Germ cell tumors of the testis are the most common cancer among young adult to middle-aged men and they are the fifth most rapidly increasing type of cancer. Although they respond better than most other cancers to treatments such as surgery, radiation and platinum-based therapies, germ cell tumors are an increasingly heavy medical and social burden. Identification of at-risk individuals prior to cancer development could lead to treatments that reduce the risk of cancer and metastasis. We are studying an animal model, the 129/Sv inbred strain, where planned crosses, large sample sizes, numerous informative markers, and developmental experiments are possible. Once linkages have been found in the mouse, the chromosomal location of homologous human genes can be predicted with considerable certainty. These predictions can be used to guide gene mapping and other genetic studies in humans. These genes can also be used to gain insight into the genetic control of the migration, proliferation and differentiation of the primordial germ cell lineage. Modifier genes that increase the frequency of mice with a tumor provide powerful ways to simplify the genetic analysis and identify many of the susceptibility genes. In turn, these results enable construction of new strains for finding other genes that guide development of the primordial germ cell lineage. Preliminary studies involve precise genetic mapping of the Ter modifier gene to Chromosome 18, identification of several candidate susceptibility loci, physical mapping of more than half of the Ter locus, construction of a Chromosome 19 congenic strain to verify linkage of several susceptibility genes, and evidence that at least one gene on the MOLF-derived Chromosome 19 segment has a germ cell tumor-promoting effect as strong as Ter. Proposed work involves identifying Ter with positional cloning, characterizing the developmental origins of the severe germ cell deficiency in Ter mice, using transgenics in a complementation test to identify BAC and YAC clones with the wild-type allele of Ter, and characterizing congenic strains to establish the effect of MOLF-derived Chromosome 19 genes on primordial germ cell function and germ cell tumorigenesis. Together these studies should provide insight into the biology and genetics of the primordial germ cell lineage, and into the etiology and pathogenesis of germ cell tumors.
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