene Expression Omnibus (GEO) database.ResultsIn the present study, certain mutated genes, including nuclear factor erythroid 2-related factor 2 (NFE2L2), catenin β1 (CTNNB1), MYCN, tumor protein p53, axis inhibition protein 1 (AXIN1) and adenomatous polyposis coli (APC) were associated with the pathogenesis of HB. During TMB and DNA mismatch repair status analyses, pediatric patients had a low TMB. All of them did not present with microsatellite instability. The immunohistochemical results indicated lower expression levels of PDL1 in HB. The complete remission (CR) rate of pediatric patients in the gene abnormality group was lower than that of the non-reported disease-associated gene abnormality group. The 2-year overall survival rate and disease-free survival rate of 19 pediatric patients with HB were 72.1% and 42.4%, respectively. Receiver operating characteristic (ROC) analysis demonstrated that CTNNB1, NFE2L2, AXIN1, APC, MYCN and insulin growth factor 2 (IGF2) may be potential biomarkers that could be used for the diagnosis of HB.ConclusionThe genotype changes in HB were more common and the CR rate of the pediatric patients with an altered genotype was lower than that of pediatric patients without an altered genotype. In addition, pediatric patients with HB exhibited lower TMB compared with adult patients. Moreover, the data indicated that CTNNB1, NFE2L2, AXIN1, APC, MYCN and IGF2 may be potential biomarkers that can be used for the diagnosis of HB.

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“…One of the major barriers to the implementation of this approach in clinical settings is the intra/inter-tumor heterogeneity, in addition to the rarity in the case of pediatric cancer. In particular, HB is a tumor with a genetic background with low mutational background and few cytogenetic alterations 12,30,[38][39][40][41] , in addition to DNA methylation changes 13,42. The present work describes the possibility of molecular stratification of HBs according to markers of hepatocyte differentiation and DNA methylation. Tumor heterogeneity could be overcome using molecular signatures that are linked to clinical data.…”

Section: Discussionmentioning

confidence: 99%

Dna Methylation as a Key Epigenetics Player for Hepatoblastoma Stratification

Rivas¹,

Aguiar²,

Fernandes³

et al. 2020

Preprint

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Background: Hepatoblastoma (HB) is a rare embryonal liver tumor occurring in the pediatric population, and although intrinsic biological differences between tumors can impact HBs prognosis, few groups have studied this aspect. Given the crescent relevance of epigenetic mechanisms in the genesis and progression of these tumors, we aim to classify HB samples according to the different stages of liver development as well as DNA methylation machinery. Procedures: Using bioinformatics tools, we evaluate the expression of 24 genes associated with epigenetics and stages of hepatocyte differentiation as well as global DNA methylation to propose a stratification model for HB. Results: Based on the gene expression profiles of DNA methylation machinery and hepatocyte differentiation markers, HBs were clustered into three groups. Besides reinforcing the molecular heterogeneity of these embryonal tumors, our data propose that a panel of 13 genes can be used for HB stratification (TET1,

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The genetic and epigenetic landscapes of hepatoblastomas

Cited by 8 publications

References 76 publications

Overexpression of UHRF1 promotes silencing of tumor suppressor genes and predicts outcome in hepatoblastoma

Overexpression of UHRF1 promotes silencing of tumor suppressor genes and predicts outcome in hepatoblastoma

Genotypic Characteristics of Hepatoblastoma as Detected by Next Generation Sequencing and Their Correlation With Clinical Efficacy

Dna Methylation as a Key Epigenetics Player for Hepatoblastoma Stratification

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