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| Author(s): |
Tatiane Cristina Rodrigues
Total Authors: 1
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| Document type: | Doctoral Thesis |
| Press: | São Paulo. |
| Institution: | Universidade de São Paulo (USP). Instituto de Biociências (IBIOC/SB) |
| Defense date: | 2015-02-04 |
| Examining board members: |
Carla Rosenberg;
Cecilia Maria Lima da Costa;
Oswaldo Keith Okamoto;
Silvia Regina Caminada de Toledo
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| Advisor: | Carla Rosenberg; Ana Cristina Victorino Krepischi |
| Abstract | |
Hepatic malignant tumors are rare in children, the embryonal tumor hepatoblastoma is the most common liver cancer in children under 5 years old but, in spite of that, accounts for only 1% of incident tumors in this age group. Due to its low incidence, among other factors, hepatoblastoma is a tumor poorly characterized at molecular level. This study included three approaches of molecular analyzes in hepatoblastomas: examination of copy number alterations (through array-CGH technique), investigation of somatic mutations in coding regions (next-generation exome sequencing) and determination of the global DNA methylation profile (bead arrays). We found a low frequency of copy number alterations, mostly consisting of large extent chromosomal gains, reflecting lower chromosomal instability than other solid adult tumors. A region at 2q24, previously associated with worse prognosis in hepatoblastomas, was found amplified in high amplitude (amplicon). Gene expression analysis of the 48 genes comprised in the amplicon segment highlighted five genes as overexpressed (DAPL1, ERMN, GALNT5, SCN1A and SCN3A). We also observed a low frequency of non-synonymous somatic mutations in our hepatoblastomas samples compared to the amount of variation found in other adult solid tumors. We described a predicted harmful non-synonymous mutation in exon 3 of CTNNB1 gene (beta-catenin), the best characterized molecular marker in hepatoblastomas. The list of somatic alterations points to a remarkable enrichment of genes from the Wnt pathway, which is well-studied in hepatoblastomas and is associated both with embryonic development and with the process of carcinogenesis. We highlighted a list of non-synonymous somatic mutations that presented high coverage in our experiments, and were absent or present at low frequency (<1%) in the general population. This study is the first to analyze global changes in cytosine methylation in hepatoblastomas, and revealed an unusual pattern of global hypomethylation in these tumors, not associated with LINE-1 repetitive regions; specifically, hepatobastomas exhibited an intermediate level of methylation, in between the patterns of mature and fetal livers. This finding supports the model in which the oncogenesis of hepatoblastoma recapitulates stages of fetal liver development. We highlighted 11 genes that showed differential pattern of DNA methylation in their promoters compared to differentiated liver. In summary, our findings show that the embryonal tumor hepatoblastoma are relatively genetically stable with lower frequency of alterations (changes in copy number and somatic mutations in coding regions) than most solid adult tumors. Simultaneously, a clear pattern of global hypomethylation of non-repetitive DNA was associated with the tumor, indicating the importance of epigenetic aspects in its tumorigenesis (AU) | |
| FAPESP's process: | 11/24007-9 - Genetic and epigenetic anomalies in the childhood tumor hepatoblastoma |
| Grantee: | Tatiane Cristina Rodrigues |
| Support Opportunities: | Scholarships in Brazil - Doctorate (Direct) |