The genomic landscape of hepatoblastoma and their progenies with HCC-like features

Eichenmüller, Melanie; Trippel, Franziska; Kreuder, M.; Beck, Alexander; Schwarzmayr, Thomas; Häberle, Beate; Cairo, Stefano; Leuschner, Ivo; Schweinitz, Dietrich von; Strom, Tim M.; Kappler, Roland

doi:10.1016/j.jhep.2014.08.009

Cited by 208 publications

(278 citation statements)

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“…Matched adjacent liver tissue samples from the surgical specimens without macroscopic or microscopic tumors served as tumor-free controls (n=9). Clinical and molecular data, such as gender, age at diagnosis, PRETEXT staging (24), including vascular invasion and multifocality, metastatic disease, histology, CTNNB1 mutation, 16-gene signature and overall survival, were retrieved from the HB99 database and our recent exome sequencing study, respectively (25).…”

Section: Methodsmentioning

confidence: 99%

Truncated neurokinin-1 receptor is an ubiquitous antitumor target in hepatoblastoma, and its expression is independent of tumor biology and stage

et al. 2015

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Abstract. The substance P (SP; also known as TAC1)/neurokinin-1 receptor (NK1R; also known as TACR1) complex is a critical part in the development of cancer. Therefore, NK1R antagonists, such as the clinical drug aprepitant, are currently under investigation as future anticancer agents. In a previous study, NK1R (TACR1) was identified as a potent anticancer target in hepatoblastoma (HB). However, little is known regarding the exact distribution of this target among HB subsets and whether it correlates with clinical features and prognosis. In the present study, mRNA was isolated from 47 children with HB, and reverse transcription-quantitative polymerase chain reaction was performed on the samples to analyze the expression of full-length-TACR1 (fl-TACR1) and truncated-TACR1 (tr-TACR1). These data were correlated with data obtained from 9 tumor-free controls, as well as with the presence of metastasis, PRETEXT, vascular invasion, histology, age of diagnosis, multifocality, CTNNB1 mutation, gender and overall survival. Additionally, the present study investigated a recently described 16-gene signature characteri zing HB known to correlate with prognosis. Compared with tumor-free liver tissue, tumorous tissue expressed TACR1 significantly higher for the truncated version (P=0.0301), and by trend also for the full-length version. Accordingly, the expression of fl-TACR1 correlated with the expression of the truncated version (P=0.0074). Furthermore, a low expression of fl-TACR1 correlated with characteristics of the 16-gene signature known to predict prognosis (P=0.0222). However, there was no correlation between tr-TACR1 and the tumor characteristics investigated, including outcome, although a clear trend was observed for some tumor characteristics. The current results reinforced the previously described findings that in HB, tr-TACR1 is overexpressed compared with tumor-free liver tissue. Furthermore, to the best of our knowledge, the present study demonstrated for the first time that tr-TACR1 is expressed ubiquitously among the different subsets of HB. Therefore, NK1R may serve as a potent anticancer target in a large variety of patients with HB, independent of tumor biology and clinical stage.

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Section: Methodsmentioning

confidence: 99%

Truncated neurokinin-1 receptor is an ubiquitous antitumor target in hepatoblastoma, and its expression is independent of tumor biology and stage

et al. 2015

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“…Overall, the exome studies performed to date have revealed a very low frequency of somatic mutations in HBs (<5 mutations per tumor) even compared to other pediatric tumors [60].…”

Section: Genetic Findings and Next-generation Sequencing Studiesmentioning

confidence: 96%

The genetic and epigenetic landscapes of hepatoblastomas

et al. 2017

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Primary liver cancers are rare in children, and the most common type is hepatoblastoma (HB), an embryonal tumor with histological features that resemble different stages of liver cell differentiation. However, mainly because of its rarity, molecular data on HB tumorigenesis remain scarce. This article reviews the current knowledge regarding genetic and epigenetic alterations reported in HB cases, with emphasis on the recent findings of next-generation sequencing studies.

