Asunto(s)

Anomalías Múltiples , Hepatoblastoma , Neoplasias Hepáticas , Humanos , Niño , Hepatoblastoma/genética , Mutación , Neoplasias Hepáticas/genética , Proteína Jagged-1/genética

RESUMEN

BACKGROUND: Hepatoblastoma (HB) is a rare embryonal liver tumor of children. Although intrinsic biological differences between tumors can affect prognosis, few groups have studied these differences. Given the recent increased attention to epigenetic mechanisms in the genesis and progression of these tumors, we aimed to classify HB samples according to the stages of liver development and DNA methylation machinery. BASIC PROCEDURES: We evaluated the expression of 24 genes associated with DNA methylation and stages of hepatocyte differentiation and global DNA methylation. Using bioinformatics tools and expression data, we propose a stratification model for HB. MAIN FINDINGS: Tumors clustered into three groups that presented specific gene expression profiles of the panel of DNA methylation enzymes and hepatocyte differentiation markers. In addition to reinforcing these embryonal tumors' molecular heterogeneity, we propose that a panel of 13 genes can stratify HBs (TET1, TET2, TET3, DNMT1, DNMT3A, UHRF1, ALB, CYP3A4, TDO2, UGT1A1, AFP, HNF4A, and FOXA2). DNA methylation machinery participates in the characterization of HBs, directly reflected in diverse DNA methylation content. The data suggested that a subset of HBs were similar to differentiated livers, with upregulation of mature hepatocyte markers, decreased expression of DNA methylation enzymes, and higher global methylation levels; these findings might predict worse outcomes. CONCLUSIONS: HBs are heterogeneous tumors. Despite using a small cohort of 21 HB samples, our findings reinforce that DNA methylation is a robust biomarker for this tumor type.

Asunto(s)

Hepatoblastoma , Neoplasias Hepáticas , Proteínas Potenciadoras de Unión a CCAAT , Metilación de ADN , Epigénesis Genética , Hepatoblastoma/genética , Humanos , Neoplasias Hepáticas/genética , Oxigenasas de Función Mixta , Pronóstico , Proteínas Proto-Oncogénicas , Ubiquitina-Proteína Ligasas

RESUMEN

Hepatoblastomas exhibit the lowest mutational burden among pediatric tumors. We previously showed that epigenetic disruption is crucial for hepatoblastoma carcinogenesis. Our data revealed hypermethylation of nicotinamide N-methyltransferase, a highly expressed gene in adipocytes and hepatocytes. The expression pattern and the role of nicotinamide N-methyltransferase in pediatric liver tumors have not yet been explored, and this study aimed to evaluate the effect of nicotinamide N-methyltransferase hypermethylation in hepatoblastomas. We evaluated 45 hepatoblastomas and 26 non-tumoral liver samples. We examined in hepatoblastomas if the observed nicotinamide N-methyltransferase promoter hypermethylation could lead to dysregulation of expression by measuring mRNA and protein levels by real-time quantitative polymerase chain reaction, immunohistochemistry, and Western blot assays. The potential impact of nicotinamide N-methyltransferase changes was evaluated on the metabolic profile by high-resolution magic angle spinning nuclear magnetic resonance spectroscopy. Significant nicotinamide N-methyltransferase downregulation was revealed in hepatoblastomas, with two orders of magnitude lower nicotinamide N-methyltransferase expression in tumor samples and hepatoblastoma cell lines than in hepatocellular carcinoma cell lines. A specific TSS1500 CpG site (cg02094283) of nicotinamide N-methyltransferase was hypermethylated in tumors, with an inverse correlation between its methylation level and nicotinamide N-methyltransferase expression. A marked global reduction of the nicotinamide N-methyltransferase protein was validated in tumors, with strong correlation between gene and protein expression. Of note, higher nicotinamide N-methyltransferase expression was statistically associated with late hepatoblastoma diagnosis, a known clinical variable of worse prognosis. In addition, untargeted metabolomics analysis detected aberrant lipid metabolism in hepatoblastomas. Data presented here showed the first evidence that nicotinamide N-methyltransferase reduction occurs in hepatoblastomas, providing further support that the nicotinamide N-methyltransferase downregulation is a wide phenomenon in liver cancer. Furthermore, this study unraveled the role of DNA methylation in the regulation of nicotinamide N-methyltransferase expression in hepatoblastomas, in addition to evaluate the potential effect of nicotinamide N-methyltransferase reduction in the metabolism of these tumors. These preliminary findings also suggested that nicotinamide N-methyltransferase level may be a potential prognostic biomarker for hepatoblastoma.

