Identification of testicular cancer driver genes by a cross-species comparative oncology approach.

BACKGROUND:Germ cell tumors arise in the testis, ovary, or extragonadal locations and have a wide range of histopathological and clinical presentations. The relative lack of animal models of germ cell tumors has impeded functional assessment of candidate driver genes. Previously, we described the development of testicular germ cell tumors in zebrafish carrying a mutation in bmpr1bb, a BMP family receptor, and demonstrated that human germ cell tumors have defects in BMP signaling. OBJECTIVE:To further credential the zebrafish model for studies of human germ cell tumor, and to elucidate conserved genetic programs underlying the development of germ cell tumor. MATERIALS AND METHODS:We used genetic techniques to ablate the germ cell lineage in developing fish and tested tumors for loss-of-heterozygosity of the wild-type allele of bmpr1bb. We performed comparative gene expression profiling of zebrafish and human germ cell tumors and carried out functional studies of selected genes. RESULTS:Ablation of germ cells completely prevents testis tumor formation in the fish, definitively establishing the germ cell origin of the tumors. Germ cell tumors in bmpr1bb heterozygous mutants retain the wild-type allele, indicating haploinsufficiency of bmpr1bb as the mechanism of tumor formation. Comparison of RNA-Seq and microarray data from human and zebrafish germ cell tumors revealed a unique overlapping signature shared by the zebrafish tumors with human seminomas, yolk sac tumors, and embryonal carcinomas. The most highly conserved gene set in this cross-species analysis included potential driver genes such as JUP, which we show to be essential for germ cell tumor cell growth. CONCLUSION:Our findings highlight the value of cross-species comparative oncology for the identification of candidate human cancer genes.

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