Hepatoblastoma

Overview

Literature Analysis

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Tag cloud generated 10 March, 2017 using data from PubMed, MeSH and CancerIndex

Mutated Genes and Abnormal Protein Expression (4)

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GeneLocationAliasesNotesTopicPapers
CTNNB1 3p22.1 CTNNB, MRD19, armadillo -CTNNB1 and Hepatoblastoma
69
IGF2 11p15.5 GRDF, IGF-II, PP9974, C11orf43 -IGF2 and Hepatoblastoma
23
SLC22A18 11p15.4 HET, ITM, BWR1A, IMPT1, TSSC5, ORCTL2, BWSCR1A, SLC22A1L, p45-BWR1A -SLC22A18 and Hepatoblastoma
2
ETV3 1q21-q23 PE1, METS, PE-1, bA110J1.4 -ETV3 and Hepatoblastoma
1

Note: list is not exhaustive. Number of papers are based on searches of PubMed (click on topic title for arbitrary criteria used).

Latest Publications

Honda S, Minato M, Suzuki H, et al.
Clinical prognostic value of DNA methylation in hepatoblastoma: Four novel tumor suppressor candidates.
Cancer Sci. 2016; 107(6):812-9 [PubMed] Free Access to Full Article Related Publications
Hepatoblastoma (HB) is very rare but the most common malignant neoplasm of the liver occurring in children. Despite improvements in therapy, outcomes for patients with advanced HB that is refractory to standard preoperative chemotherapy remain unsatisfactory. To improve the survival rate among this group, identification of novel prognostic markers and therapeutic targets is needed. We have previously reported that altered DNA methylation patterns are of biological and clinical importance in HB. In the present study, using genome-wide methylation analysis and bisulfite pyrosequencing with specimens from HB tumors, we detected nine methylated genes. We then focused on four of those genes, GPR180, MST1R, OCIAD2, and PARP6, because they likely encode tumor suppressors and their increase of methylation was associated with a poor prognosis. The methylation status of the four genes was also associated with age at diagnosis, and significant association with the presence of metastatic tumors was seen in three of the four genes. Multivariate analysis revealed that the presence of metastatic tumors and increase of methylation of GPR180 were independent prognostic factors affecting event-free survival. These findings indicate that the four novel tumor suppressor candidates are potentially useful molecular markers predictive of a poor outcome in HB patients, which may serve as the basis for improved therapeutic strategies when clinical trials are carried out.

Canal F, Anthony E, Lescure A, et al.
A kinome siRNA screen identifies HGS as a potential target for liver cancers with oncogenic mutations in CTNNB1.
BMC Cancer. 2015; 15:1020 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Aberrant activation of the Wnt/β-catenin pathway is a major and frequent event in liver cancer, but inhibition of oncogenic β-catenin signaling has proven challenging. The identification of genes that are synthetically lethal in β-catenin-activated cancer cells would provide new targets for therapeutic drug design.
METHODS: We transfected the parental HuH6 hepatoblastoma cell line with a doxycycline-inducible shRNA against CTNNB1 (gene coding for β-catenin) to obtain an isogenic cell line pair with or without aberrant β-catenin signaling. Using this hepatoblastoma isogenic cell line pair, we performed a human kinome-wide siRNA screen to identify synthetic lethal interactions with oncogenic CTNNB1. The phenotypic readouts of the screen were cell proliferation, cell cycle arrest and apoptosis, which were assessed by image-based analysis. In addition, apoptosis was assessed by flow cytometric experiments and immunoblotting. The potential synthetic lethal relationship between candidates genes identified in the screen and oncogenic CTNNB1 was also investigated in a different cellular context, a colorectal HCT116 isogenic cell line pair.
RESULTS: We first determined the experimental conditions that led to the efficient expression of shRNA against CTNNB1 and maximal reduction of β-catenin signaling activity in response to doxycycline treatment. Following high throughput screening in which 687 genes coding for kinases and proteins related to kinases (such as pseudokinases and phosphatases) were targeted, we identified 52 genes required for HuH6 survival. The silencing of five of these genes selectively impaired the viability of HuH6 cells with high β-catenin signaling: HGS, STRADA, FES, BRAF and PKMYT1. Among these candidates, HGS depletion had the strongest inhibitory effect on cell growth and led to apoptosis specifically in HuH6 with high β-catenin activity, while HuH6 with low β-catenin activity were spared. In addition, HGS was identified as a potential synthetic lethal partner of oncogenic CTNNB1 in the HCT116 colorectal isogenic cell line pair.
CONCLUSIONS: These results demonstrate the existence of crosstalk between β-catenin signaling and HGS. Importantly, HGS depletion specifically affected cells with uncontrolled β-catenin signaling activity in two different types of cancer (Hepatoblastoma HuH6 and colorectal HCT116), and thus may represent a new potential target for novel therapeutic strategies in liver and colorectal cancer.

Gödeke J, Luxenburger E, Trippel F, et al.
Low expression of N-myc downstream-regulated gene 2 (NDRG2) correlates with poor prognosis in hepatoblastoma.
Hepatol Int. 2016; 10(2):370-6 [PubMed] Related Publications
BACKGROUND/PURPOSE OF THE STUDY: Despite tremendous progress in therapy, about 30% of patients with hepatoblastoma still succumb to the disease. Thus, the development of improved therapies as well as the identification of prognostic factors are urgently needed.
METHODS: In the present study, expression and promoter methylation of the N-myc downstream-regulated gene (NDRG2), a tumor suppressor gene contributing to the regulation of the Wnt signalling pathway, was analysed in 38 hepatoblastoma samples by real-time reverse transcription-PCR and pyrosequencing, respectively.
RESULTS: The NDRG2 gene was highly expressed in normal pediatric liver tissue, but was significantly downregulated in heptoblastoma primary tumors. Detailed methylation analysis of CpG sites in the NDRG2 promoter region revealed a general high degree of DNA methylation in hepatoblastoma, which correlated with the suppression of NDRG2. By analyzing clinicopathological features we could demonstrate a strong association between low NDRG2 expression and tumor metastasis. Importantly, the overall survival analysis by Kaplan-Meier revealed that high NDRG2 expression was correlated with a higher survival rate in hepatoblastoma patients.
CONCLUSION: Our data show that downregulation of NDRG2 may play an important role in advanced hepatoblastomas.

