Testicular germ cell tumors (TGCTs) are the most common cancer affecting young men, and the incidence has increased dramatically in the last 50 years. The genetic control of susceptibility is unusually complex, and with a single exception genetic variants that control susceptibility elude discovery in humans. We discovered the identity of three genetic modifiers that modulate susceptibility in a mouse model. Deadend1*Ter, which increases susceptibility, is related to genes involved in RNA editing and blocks access of specific miRNAs to their target mRNAs. Similarly, we showed that partial deficiency for the Eif2s2 translation initiation factor at the agouti-yellow locus suppresses susceptibility. Finally, we showed that loss of the transmembrane but not the soluble isoform of the Kit ligand increases susceptibility in mice. Two recent papers showed that Kit ligand is a major TCGT susceptibility gene in humans. Together these results suggest that interactions between 5'cap and 3'UTR in target mRNAs modulate global and perhaps transcript-specific translation. TGCT stem cells appear to be unusually sensitive to changes in translation rates. With these important discoveries that TGCT modifier genes involve related functions, we can now address specific questions about mechanisms of tumorigenesis for a developmentally important stem cell lineage - primordial germ cells. In addition, we found spontaneous metastasis in several TGCT susceptible strains. TGCT metastasis occurs frequently in humans and the mechanisms are poorly understood. Our exciting discovery therefore enables unique studies of the mechanisms of TGCT metastasis that were not previously possible. We propose Specific Aims to address four questions: (1) What are the mechanisms for TGCT suppressor effects of Eif2s2 haplosufficiency? (2) Do Dnd1 mutants affect RNA editing? (3) Do RNA editing mutants affect TGCT susceptibility? (4) What are the characteristics of putative TGCT metastases in mouse models?
Testicular cancer is one of the most common malignancies affecting young men. Although the genetic control of susceptibility is unusually strong, little progress has been made finding these genes that could be used define the mechanisms of susceptibility and that could serve as diagnostic markers or as treatment targets. We discovered three TGCT susceptibility genes, two of which suggest that control of mRNA translation has dramatic effects on susceptibility. In this application, we propose studies to test hypotheses about mechanisms by which changes in translation control modulate TGCT susceptibility. We also discovered, and propose to characterize spontaneous TGCT metastases in several of our mouse models.
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