Asunto(s)

Metilación de ADN , Regulación hacia Abajo , Hepatoblastoma/genética , Neoplasias Hepáticas/genética , Nicotinamida N-Metiltransferasa/genética , Regiones Promotoras Genéticas/genética , Adolescente , Línea Celular Tumoral , Niño , Preescolar , Femenino , Regulación Neoplásica de la Expresión Génica , Células Hep G2 , Hepatoblastoma/metabolismo , Hepatoblastoma/patología , Humanos , Lactante , Recién Nacido , Estimación de Kaplan-Meier , Hígado/metabolismo , Hígado/patología , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Masculino , Metabolómica/métodos , Nicotinamida N-Metiltransferasa/metabolismo

RESUMEN

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 (AU)

Asunto(s)

Humanos , Niño , Hepatoblastoma/genética , Neoplasias de Células Germinales y Embrionarias/genética , Predisposición Genética a la Enfermedad , Epigenómica , Neoplasias Hepáticas/genética , Mutación

RESUMEN

The aim of this study was to investigate the expression of CD44 and its clinical significance in children suffering from hepatoblastoma (HB). CD44 expression was detected with immunohistochemistry staining in 30 samples from hepatoblastoma children and 10 normal liver tissue samples from normal children. The data obtained was statistically analyzed using the chi-square test, using the SPSS (v.11.0) software. The rate of CD44 expression was significantly higher (66.7%) in hepatoblastoma tissues than in normal liver tissues (χ(2) = 4.848, P < 0.05). The rate of CD44 expression was significantly higher in children with stage III or IV hepatoblastoma (83.3%) than that in children with stage I and II hepatoblastoma (χ(2) ＝ 5.625, P < 0.05) (41.7%). Therefore, CD44 expression might play an important role in the pathogenesis, progression, and prognosis of HB in children.

Asunto(s)

Hepatoblastoma/metabolismo , Hepatoblastoma/patología , Receptores de Hialuranos/metabolismo , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patología , Niño , Progresión de la Enfermedad , Femenino , Expresión Génica , Hepatoblastoma/genética , Humanos , Receptores de Hialuranos/genética , Inmunohistoquímica , Neoplasias Hepáticas/genética , Masculino , Estadificación de Neoplasias , Pronóstico

RESUMEN

Pediatric tumors are heterogenous and can be quite varied in appearance. However, those in the infamous "small round blue-cell tumor" group, with their hyperchromatic nuclei and small amount of cytoplasm can be challenging, and their diagnosis and prognostication require cost-efficient and focused immunohistochemistry and ancillary testing. Ideally, ample material should be obtained for routine histology and ancillary testing, including immunohistochemistry, fluorescent in situ hybridization, fresh tissue for cytogenetic studies, and snap-frozen tumor for DNA/RNA extraction both for routine molecular testing (ie, reverse-transcription PCR studies), as well as future research study protocols (genome wide studies, targeted gene sequencing). This review focuses on the main pediatric tumors with emphasis on immunophenotype, keeping in mind that a directed panel approach yields the highest yield with combination of clinical history, histologic features, and ancillary molecular testing.

Asunto(s)

Biomarcadores de Tumor/genética , Inmunofenotipificación , Fenotipo , Niño , Tumor Desmoplásico de Células Pequeñas Redondas/diagnóstico , Tumor Desmoplásico de Células Pequeñas Redondas/genética , Tumor Desmoplásico de Células Pequeñas Redondas/patología , Fibrosarcoma/diagnóstico , Fibrosarcoma/genética , Fibrosarcoma/patología , Hepatoblastoma/diagnóstico , Hepatoblastoma/genética , Hepatoblastoma/patología , Humanos , Inmunohistoquímica , Hibridación Fluorescente in Situ , Neuroblastoma/diagnóstico , Neuroblastoma/genética , Neuroblastoma/patología , Blastoma Pulmonar/diagnóstico , Blastoma Pulmonar/genética , Blastoma Pulmonar/patología , Rabdomiosarcoma/diagnóstico , Rabdomiosarcoma/genética , Rabdomiosarcoma/patología , Sarcoma de Parte Blanda Alveolar/diagnóstico , Sarcoma de Parte Blanda Alveolar/genética , Sarcoma de Parte Blanda Alveolar/patología , Sarcoma de Ewing/diagnóstico , Sarcoma de Ewing/genética , Sarcoma de Ewing/patología , Sarcoma Sinovial/diagnóstico , Sarcoma Sinovial/genética , Sarcoma Sinovial/patología , Tumor de Wilms/diagnóstico , Tumor de Wilms/genética , Tumor de Wilms/patología

RESUMEN

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.