Leichter AL, Purcell RV, Sullivan MJ, et al.
Multi-platform microRNA profiling of hepatoblastoma patients using formalin fixed paraffin embedded archival samples.
Gigascience. 2015; 4:54 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Formalin fixed paraffin embedded (FFPE) samples are a valuable resource in cancer research and have the potential to be extensively used. However, they are often underused because of degradation and chemical modifications occurring in the RNA that can present obstacles in downstream analysis. In routine medical care, FFPE material is examined and archived, therefore clinical collections of many types of cancers exist. It is beneficial to assess and record the quality of data that can be obtained from this type of material. The current study investigated three independent platforms and their ability to profile microRNAs (miRNAs) within FFPE samples from hepatoblastoma (HB) patients.
FINDINGS: Here we present three types of datasets consisting of miRNA profiles for 13 HB patients with different tumour types and molecular variations. The three platforms that were used to generate these data are: next-generation sequencing (Illumina MiSeq), microarray (Affymetrix(®) GeneChip(®) miRNA 3.0 array) and NanoString (nCounter, Human v2 miRNA Assay). The mature miRNAs identified are based on miRBase version 17 and 18.
CONCLUSIONS: These datasets provide a global landscape of miRNA expression for a rare childhood cancer that has not previously been well characterised. These data could serve as a resource for future studies aiming to make comparisons of HB miRNA profiles and to document aberrant miRNA expression in this type of cancer.

Bhusari S, Pandiri AR, Nagai H, et al.
Genomic Profiling Reveals Unique Molecular Alterations in Hepatoblastomas and Adjacent Hepatocellular Carcinomas in B6C3F1 Mice.
Toxicol Pathol. 2015; 43(8):1114-26 [PubMed] Free Access to Full Article Related Publications
The cell of origin of hepatoblastoma (HB) in humans and mice is unknown; it is hypothesized to be a transformed hepatocyte, oval cell, or hepatic progenitor cell. In mice, current dogma is that HBs arise from preexisting hepatocellular neoplasms as a result of further neoplastic transformation. However, there is little evidence supporting this direct relationship. To better understand the relationship between hepatocellular carcinoma (HCC) and HB and determine molecular similarities between mouse and human HB, global gene expression analysis and targeted mutation analysis were performed using HB, HCC, and adjacent liver from the same animals in a recent National Toxicology Program bioassay. There were significant differences in Hras and Ctnnb1 mutation spectra, and by microarray, HBs showed dysregulation of embryonic development, stem cell pluripotency, and genomic imprinting compared to HCC. Meta-analysis showed similarities between HB, early mouse embryonic liver, and hepatocyte-derived stem/progenitor cells compared to HCC. Our data show that there are striking differences between HB and HCC and suggest that HB is a significantly different entity that may arise from a hepatic precursor cell. Furthermore, mouse HB is similar to the human disease at the pathway level and therefore is likely a relevant model for evaluating human cancer hazard.

Chatterjee A, Leichter AL, Fan V, et al.
A cross comparison of technologies for the detection of microRNAs in clinical FFPE samples of hepatoblastoma patients.
Sci Rep. 2015; 5:10438 [PubMed] Free Access to Full Article Related Publications
Although formalin fixed paraffin embedded (FFPE) tissue is a major biological source in cancer research, it is challenging to work with due to macromolecular fragmentation and nucleic acid crosslinking. Therefore, it is important to characterise the quality of data that can be obtained from FFPE samples. We have compared three independent platforms (next generation sequencing, microarray and NanoString) for profiling microRNAs (miRNAs) using clinical FFPE samples from hepatoblastoma (HB) patients. The number of detected miRNAs ranged from 228 to 345 (median = 294) using the next generation sequencing platform, whereas 79 to 125 (median = 112) miRNAs were identified using microarrays in three HB samples, including technical replicates. NanoString identified 299 to 372 miRNAs in two samples. Between the platforms, we observed high reproducibility and significant levels of shared detection. However, for commonly detected miRNAs, a strong correlation between platforms was not observed. Analysis of 10 additional HB samples with NanoString identified significantly overlapping miRNA expression profiles, and an alternative pattern was identified in a poorly differentiated HB with an aggressive phenotype. This investigation serves as a roadmap for future studies investigating miRNA expression in clinical FFPE samples, and as a guideline for the selection of an appropriate platform.

Fu X, Cui P, Chen F, et al.
Thymosin β4 promotes hepatoblastoma metastasis via the induction of epithelial-mesenchymal transition.
Mol Med Rep. 2015; 12(1):127-32 [PubMed] Free Access to Full Article Related Publications
Hepatoblastoma (HB) is the most common malignant hepatic tumor in children and complete surgical resection offers the highest possibility for cure in this disease. Tumor metastasis is the principle obstacle to the development of efficient treatments for patients with HB. The present study aimed to measure the expression levels of thymosin β4 (Tβ4) in liver samples from patients with HB and to investigate the involvement of Tβ4 in HB metastasis. The expression of Tβ4 was significantly higher in liver samples from patients with metastatic HB and in the HepG2 metastatic HB cell line, compared with that in adjacent healthy liver samples and in the L02 healthy hepatic cell line. By contrast, the expression levels of epithelial-cadherin (E-cadherin) and cytosolic accumulation of β-catenin, the two most prominent markers involved in epithelial-mesenchymal transition (EMT), were reduced in liver specimens from patients with metastatic HB compared with that of healthy adjacent control tissue. HepG2 cells were transfected with small interfering-RNA in order to downregulate Tβ4 gene expression. This resulted in a reduced cell migratory capacity compared with control cells. Tβ4 gene expression knockdown significantly inhibited transforming growth factor β1-mediated-EMT in vitro by upregulating the expression of E-cadherin. The results of the present study suggested that Tβ4 may promote HB metastasis via the induction of EMT, and that Tβ4 may therefore be a target for the development of novel treatments for patients with HB.

