The Use of a Zebrafish Germ Cell Tumor Mutant to Identify Putative Genetic Mutation Drivers in Human Testicular Germ Cells Tumors

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Summary: Testicular Germ Cell Tumors (TGCTs) are the most common type of cancer affecting younger men between the ages of 20 and 40 years old. TGCTs typically respond well to current treatments, yet about 5% of cases are resistant. Furthermore, current treatments can have many adverse side affects that extend later in life warranting the need for improved, more targeted therapies. However, the genetic and molecular causes of TGCTs are largely unknown. To develop improved treatments for this disease requires a better understanding of the molecular underpinnings of TGCT formation. The aims of the project are to uncover mutations that drive TGCT tumorigenesis and/or increase susceptibility, and identify putative causative variants in human TGCTs through two main approaches: 1) develop an animal model with a high incidence of TGCTs, and 2) genome sequencing of tumor samples derived from patients. TGCTs consist of several subtypes, only one of which has an available mammalian model. Furthermore, TGCT cell lines are notoriously difficult to derive and are therefore largely unavailable. The zebrafish is an excellent animal model for many human diseases, including cancer. Strikingly, two zebrafish mutant lines have been identified that give rise to seminoma-type TGCT, which is the most common TGCT. Studies of these existing mutants identified mutated or misregulated genes in human TGCTs. We identified a novel zebrafish mutant line with a high incidence of TGCTs, named zgt (zebrafish germ cell tumor). This mutant is distinct from known zebrafish TGCT mutants and thus provides novel inroads to discovering molecular mechanisms underlying TGCT formation. To test for drivers of TGCTs in humans, this pilot proposes a genomic sequencing approach of patient samples with the goal of discovering mutations that arise during TGCT formation and thus may drive tumorigenesis. To facilitate identification of rare alleles, the project will use the knowledge gained from studies of our zebrafish model to guide targeted searches for mutations in human patient samples. This approach will facilitate the identification of mutations that may drive tumorigenesis, even with a limited number of primary tumor samples. Through this work, this pilot project will establish a new animal model for TGCT studies that will be used to uncover genetic and mechanistic causes of tumor formation. The project will translate the knowledge gained from the animal model through comparisons with genomic analysis attained from tumors derived from human patients, which will facilitate the identification of potential areas for therapeutic intervention. This project directly relates to the goals of the U54 Partnership as it supports collaborative research between oncologists and pathologists at DF/HCC and a basic science research group at UMass Boston. This collaboration is essential in establishing the project's translational model and building the cancer research program at UMass Boston. Furthermore, this project will provide opportunities for underrepresented minority (URM) students to engage in cancer research, and support career development of early stage investigators.