Epigenomic studies in hepatoblastoma

Abstract

Germinative changes in genes predisposing to cancer may anticipate the age of onset of tumor involvement, and it has been estimated that between 25 and 30% of pediatric tumors can be associated with inherited or new genetic constitutive causes. Recently, Zhang et al (2016) reported germline mutations in cancer-predisposing genes in 8.5% of the children and adolescents with cancer; strikingly, family history did not predict the presence of an underlying predisposition syndrome in this cohort.Mostly diagnosed in children under the age of 18 months, the majority of HBs are sporadic cases, although its incidence is elevated in certain genetic syndromes with known constitutive genetic mutations, including Beckwith-Wiedemann and familial adenomatous polyposis. Exome studies of HB samples highlighted in general a relatively stable genome in this type of pediatric liver tumor,which presents a low mutational burden of both SNVs/indels and copy number alterations. The relatively low number of genetic mutations reported for both adult and pediatric liver cancers sheds light on the relevance of epigenetic mechanisms for hepatic tumorigenesis. Recently, we reported that hepatoblastomas exhibited a widespread and non-stochastic pattern of global low-level hypomethylation, with results suggesting an arrest at early stages of liver cell differentiation. Cytosine methylation, mainly in CpG islands located at gene promoter, can modulate temporal and spatial gene expression. Using the power of next-generation sequencing (NGS), both genome-wide analysis and targeted approaches can be applied to investigate DNA methylation profiles at a single nucleotide level.Therefore, the proposed fellowship consists of two main objectives: a) DNA methylation analysis of an external group of hepatoblastomas samples (from the Texas Children's Hospital) by Methyl-Seq; b) Integrative analysis of different biological data (DNA methylation, exome data and gene expression) derived from the same group of HBs.Talita Aguiar will be involved in the laboratory and bioinformatic work required to accomplish her project throughout the entire duration of her stay. During the first months, the fellow will focus on improving her knowledge of bioinformatic and DNA methylation analysis techniques to be later utilized in the production and evaluation of epigenomic data obtained from hepatoblastoma (HB) patients.The fellowship at the Texas Children's Hospital will permit investigate other biological mechanisms involved with the tumorigenesis of hepatoblastomas. The Dra Lopez-Terrada's group has unleashed efforts in genetic and molecular studies documenting recurrent chromosomal abnormalities and aberrant activation of developmental and oncogenic signaling pathways in hepatoblastomas. Molecular subclasses and gene signatures that could be used to stratify patients with hepatoblastoma were also recently identified by her group. In addition, she has participated in studies aiming to aggregate information relevant to clinical practice. (AU)