Saida S, Watanabe K, Kato I, et al.
Prognostic significance of aminopeptidase-N (CD13) in hepatoblastoma.
Pediatr Int. 2015; 57(4):558-66 [PubMed] Related Publications
BACKGROUND: Hepatoblastoma is a rare childhood malignant tumor that originates from immature hepatic cells. Aminopeptidase-N(CD13), an ectopeptidase that promotes tumor invasion and metastasis, is expressed in fetal stage hepatic progenitor cells, although its role in hepatoblastoma remains unclear.
METHODS: The expression pattern of CD13 was investigated on immunohistochemistry in 30 tissue samples from 27 hepatoblastoma patients (16 with predominantly embryonal [pE] histology and 14 with predominantly fetal [pF] histology). Immunoreactive score (IRS) was used to quantify staining data, and the relationship between CD13 expression, clinicopathological factors, and clinical outcome was investigated. The biological function of CD13 was also examined in the hepatoblastoma cell lines Huh6 and HepG2.
RESULTS: All specimens stained positive for CD13, with higher CD13 expression in pE than in pF hepatoblastoma samples (median IRS, 4; range, 2-9 vs 2; range, 1-4). Strong CD13 expression was correlated with vascular invasion. Five year event-free survival and overall survival were better in patients with CD13(low) than in those with CD13(high) tumors (100% vs 51.0%, P = 0.026; and 100% vs 74.0%, P = 0.114, respectively). A CD13-neutralizing antibody and the potent CD13 inhibitor, Ubenimex, suppressed invasive activity in HepG2 cells in vitro.
CONCLUSIONS: CD13 expression is associated with hepatoblastoma invasiveness and could be a novel prognostic marker for hepatoblastoma.

Quan M, Liu S, Wang Q, et al.
NS5ATP9 Promotes Beclin 1-Dependent Starvation-Induced Autophagy of Hepatoblastoma Cells.
J Cell Biochem. 2015; 116(8):1574-82 [PubMed] Related Publications
NS5ATP9, a gene up-regulated by NS5A, plays a crucial oncogenic role in several types of human tumours. However, the underlying mechanisms remain unclear. Autophagy, an evolutionarily conserved catabolic process, maintains cellular homeostasis under stress conditions, such as starvation, and plays a crucial role in tumour initiation and progression. Here, we report that NS5ATP9 mRNA and protein expression was up-regulated in starved HepG2 cells and that the up-regulated NS5ATP9 played a functional role in starvation-induced autophagy. Overexpression or silencing of this gene showed contrasting effects on Beclin 1 and on starvation-induced autophagy. Furthermore, NS5ATP9-mediated autophagy is required for promotion of tumour cell growth, and this effect could be inhibited with 3-methyladenine, chloroquine or by Beclin 1-silencing. Thus, the mechanism for NS5ATP9-promoted autophagy is Beclin 1-dependent in the condition of starvation, and for hepatoblastoma cell growth is also Beclin 1-dependent.

Rodrigues TC, Fidalgo F, da Costa CM, et al.
Upregulated genes at 2q24 gains as candidate oncogenes in hepatoblastomas.
Future Oncol. 2014; 10(15):2449-57 [PubMed] Related Publications
AIM: Cytogenetic data of hepatoblastomas, a rare embryonal tumor of the liver, mostly consist of descriptions of whole-chromosome aneuploidies and large chromosome alterations. High-resolution cytogenetics may provide clues to hepatoblastoma tumorigenesis and indicate markers with clinical significance.
PATIENTS & METHODS: We used array-CGH (180K) to screen for genomic imbalances in nine hepatoblastomas. Additionally, we investigated the expression pattern of selected genes exhibiting copy number changes.
RESULTS: Analysis showed mainly whole-chromosome or chromosome-arm aneuploidies, but some focal aberrations were also mapped. Expression analysis of 48 genes mapped at one 10 Mb amplification at 2q24 revealed upregulation of DAPL1, ERMN, GALNT5, SCN1A and SCN3A in the set of tumors compared with differentiated livers.
CONCLUSION: These genes appear as candidates for hepatoblastoma tumorigenesis.

Eichenmüller M, Trippel F, Kreuder M, et al.
The genomic landscape of hepatoblastoma and their progenies with HCC-like features.
J Hepatol. 2014; 61(6):1312-20 [PubMed] Related Publications
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 a genetically very simple tumour (2.9 mutations per tumour) with recurrent mutations in ß-catenin (CTNNB1) (12/15 cases) and the transcription factor 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 telomerase reverse-transcriptase (TERT) promoter mutations. Targeted genotyping of 33 primary tumours 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 signalling. Clinically, overexpression of the NFE2L2 target gene NQO1 in tumours 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.

