Genetic Control of Susceptibility to Testicular Cancer

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DESCRIPTION (provided by applicant): Testicular germ cells tumors (TGCTs) are the most common cancer affecting young men and their incidence has been rising dramatically world-wide. Genetic markers for inherited risk are needed to identify susceptible individuals for regular surveillance and early treatment. Many TGCTs arise from primordial germ cells (PGCs) during fetal development. Little is known about the genetics or biology of this pluripotent stem cell lineage. The 129 family of inbred strains are the only strains in which spontaneous TGCTs occur at an appreciable frequency (5%). Several single gene mutations such as Ter, Ay and SI modulate susceptibility on the sensitized 129 genetic background. These strains and mutants are the foundation for genetic and developmental studies of PGC development and TGCT susceptibility. During the previous grant period, we showed that (a) Ter, the most potent TGCT modifier known, results from a mutation in the Deadend gene, (b) the TGCT suppressor at the Ay locus is Raly or Eif2b2 but not agouti, and also that the MGF enhancer is located in a 120 kb interval in which MGF is the only conventional gene, and (c) several single modifiers interact to modulate TGCT susceptibility, including dramatically reduced susceptibility in p53/+ SIJ/+ double mutant mice. We propose four Specific Aims: Specific Aim 1. What is the identity of the TGCT suppressor in Ay mutants and the enhancer in Kitl*SI mice? Specific Aim 2. What is the nature of the interactions between TGCT susceptibility modifier genes? Specific Aim 3. Does the Y chromosome affect TGCT susceptibility? Specific Aim 4. Do mutations in RNA editing genes affect TGCT susceptibility? Our discovery that the most potent TGCT modifier gene (Ter) probably involves anomalies in RNA editing raises exciting new opportunities to explore the role of this remarkable but poorly understood process in stem cell biology and TGCT susceptibility.