Asunto(s)

Cromosomas Humanos Par 2/genética , Hepatoblastoma/genética , Neoplasias Hepáticas/genética , Aneuploidia , Aberraciones Cromosómicas , Expresión Génica , Regulación Neoplásica de la Expresión Génica , Estudios de Asociación Genética , Humanos , Oncogenes , Estudios Retrospectivos , Regulación hacia Arriba

RESUMEN

Primary liver tumors in children are rare with hepatoblastoma (HB) being the most common malignancy. Clear cell carcinoma, a variant of hepatocellular carcinoma (HCC), is another rare tumor of the liver that tends to affect adults. We describe the diagnosis and management of the only known documented case of a primary clear cell HCC arising twenty-five years after the patient was successfully treated with chemotherapy and surgical resection for a malignant HB as an infant. While some evidence has shown a genetic link between HB and various types of HCC, other research has shown distinct chromosomal alterations and molecular mechanisms unique to both. Further knowledge of liver tumorigenesis will help elucidate the complicated genetic, molecular, and environmental factors involved in the development of these two rare hepatic malignancies.

Asunto(s)

Carcinoma Hepatocelular/diagnóstico , Hepatoblastoma/tratamiento farmacológico , Hepatoblastoma/cirugía , Neoplasias Hepáticas/diagnóstico , Adulto , Biopsia , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patología , Terapia Combinada , Predisposición Genética a la Enfermedad/genética , Hepatoblastoma/genética , Humanos , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Imagen por Resonancia Magnética , Masculino , Factores de Tiempo , Resultado del Tratamiento

Asunto(s)

Síndrome de Beckwith-Wiedemann/genética , Gigantismo/genética , Hepatoblastoma/genética , Neoplasias Hepáticas/genética , Síndrome de Beckwith-Wiedemann/diagnóstico , Cromosomas Humanos Par 11/genética , Metilación de ADN/genética , Predisposición Genética a la Enfermedad/genética , Histona Metiltransferasas , N-Metiltransferasa de Histona-Lisina , Humanos , Péptidos y Proteínas de Señalización Intracelular/genética , Mutación/genética , Proteínas Nucleares/genética , Fenotipo , Síndrome , Dedos de Zinc/genética

RESUMEN

Hepatoblastoma comprises only 1% of all cancers in childhood. Because of its low frequency, a small number of prognostic factors are described in hepatoblastoma and most of them are related to resectability. Microarray studies showed a large number of underexpressed genes in hepatoblastoma. Because aberrant DNA methylation has been recognized as an alternative mechanism for tumor suppressor gene inactivation, this could be involved with gene downregulation in these tumors. Despite the rarity of hepatoblastoma, this study evaluated the methylation pattern of 25 genes in 20 paraffin-embedded tumor specimens and five non-neoplastic liver samples (normal control) by quantitative methylation-specific PCR (QMSP). The examination of the methylation profile of hepatoblastoma samples and normal liver specimens revealed a high tumor-specific DNA hypermethylation in the promoter regions of five genes (APC, CDH1, MT1G, RASSF1A, and SOCS1). Furthermore, MT1G hypermethylation showed a significant correlation with poor prognosis of patients with hepatoblastoma. This study represents the first quantitative evaluation of promoter hypermethylation in hepatoblastoma and demonstrated that aberrant methylation is a frequent event in this malignancy. Furthermore, our data provide evidence that MT1G hypermethylation may be useful as prognostic indicator for this disease and suggest that patients with hepatoblastoma may benefit from demethylating drug treatments.

Asunto(s)

Biomarcadores de Tumor/genética , Metilación de ADN , Hepatoblastoma/genética , Neoplasias Hepáticas/genética , Metalotioneína/genética , Adolescente , Niño , Preescolar , Femenino , Hepatoblastoma/diagnóstico , Hepatoblastoma/patología , Humanos , Lactante , Recién Nacido , Estimación de Kaplan-Meier , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/patología , Masculino , Metalotioneína/metabolismo , Pronóstico , Regiones Promotoras Genéticas , Estudios Retrospectivos

RESUMEN

We report a case of hepatoblastoma that developed in a child with Sotos syndrome, an overgrowth syndrome with an increased risk of neoplasms. Genome-wide analysis of copy number alterations showed a gain of chromosome 2, uniparental disomy of 18q, and microdeletion of 5q35.