Azlin AH, Looi LM, Cheah PL
Tissue microarray immunohistochemical profiles of p53 and pRB in hepatocellular carcinoma and hepatoblastoma.
Asian Pac J Cancer Prev. 2014; 15(9):3959-63 [PubMed] Related Publications
The tumour suppressor genes, p53 and pRb, are known to play important roles in neoplastic transformation. While molecular routes to the uncontrolled growth of hepatocytes, leading to primary liver cancer have generated considerable interest, the roles of p53 and pRb mutations in hepatocellular carcinoma (HCC) and hepatoblastoma (HB) remain to be clarified. We examined the immunohistochemical expression of p53 and pRb gene products in 26 HCC and 9 HB, sampled into tissue microarray blocks. 10 (38%) of 26 HCC showed > 10% tumour nuclear staining for p53 protein, 3 of these also being HbsAg positive. Conversely, none of 9 HB expressed nuclear p53 immunopositivity. Some 24 (92%) HCC and 8 (89%) HB showed loss of pRb nuclear expression. Two of the 26 HCC and one of the 9 HB showed >10% tumour nuclear staining for pRb protein. Our results suggest that p53 does not have an important role in the development of HB but may contribute in HCC. There is also loss of pRb expression in the majority of HCC and HB, supporting loss of pRb gene function in the hepatocarcinogenesis pathway. However, a comparison of the staining profiles of p53 and pRb proteins in HCC and HB did not reveal a consistent pattern to differentiate between the two types of tumours immunohistochemically. Hence the use of p53 and pRB protein expression has no contribution in the situation where there is a diagnostic difficulty in deciding between HCC and HB.

Jia D, Dong R, Jing Y, et al.
Exome sequencing of hepatoblastoma reveals novel mutations and cancer genes in the Wnt pathway and ubiquitin ligase complex.
Hepatology. 2014; 60(5):1686-96 [PubMed] Related Publications
UNLABELLED: Hepatoblastoma (HB) is the most common primary liver tumor in children. Mutations in the β-catenin gene that lead to constitutive activation of the Wnt pathway have been detected in a large proportion of HB tumors. To identify novel mutations in HB, we performed whole-exome sequencing of six paired HB tumors and their corresponding lymphocytes. This identified 24 somatic nonsynonymous mutations in 21 genes, many of which were novel, including three novel mutations targeting the CTNNB1 (G512V) and CAPRIN2 (R968H/S969C) genes in the Wnt pathway, and genes previously shown to be involved in the ubiquitin ligase complex (SPOP, KLHL22, TRPC4AP, and RNF169). Functionally, both the CTNNB1 (G512V) and CAPRIN2 (R968H/S969C) were observed to be gain-of-functional mutations, and the CAPRIN2 (R968H/S969C) was also shown to activate the Wnt pathway in HB cells. These findings suggested the activation of the Wnt pathway in HB, which was confirmed by immunohistochemical staining of the β-catenin in 42 HB tumors. We further used short hairpin RNA (shRNA)-mediated interference to assess the effect of 21 mutated genes on HB cell survival. The results suggested that one novel oncogene (CAPRIN2) and three tumor suppressors (SPOP, OR5I1, and CDC20B) influence HB cell growth. Moreover, we found that SPOP S119N is a loss-of-function mutation in HB cells. We finally demonstrated that one of the mechanisms by which SPOP inhibits HB cell proliferation is through regulating CDKN2B expression.
CONCLUSION: These results extend the landscape of genetic alterations in HB and highlight the dysregulation of Wnt and ubiquitin pathways in HB tumorigenesis.

Rahmutulla B, Matsushita K, Satoh M, et al.
Alternative splicing of FBP-interacting repressor coordinates c-Myc, P27Kip1/cyclinE and Ku86/XRCC5 expression as a molecular sensor for bleomycin-induced DNA damage pathway.
Oncotarget. 2014; 5(9):2404-17 [PubMed] Free Access to Full Article Related Publications
The far-upstream element-binding protein-interacting repressor (FIR) is a c-myc transcriptional suppressor. FIR is alternatively spliced to lack the transcriptional repression domain within exon 2 (FIRΔexon2) in colorectal cancers. FIR and FIRΔexon2 form homo- or heterodimers that complex with SAP155. SAP155, a subunit of the essential splicing factor 3b subcomplex in the spliceosome, is required for proper P27Kip1 pre-mRNA splicing, and P27Kip1 arrests cells at G1. In contrast, FIR was co-immunoprecipitated with Ku86 and DNA-PKcs. siRNA against Ku86/Ku70 decreased FIR and P27Kip1 expression, whereas siRNA against FIR decreased Ku86/XRCC5 and P27Kip1 expression. Thus the mechanical interaction of FIR/FIRΔexon2/SAP155 bridges c-myc and P27Kip1 expression, potentially integrates cell-cycle progression and c-myc transcription in cell. Bleomycin(BLM) is an anticancer agent that introduces DNA breaks. Because DNA breaks generate the recruitment of Ku86/Ku70 to bind to the broken DNA ends, the possible involvement of FIR and Ku86/Ku70 interaction in the BLM-induced DNA damage repair response was investigated in this study. First, BLM treatment reduced SAP155 expression and increased FIR and FIRΔexon2 mRNA expression as well as the ratio of FIRΔexon2:FIR in hepatoblastoma cells (HLE and HLF). Second, FIR or FIRΔexon2 adenovirus vectors (Ad-FIR or Ad-FIRΔexon2) increased Ku86/Ku70 and P27Kip1 expression in vitro. Third, BLM decreased P27Kip1 protein expression, whereas increased P27Kip1 and γH2AX expression with Ad-FIRΔexon2. Together, the interaction of FIR/SAP155 modulates FIR splicing and involves in cell-cycle control or cell fate via P27Kip1 and c-myc in BLM-induced DNA damage pathway. This novel function of FIR splicing will contribute to clinical studies of cancer management through elucidating the mechanical interaction of FIR/FIRΔexon2/SAP155 as a potential target for cancer treatment.

