Correlative Genetic Markers in Childhood Hepatoblastoma

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DESCRIPTION (provided by applicant): Characterization of genetic changes in cancer, particularly chromosomal translocations, has led to a better understanding of tumorigenic pathways and also has served to develop diagnostic and prognostic markers which allow stratification of treatment regimens by risk groups. In addition, characterization of chromosomal translocations and their gene products have led to the development of novel targeted therapies that are much less toxic than conventional cytotoxic chemotherapy. Hepatoblastoma, the most common tumor of the liver in children, is characterized by specific chromosomal changes, the most common being trisomy of chromosomes 2, 8 and 20. Hepatoblastoma is also characterized by a family of translocations involving a common breakpoint at chromosome 1q12. Interestingly, the first four tumors we reported which demonstrated a similar, recurring translocation, t(1;4)(q12;q34) were all observed in high-stage tumors. Within our large series of karyotypes, frequent translocation are observed in which the long arm of chromosome 1 is translocated to other chromosomal loci, all with a resultant gain of genetic material on chromosome 1 and loss of genetic material on the reciprocal chromosome. We have recently determined using oligonucleotide array comparative genomic hybridization (oaCGH) that the translocation breakpoint lies in the vicinity of NOTCH2, a gene involved in liver development and specifically in hepatoblast differentiation. NOTCH2 is expressed at high levels in hepatoblastoma tumor samples and at low levels in non-malignant liver tissue suggesting that it may play an important role in tumorigenesis. The overall goal of this project is to correlate our observed chromosomal changes in hepatoblastoma with clinical features. Specifically, we hypothesize that chromosomal trisomies are associated with a worse outcome. Likewise we hypothesize that tumors which have the observed translocations involving NOTCH2 have a more aggressive phenotype. Utilizing oaCGH, chromosomal copy number changes will be analyzed in our unique resource of 220 hepatoblastoma tumor tissues ascertained as part of cooperative group protocols and annotated with clinical data. Using a series of very finely tiled oligonucleotides, we will characterize the breakpoint on chromosome 1. Class discovery methodology will be used to characterize patterns of multiple copy number changes among multiple tumor samples. Realization of these aims will lead to the development of markers that will help predict outcome and thereby serve to guide future therapies, either in the stratification into risk groups or in the development of novel therapies. A product of this project will be a powerful databank of genomic copy number changes which will be made available to researchers as a resource to further the understanding of genetic etiologies of liver tumorigenesis in children. In addition, this pilot study will generate preliminary data to plan prospective treatment studies with correlative genetic studies. 7. PUBLIC HEALTH RELEVANCE: Hepatoblastoma is a cancer of the liver that develops in infants and young children and is often difficult to successfully treat. Hepatoblastoma tumor tissues are characterized by well- defined chromosome changes, the clinical relevance of which is unknown. This study will examine chromosome changes in 220 hepatoblastoma tumor specimens and will determine if these alterations can be used to predict patient outcome and hence guide future therapies.