Asunto(s)

Anomalías Múltiples/patología , Trastornos del Crecimiento/patología , Hepatoblastoma/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Neoplasias Hepáticas/genética , Proteínas Nucleares/genética , Anomalías Múltiples/genética , Aneuploidia , Deleción Cromosómica , Trastornos del Crecimiento/complicaciones , Trastornos del Crecimiento/genética , Hepatoblastoma/diagnóstico , Hepatoblastoma/terapia , Histona Metiltransferasas , N-Metiltransferasa de Histona-Lisina , Humanos , Lactante , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/terapia , Masculino , Polimorfismo de Nucleótido Simple/genética , Síndrome

Asunto(s)

Hepatoblastoma/diagnóstico , Hepatoblastoma/terapia , Neoplasias Hepáticas/diagnóstico , Neoplasias Hepáticas/terapia , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Biomarcadores de Tumor/sangre , Terapia Combinada , Hepatectomía , Hepatoblastoma/genética , Hepatoblastoma/patología , Hepatoblastoma/secundario , Humanos , Lactante , Recién Nacido de Bajo Peso , Recién Nacido , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patología , Trasplante de Hígado , Neoplasias Pulmonares/secundario , Estadificación de Neoplasias/métodos , Síndromes Neoplásicos Hereditarios/genética , Trisomía , alfa-Fetoproteínas/análisis , beta Catenina/genética

RESUMEN

Primary malignant epithelial tumors of the liver (PMETL) are rare in the pediatric age group, and very little is known about their biology as compared with adult tumors. The prognostic value of the DNA contents measured by image analysis and expression of oncogene c-erb2 and tumor suppressor gene p53 were studied in 30 cases of PMETL in children, including 24 with hepatoblastomas (HB) and 6 with hepatocellular carcinomas (HCC). p53 overexpression was detected in 12 out of 26 cases (46.0%), or in 3 of 5 HCC and 9 of 21 HB cases. A relatively high concordance of staining was observed with the two antibodies used (clone DO7, Dako and clone DO1, Santa Cruz Biotechnology). c-erb-B2 did not yield the characteristic membrane staining in any of the 27 cases in which reliable staining was obtained. However, 1 out of 4 patients with HCC and 1 of 23 with HB revealed strong granular cytoplasmic staining in several neoplastic cells. Interestingly, these were two of the three aneuploid multiploid cases. DNA histograms of 13 out of 29 cases (54.8%) were classified as DNA aneuploid (5/6 HCC and 8/23 HB): nine were hyperdiploid, one was hypodiploid (1HB), and three were multiploid (2HB and 1HCC). In the HB group, DNA aneuploidy was strongly associated with embryonal histological areas, suggesting that a disturbance in the process of cell differentiation is associated with marked genetic aberrations. Only the group of HB was submitted to univariate analysis of survival by the Kaplan-Meier method for age (< 24 months vs. > or = 24 months), sex, preoperative chemotherapy (yes vs. no), residual disease (metastasis, and/or unresectable tumor), p53 expression by immunohistochemistry (positive vs. negative), and DNA ploidy (diploid vs. aneuploid). Only residual disease at the time of diagnosis (P < 0.017) and preoperative chemotherapy (0.030) were found to be negatively correlated with biological behavior, estimated as overall survival. DNA aneuploidy tumors (P < 0.125) and male patients (P = 0.123) showed a trend toward a more aggressive clinical behavior, although the difference was not statistically significant. Combining DNA ploidy and residual disease, patients were categorized into three groups: group I, patients with no adverse prognostic factors, i.e., diploid tumors without residual disease; group II, patients with only one adverse prognostic factor, i.e., aneuploid tumor or residual disease; and group III, patients with both adverse factors, aneuploid tumors and residual disease at time of diagnosis. A log-rank test comparing the three survival curves showed a statistically significant difference between them (P < 0.003). Although the series of cases is small, the results of this study highlight the importance of including DNA ploidy in the protocols designed for HB in children by international cooperative groups.

Asunto(s)

Carcinoma Hepatocelular/genética , ADN de Neoplasias/análisis , Regulación Neoplásica de la Expresión Génica , Hepatoblastoma/genética , Neoplasias Hepáticas/genética , Oncogenes/genética , Adolescente , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Masculino , Ploidias , Pronóstico , Receptor ErbB-2/biosíntesis , Receptor ErbB-2/genética , Estudios Retrospectivos , Análisis de Supervivencia , Proteína p53 Supresora de Tumor/biosíntesis , Proteína p53 Supresora de Tumor/genética