Gyugos M, Lendvai G, Kenessey I, et al.
MicroRNA expression might predict prognosis of epithelial hepatoblastoma.
Virchows Arch. 2014; 464(4):419-27 [PubMed] Related Publications
Hepatoblastoma (HB) is the most common primary liver cancer in childhood. The fetal and mixed embryonal/fetal epithelial subtypes of HB differ not only in grade of differentiation but probably also in prognosis. We aimed to determine microRNA (miRNA) expression patterns of the main subtypes of epithelial HBs to reveal differences and relate them to survival. We studied 20 cases of epithelial HB, subtyped as pure fetal (n = 12) or embryonal/fetal (n = 8). Tissues were sampled according to subtype to arrive at 15 purely fetal and eight purely embryonal samples (n = 8) and 15 samples of non-tumorous surrounding liver (SL). Relative expression of miR-17-5p, miR-18a, miR-21, miR-34a, miR-96, miR-122, miR-181a, miR-195, miR-210, miR-214, miR-221, miR-222, miR-223, and miR-224 was determined by TaqMan MicroRNA Assays applying miR-140 as reference. A higher level of miR-18a (p < 0.01) was found in embryonal samples than in fetal samples. Lower miR-17-5p, miR-195, miR-210, miR-214, and higher miR-221 levels were detected in fetal samples (p < 0.02) in comparison with SL samples, whereas a lower miR-122 level was observed in embryonal samples (p < 0.003). Histological subtype did not correlate with survival; however, high miR-21, low miR-222, and low miR-224 levels proved to be independently prognostic for HB with significantly increased overall survival (p < 0.03). The fetal and embryonal components of epithelial HB, as well as SL, revealed different miRNA expression patterns. Furthermore, miR-21, miR-222, and miR-224 levels predict overall survival of HB patients regardless of epithelial subtype.

Dong R, Jia D, Xue P, et al.
Genome-wide analysis of long noncoding RNA (lncRNA) expression in hepatoblastoma tissues.
PLoS One. 2014; 9(1):e85599 [PubMed] Free Access to Full Article Related Publications
Long noncoding RNAs (lncRNAs) have crucial roles in cancer biology. We performed a genome-wide analysis of lncRNA expression in hepatoblastoma tissues to identify novel targets for further study of hepatoblastoma. Hepatoblastoma and normal liver tissue samples were obtained from hepatoblastoma patients. The genome-wide analysis of lncRNA expression in these tissues was performed using a 4×180 K lncRNA microarray and Sureprint G3 Human lncRNA Chips. Quantitative RT-PCR (qRT-PCR) was performed to confirm these results. The differential expressions of lncRNAs and mRNAs were identified through fold-change filtering. Gene Ontology (GO) and pathway analyses were performed using the standard enrichment computation method. Associations between lncRNAs and adjacent protein-coding genes were determined through complex transcriptional loci analysis. We found that 2736 lncRNAs were differentially expressed in hepatoblastoma tissues. Among these, 1757 lncRNAs were upregulated more than two-fold relative to normal tissues and 979 lncRNAs were downregulated. Moreover, in hepatoblastoma there were 420 matched lncRNA-mRNA pairs for 120 differentially expressed lncRNAs, and 167 differentially expressed mRNAs. The co-expression network analysis predicted 252 network nodes and 420 connections between 120 lncRNAs and 132 coding genes. Within this co-expression network, 369 pairs were positive, and 51 pairs were negative. Lastly, qRT-PCR data verified six upregulated and downregulated lncRNAs in hepatoblastoma, plus endothelial cell-specific molecule 1 (ESM1) mRNA. Our results demonstrated that expression of these aberrant lncRNAs could respond to hepatoblastoma development. Further study of these lncRNAs could provide useful insight into hepatoblastoma biology.

Fujita A, Ochi N, Fujimaki H, et al.
A novel WTX mutation in a female patient with osteopathia striata with cranial sclerosis and hepatoblastoma.
Am J Med Genet A. 2014; 164A(4):998-1002 [PubMed] Related Publications
Osteopathia striata with cranial sclerosis (OSCS) is an X-linked dominant sclerosing bone dysplasia. Typically affected females show macrocephaly, characteristic facial appearance, cleft palate, mild learning difficulties, hearing loss, sclerosis of the long bones and skull, and longitudinal striations visible on radiographs of the long bones, pelvis and scapulae. Typically affected males usually die at the fetal or early neonatal stage. Because of its variable expressivity, which ranges from asymptomatic to fetal death, clinical diagnosis of OSCS can be difficult. Here, we identify a unique female patient presenting with severe macrocephaly, characteristic facial appearance, developmental delay, and hepatoblastoma. Exome sequencing identified a novel de novo nonsense mutation (c.1045C>T, p.Glu349*) in the WTX gene associated with OSCS. The OSCS diagnosis was confirmed in this patient based on the hallmark appearance of longitudinal striations in long bones when viewed by X-ray. WTX is also known as a tumor suppressor gene, and somatic mutations in that gene have been identified in Wilms tumors. In addition to this patient, although two patients with OSCS have been reported to have colorectal cancer or ovarian cancer, Wilms tumor has never been reported in association with this disorder. Tumor susceptibility in patients with OSCS is discussed.