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“…A high expression of this antioxidant/detoxifying enzyme has been found in the aggressive C2 subtype of HB and is associated to significantly reduced survival compared to patients with lower expression of this gene [24]. NQO1 catalyzes the reduction of anthracyclines to less potent semiquinone radicals and it has been demonstrated that enhanced expression of NQO1 confers resistance to doxorubicin and other chemotherapeutic agents in cholangiocarcinoma cell lines [25].…”

Section: Mocmentioning

confidence: 99%

“…Hallmark cytogenetic changes in HB include the acquisition of additional copies of whole chromosomes and a recurring unbalanced translocation involving 1q [26,27]. The copy number variation profile of HB shows more frequent gain than losses in different studies [10,22,24]. Regarding chemoresistance, we must keep in mind that changes in expression and/or the presence of mutations in an important number of genes contributing to different mechanisms of chemoresistance in liver cancers, either affecting the intracellular amount of active drugs or affecting their effectiveness can be responsible for the lack of response to chemotherapy [28][29][30].…”

Section: Mocmentioning

confidence: 99%

“…Recently, mutations in the CAPRIN2 gene have been also described to activate Wnt pathway in HB [22] and novel mutations affecting different components of several ubiquitin ligase complexes have been identified and could be considered as potential actors in the etiopathogenesis of HB [22]. Mutations in the nuclear factor "erythroid-derived 2-like 2", NFE2L2 or NRF2 have been reported to occur in 8% of HB [23,24], but also in other types of tumors, including HCC. Changes in the expression of genes involved in chemoresistance/chemoprotection in HB.…”

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Hepatoblastoma Etiopathogenesis

RIR¹,

Armengol²,

JJG³

2016

J Carcinog Mutagene

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EditorialHepatoblastoma (HB) is the predominant form of pediatric liver cancer, usually arising in young children under 3 years of age [1], but it is a rare pediatric cancer with a very low worldwide incidence (<2 cases per million children under 18 years) [2]. Hepatocellular carcinoma (HCC) can also be diagnosed in children but with much lower incidence, usually found in the teenage population in association with predisposing conditions, such as the presence of underlying liver diseases (i.e., tyrosinemia and several cholestatic syndromes). As compared with HB, the prognostic of HCC is often poorer. A third type of primary liver cancer that appears at the late childhood and adolescence was initially called transitional liver cell tumor (TLCT), because it has a mixture of histological patterns characteristic of HB and HCC [3]. This cancer has been recently classified in a new provisional category named hepatocellular neoplasm not otherwise specified [4], awaiting for a better characterization, in an international symposium aiming to develop a consensus classification system for pediatric liver malignancies.Overall survival of patients with HB has notably improved from 30% in the 1970s to 70-80% nowadays thanks to the incorporation to the treatment of adjuvant and neoadjuvant chemotherapy using cisplatin and doxorubicin combined with efficient surgical approaches, including liver transplantation [5]. However, there are very limited treatment options for patients suffering from immature, invasive, and metastatic HB resistant to conventional first-line chemotherapeutic protocols, being the survival of these patients usually less than 3 years. The International Childhood Liver Tumor Strategy Group (SIOPEL) defined a prognostic stratification system of HB patients taking into consideration PRETEXT stage, metastatic disease, serum α-fetoprotein levels, multifocality, age and histology characterized by small undifferentiated cells [6]. Importantly, a recent study of the Children's Hepatic tumors International Collaboration (CHIC) group has confirmed these prognostic risk factors and identified new ones through a large-scale analysis using an extensive database including 1605 HB cases [7]. Patient stratification and treatment taking into account molecular biomarkers are the future challenges facing clinicians. High-throughput molecular studies of aggressive tumors highly refractory to anticancer drugs have the unique potential to provide a rational basis and new tools (biomarkers/molecular targets) for improving patient stratification and defining more specific and molecular-based therapies.Because HB is a rare tumor, most of the few existing studies have been carried out in small groups of patients, and this fact, together with the existence of several histologic subtypes without a clear consensus for their classification, has hindered advances in the characterization of different aspects of this liver cancer. Histologically, HB is usually composed of combinations of epithelial, mesenchymal, undifferentiated and other ...

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The genomic landscape of hepatoblastoma and their progenies with HCC-like features

Cited by 208 publications

References 41 publications

Truncated neurokinin-1 receptor is an ubiquitous antitumor target in hepatoblastoma, and its expression is independent of tumor biology and stage

Truncated neurokinin-1 receptor is an ubiquitous antitumor target in hepatoblastoma, and its expression is independent of tumor biology and stage

The genetic and epigenetic landscapes of hepatoblastomas

Hepatoblastoma Etiopathogenesis

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