International Mammalian Genome Society

logo18th International Mouse Genome Conference

17-22 October 2004, Seattle, USA


POSTER 37 - SUPPRESSORS AND ENHANCERS OF TESTICULAR CANCER SUSCEPTIBILITY IN DOUBLE-MUTANT MICE

Lam MYJ, Youngren KK, Nadeau JH

Case Western Reserve University, Cleveland, United States

Linkage studies with the 129/Sv strain, which has a low rate (1-5%) of spontaneous testicular germ tumors (TGCTs), reveal exceptional complexity in the genetic control of susceptibility. Currently, susceptibility genes have not been identified and pathways that lead from primordial germ cells (PGCs) to stem cells to TGCTs are unknown. Various Mendelian traits in mice affect susceptibility only on the 129/Sv genetic background, suggesting that these mutations act as modifiers of tumorigenesis. We tested pairwise interactions among the five known modifier genes, by comparing TGCT frequency in single and double-mutant mice, to identify combinations that show enhancer or suppressor effects. Trp53+/- MgfSlJ+/- double-mutant males had a tumor frequency that was four-fold lower than the rate expected if each modifier acted independently. Normally, TRP53 arrests cells to allow repair of DNA damage or programmed cell death, whereas MGF is essential for survival of PGCs and TGCT stem cells. Reduced TGCT susceptibility suggests that interactions between DNA repair, apoptosis and MGF-KIT signal transduction modulate tumorigenesis.  Studies are underway to characterize the nature of the interaction between TRP53 and MGF.  Preliminary results indicate that Trp53 mRNA expression is elevated in the testis of double-heterozygous mutants, suggesting a dosage effect resulting from a novel mechanism to up-regulate TRP53 and suppress tumorigenesis.  In  parallel, we discovered other examples of suppressors (Ay and 129/Sv-Chr19M) and enhancers (MgfSlJ and 129/Sv-Chr19M). Together, these results provide insights to apoptosis, cell cycle control, cell lineage determination and signal transduction that control PGC biology and TGCT susceptibility.

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