Kosaki R, Takenouchi T, Takeda N, et al.
Somatic CTNNB1 mutation in hepatoblastoma from a patient with Simpson-Golabi-Behmel syndrome and germline GPC3 mutation.
Am J Med Genet A. 2014; 164A(4):993-7 [PubMed] Related Publications
Simpson-Golabi-Behmel syndrome is a rare overgrowth syndrome caused by the GPC3 mutation at Xq26 and is clinically characterized by multiple congenital abnormalities, intellectual disability, pre/postnatal overgrowth, distinctive craniofacial features, macrocephaly, and organomegaly. Although this syndrome is known to be associated with a risk for embryonal tumors, similar to other overgrowth syndromes, the pathogenetic basis of this mode of tumorigenesis remains largely unknown. Here, we report a boy with Simpson-Golabi-Behmel syndrome who had a germline loss-of function mutation in GPC3. At 9 months of age, he developed hepatoblastoma. A comparison of exome analysis results for the germline genome and for the tumor genome revealed a somatic mutation, p.Ile35Ser, within the degradation targeting box of β-catenin. The same somatic mutation in CTNNB1 has been repeatedly reported in hepatoblastoma and other cancers. This finding suggested that the CTNNB1 mutation in the tumor tissue represents a driver mutation and that both the GPC3 and the CTNNB1 mutations contributed to tumorigenesis in a clearly defined sequential manner in the propositus. The current observation of a somatic CTNNB1 mutation in a hepatoblastoma from a patient with a germline GPC3 mutation supports the notion that the mutation in GPC3 may influence one of the initial steps in tumorigenesis and the progression to hepatoblastoma.

Rumbajan JM, Maeda T, Souzaki R, et al.
Comprehensive analyses of imprinted differentially methylated regions reveal epigenetic and genetic characteristics in hepatoblastoma.
BMC Cancer. 2013; 13:608 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: Aberrant methylation at imprinted differentially methylated regions (DMRs) in human 11p15.5 has been reported in many tumors including hepatoblastoma. However, the methylation status of imprinted DMRs in imprinted loci scattered through the human genome has not been analyzed yet in any tumors.
METHODS: The methylation statuses of 33 imprinted DMRs were analyzed in 12 hepatoblastomas and adjacent normal liver tissue by MALDI-TOF MS and pyrosequencing. Uniparental disomy (UPD) and copy number abnormalities were investigated with DNA polymorphisms.
RESULTS: Among 33 DMRs analyzed, 18 showed aberrant methylation in at least 1 tumor. There was large deviation in the incidence of aberrant methylation among the DMRs. KvDMR1 and IGF2-DMR0 were the most frequently hypomethylated DMRs. INPP5Fv2-DMR and RB1-DMR were hypermethylated with high frequencies. Hypomethylation was observed at certain DMRs not only in tumors but also in a small number of adjacent histologically normal liver tissue, whereas hypermethylation was observed only in tumor samples. The methylation levels of long interspersed nuclear element-1 (LINE-1) did not show large differences between tumor tissue and normal liver controls. Chromosomal abnormalities were also found in some tumors. 11p15.5 and 20q13.3 loci showed the frequent occurrence of both genetic and epigenetic alterations.
CONCLUSIONS: Our analyses revealed tumor-specific aberrant hypermethylation at some imprinted DMRs in 12 hepatoblastomas with additional suggestion for the possibility of hypomethylation prior to tumor development. Some loci showed both genetic and epigenetic alterations with high frequencies. These findings will aid in understanding the development of hepatoblastoma.

Akhavanfard S, Vargas SO, Han M, et al.
Inactivation of the tumor suppressor WTX in a subset of pediatric tumors.
Genes Chromosomes Cancer. 2014; 53(1):67-77 [PubMed] Related Publications
WTX is a tumor suppressor gene expressed during embryonic development and inactivated in 20-30% of cases of Wilms tumor, the most common pediatric kidney cancer. WTX has been implicated in several cellular processes including Wnt signaling, WT1 transcription, NRF2 degradation, and p53 function. Given that WTX is widely expressed during embryonic development and has been recently shown to regulate mesenchymal precursor cells in several organs, we tested for the potential involvement of WTX in a panel of pediatric tumors and adult sarcomas. A total of 353 tumors were screened for WTX deletions by fluorescence in situ hybridization (FISH). Discrete somatic WTX deletions were identified in two cases, one hepatoblastoma and one embryonal rhabdomyosarcoma, and confirmed by array comparative genomic hybridization. Direct sequencing of the full WTX open reading frame in 24 hepatoblastomas and 21 embryonal rhabdomyosarcomas did not identify additional mutations in these tumor types. The presence of WTX mRNA was confirmed in hepatoblastomas and embryonal rhabdomyosarcomas without WTX deletions by RNA-in situ hybridization. Notably, tumors with evidence of WTX inactivation, Wilms tumor, hepatoblastoma and rhabdomyosarcoma, are primitive tumors that resemble undifferentiated precursor cells and are linked to overgrowth syndromes. These results indicate that WTX inactivation occurs in a wider variety of tumor types than previously appreciated and point to shared pathogenic mechanisms between a subset of pediatric malignancies.

Honda S, Miyagi H, Suzuki H, et al.
RASSF1A methylation indicates a poor prognosis in hepatoblastoma patients.
Pediatr Surg Int. 2013; 29(11):1147-52 [PubMed] Related Publications
PURPOSE: The RAS association domain family protein 1 (RASSF1A) is known to be frequently inactivated by promoter hypermethylation in cancers. This study investigated the association of RASSF1A methylation with clinical outcomes in hepatoblastoma patients and whether it is correlated with the histological phenotype of hepatoblastoma tumors.
METHODS: Seventy-four hepatoblastoma tumors were obtained from patients enrolled in the Japanese study group for pediatric liver tumor protocol-2. From nine formalin-fixed, paraffin-embedded specimens, we extracted DNA by dissection under a light microscope. We examined the methylation status of the RASSF1A promoter region by bisulfite pyrosequencing.
RESULTS: Twenty-five (33.8 %) hepatoblastoma tumors were classified as having methylated RASSF1A. The RASSF1A methylation was significantly associated with metastatic tumors and a poor prognosis. Despite the complete resection, five pretreatment extent of disease II tumors showed recurrence or distant metastasis postoperatively. Among these cases, four tumors were found to show RASSF1A methylation. When compared to histologically different types of cell, RASSF1A methylation values in samples of the normal liver, fetal type, and embryonal type, were significantly elevated in ascending order.
CONCLUSIONS: We confirmed that RASSF1A methylation is a significant prognostic indicator in hepatoblastomas, and it may become a promising molecular marker to stratify patients into appropriate risk groups.

Tan ZH, Lai A, Chen CK, et al.
Association of trisomy 18 with hepatoblastoma and its implications.
Eur J Pediatr. 2014; 173(12):1595-8 [PubMed] Related Publications
UNLABELLED: Hepatoblastoma is a highly malignant embryonal liver tumor that occurs almost exclusively in infants and toddlers. Trisomy 18 is the second most common autosomal trisomy after trisomy 21 and is generally considered a lethal disorder. Ten cases of hepatoblastoma in children with trisomy 18 have been published to date. Here, we report on two female patients with trisomy 18 and pretreatment extent of disease (PRETEXT) stage 1 hepatoblastoma, which support the presence of a nonrandom association between hepatoblastoma and trisomy 18. Both patients underwent primary surgical resection without any neoadjuvant or adjuvant chemotherapy. The histologies returned as pure fetal epithelial type, and combined fetal and embryonal epithelial type. There was no evidence of recurrence on serial abdominal ultrasound and serum alpha-fetoprotein levels on follow-up.
CONCLUSION: Primary surgical resection is a treatment approach that can be considered in children with trisomy 18 and PRETEXT stage 1 tumor. However, in view of the overall prognosis for trisomy 18, the decision on the optimal treatment is a delicate one and has to be individualized in the context of the best interests of the child.

Zhou S, Ranganathan S, Venkatramani R, et al.
Teratoid hepatoblastoma with abundant cholangioblastic component in a child with full trisomy 13.
Pediatr Dev Pathol. 2013 Nov-Dec; 16(6):438-41 [PubMed] Related Publications
Teratoid hepatoblastoma is a rare histological subtype of hepatoblastoma. A 15-month-old girl with full trisomy 13 presented with a liver mass (6 × 4.4 × 3.4 cm). Histological examination showed a teratoid hepatoblastoma with very different differentiation patterns intermixed with each other. Approximately 30% of the tumor demonstrated a primitive glandular epithelium component, which had a moderate to well-differentiated adenocarcinoma-like morphology, and features of mucinous epithelium with a biliary immunophenotype. We designated it as cholangioblastic component. The child received 4 cycles of monotherapy with doxorubicin after complete resection and showed no evidence of residual tumor 8 months after surgery. Our case is not only the 1st report of hepatoblastoma in trisomy 13 but also represents a unique example with a large glandular epithelium component with cholangioblastic features. Increased awareness of this entity and further molecular studies are needed for better understanding of the pathogenesis of teratoid hepatoblastoma.

Mateos ME, Beyer K, López-Laso E, et al.
Simpson-Golabi-Behmel syndrome type 1 and hepatoblastoma in a patient with a novel exon 2-4 duplication of the GPC3 gene.
Am J Med Genet A. 2013; 161A(5):1091-5 [PubMed] Related Publications
Mutations in the gene encoding glypican (GPC) 3 appear to be responsible for most cases of Simpson-Golabi-Behmel syndrome type 1. Duplication of the GPC4 gene has also been associated to this syndrome; however, no duplications involving GPC3 have been related. We describe a family that harbors a novel exon 2-4 duplication event leading to a truncating germline mutation of the GPC3 gene that, to our knowledge, has not been previously reported. GPC3 transcripts that carry this duplication bear non-functional proteins making its pathogenic role highly probable. The absence of a functional GPC3 may alter the normal differentiation of embryonal mesodermal tissues predisposing to the development of embryonal tumors, as the index case studied who developed a hepatoblastoma at age 9 months.

Calton EA, Temple IK, Mackay DJ, et al.
Hepatoblastoma in a child with a paternally-inherited ABCC8 mutation and mosaic paternal uniparental disomy 11p causing focal congenital hyperinsulinism.
Eur J Med Genet. 2013; 56(2):114-7 [PubMed] Related Publications
Hepatoblastoma is a tumour of early childhood occurring in association with genetic syndromes including Beckwith-Wiedemann Syndrome (BWS) which results from dominance of paternally-inherited genes on chromosome 11p15. We report a child without clinical BWS, neonatally diagnosed with focal congenital hyperinsulinism resulting from a paternally-inherited recessively-acting mutation of ABCC8 and pancreatic paternal uniparental disomy (UPD) for chromosome 11p15, who subsequently developed hepatoblastoma. Genetic testing showed UPD 11p15 in the pancreas and liver but not systemically, allowing the expression of mutated ABCC8 in both tissues. Infants with large or multifocal forms of focal congenital hyperinsulinism may be at risk of BWS-like tumours due to mosaic UPD despite negative whole-blood and buccal DNA testing and tumour surveillance should be considered for this minority.

Horii M, Horiuchi H, Momoeda M, et al.
Hepatoblastoma in an infant with paternal uniparental disomy 14.
Congenit Anom (Kyoto). 2012; 52(4):219-20 [PubMed] Related Publications
A 29-year-old primigravida developed polyhydramnios at 24 weeks of gestation, requiring six serial amnioreductions. In addition, prenatal ultrasound examinations revealed a fetus with small stomach pouch, small thorax, slightly shortened limbs, and skin edema; paternal uniparental disomy 14(upd(14)pat) phenotype was suspected. At 37 weeks, the patient delivered a 2558 g female infant with characteristic facial features, webbed neck, thoracic deformity, abdominal wall defect, skin edema, overlapping fingers, placentomegaly, and small thorax with 'coat-hanger' appearance of the ribs on chest X-ray. A phenotype consistent with upd(14)pat was confirmed by DNA analysis. Although the infant's condition was initially stable, hepatoblastoma was subsequently detected and right hepatectomy was performed on day 224. On day 382, the infant was discharged with in-home respiratory management.

Moore SW, Tshifularo N, Grobbelaar J
Lessons from the hepatoblastoma-familial polyposis connection.
S Afr Med J. 2012; 102(11 Pt 2):888-9 [PubMed] Related Publications
BACKGROUND: Approximately one-third of hepatoblastoma (HB) patients have associated congenital abnormalities, but familial recurrence is rare, except in association with familial adenomatous polyposis (FAP). This correlation may be missed if not actively sought, with implications for long-term outcome and management.
METHODS: We retrospectively investigated 3 families with an HB-familial polyposis connection, from a cohort of 113 FAP families (1989 - 2010). Data were analysed to assess clinical problem, treatment, complications and management. Long-term morbidity and functional outcome were analysed to identify management difficulties.
RESULTS: Three FAP families (2.65%) had an HB association. In one case, undiagnosed FAP at the time of HB diagnosis was only detected 5 years later, when the mother presented with advanced colorectal carcinoma. A chromosome 5 APC gene mutation (exon 15 codon 793 C→T) was then identified. In a second case, a non-related male child presented with a stage 4 multifocal HB with lung metastases. Genetic studies identified an APC gene mutation (exon 6 codon 232 C→T). Further family investigation showed >20 related FAP patients. A third HB-FAP association was identified in a known FAP family early in the study, prior to the availability of genetic testing.
CONCLUSION: Although a rare association, a family history of FAP in HB patients is an important 'hidden connection'. Germline variation may be outside the usual FAP gene site. Identifying families with unknown HB/FAP is important due to long-term management implications and follow-up.

Tomlinson GE, Kappler R
Genetics and epigenetics of hepatoblastoma.
Pediatr Blood Cancer. 2012; 59(5):785-92 [PubMed] Related Publications
A number of unique genetic features are observed in hepatoblastoma that have provided insights into the origins of hepatoblastoma. Hallmark cytogenetic changes in hepatoblastoma include the acquisition of additional copies of whole chromosomes and a recurring unbalanced translocation involving 1q. Genetic syndromes are associated with approximately 15% of hepatoblastoma and the understanding and recognition of these syndromes will be important in determining future surveillance studies needed to prevent additional cancers in survivors as well as in some case guide the care of family members. This article will review the genetic changes, both germ line and acquired, that are recurring events in hepatoblastoma, with emphasis on how these genetic changes could work together with other developmental factors and influence cancer predisposition, tumor growth, as well as aid in prognosis. Tumor-specific signatures based on transcriptional or epigenetic alterations will be reviewed that might be used in the future to better diagnose and subtype the disease as well as predict prognosis and response to therapy.

Assmann G, Kappler R, Zeindl-Eberhart E, et al.
β-Catenin mutations in 2 nested stromal epithelial tumors of the liver--a neoplasia with defective mesenchymal-epithelial transition.
Hum Pathol. 2012; 43(11):1815-27 [PubMed] Related Publications
Nested stromal epithelial tumor of the liver is a rare neoplasm of early childhood and adolescence with a characteristic nested morphology of spindle and epithelioid cells. Histogenesis and pathogenesis of this neoplasm are, however, still unclear. Because the characteristic nested morphology with spindle mesenchymal and epithelioid cells is suggestive of altered mesenchymal-epithelial transition and β-catenin mutations are rather common in other liver tumors such as hepatoblastomas, we investigated the β-catenin gene in 2 nested stromal epithelial tumors of the liver and analyzed additional factors involved in mesenchymal-epithelial transition, such as E-cadherin, vimentin, c-Met, TWIST, SNAIL, and SLUG by molecular genetic and immunohistochemical methods. Mutation analysis of both cases revealed large deletions in exon 3 of the β-catenin gene (155 and 228 base pairs), resulting in an accumulation of β-catenin in the cytoplasm and nuclei of tumor cells, as evidenced by immunohistochemistry. The expression of the mesenchymal-epithelial transition factors SNAIL, SLUG, TWIST, c-Met, vimentin, and β-catenin was generally increased, whereas E-cadherin was decreased. Morphological and immunohistochemical analysis, however, showed a variable expression pattern of various epithelial and mesenchymal markers both in the spindle and epithelioid cell compartments of the tumors, thus illustrating the transitional status of the tumor cells. In conclusion, our data clearly identify protein stabilizing mutations of the β-catenin gene as a common feature of nested stromal epithelial tumors of the liver, similarly as in hepatoblastomas. Therefore, nested stromal epithelial tumors of the liver may be regarded as a variant of hepatoblastoma, despite differing from it in clinical and morphological aspects. The characteristic epithelioid-spindle morphology along with the incomplete epithelial differentiation proposes impaired mesenchymal-epithelial transition as a possible pathogenetic mechanism of this rare tumor. However, because only 2 cases were studied, this hypothesis awaits further validation.

Evers C, Gaspar H, Kloor M, et al.
Hepatoblastoma in two siblings and familial adenomatous polyposis: causal nexus or coincidence?
Fam Cancer. 2012; 11(3):529-33 [PubMed] Related Publications
Infantile and childhood hepatoblastoma (HB) occurs more frequently in children with hereditary predisposition to familial adenomatous polyposis (FAP) than in the general population. The occurrence of HB in two infant siblings is reported. The sister died of the disease. The brother survived the HB and was later diagnosed with familial adenomatous polyposis and advanced rectal cancer. He was found to carry a germline mutation of the APC gene. Presuming that the HB in the two siblings was the first manifestation of FAP we performed APC mutation analysis in DNA from archived tumour tissue of his sister and in blood samples of both parents. Surprisingly, the mutation was neither found in both parents, nor in the tissue samples of the sister. We outline the impact of this finding for genetic counselling and review the literature on FAP and HB.

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