The role of the mouse y chromosome on susceptibility to testicular germ cell tumors.

Testicular germ cell tumors (TGCT) are sex limited, occurring only in males with a Y chromosome. Recently, the gr/gr deletion on the human Y chromosome was associated with increased risk of TGCTs. In addition, the presence of Y chromosome sequences is associated with TGCTs in cases of gonadal dysgenesis. TGCTs in strain 129 males recapitulate many aspects of testicular cancer in human infants and can be used to evaluate the role of the Y chromosome in TGCT risk. We used chromosome substitution strains and a sex-reversing mutant to test the role of the Y chromosome on TGCT susceptibility. Our results show that a Y-linked gene that does not differ among the tested strains is essential for tumorigenesis.

Deletion of eIF2beta suppresses testicular cancer incidence and causes recessive lethality in agouti-yellow mice.

The agouti-yellow (A(y)) deletion is the only genetic modifier known to suppress testicular germ cell tumor (TGCT) susceptibility in mice or humans. The A(y) mutation deletes Raly and Eif2s2, and induces the ectopic expression of agouti, all of which are potential TGCT-modifying mutations. Here we report that the reduced TGCT incidence of heterozygous A(y) males and the recessive embryonic lethality of A(y) are caused by the deletion of Eif2s2, the beta subunit of translation initiation factor eIF2. We found that the incidence of affected males was reduced 2-fold in mice that were partially deficient for Eif2s2 and that embryonic lethality occurred near the time of implantation in mice that were fully deficient for Eif2s2. In contrast, neither reduced expression of Raly in gene-trap mice nor ectopic expression of agouti in transgenic or viable-yellow (A(vy)) mutants affected TGCT incidence or embryonic viability. In addition, we provide evidence that partial deficiency of Eif2s2 attenuated germ cell proliferation and differentiation, both of which are important to TGCT formation. These results show that germ cell development and TGCT pathogenesis are sensitive to the availability of the eIF2 translation initiation complex and to changes in the rate of translation.

Loss of the transmembrane but not the soluble kit ligand isoform increases testicular germ cell tumor susceptibility in mice.

Several genetic variants act as modifiers of testicular germ cell tumor (TGCT) susceptibility in the 129/Sv mouse model of human pediatric TGCTs. One such modifier, the Steel locus, encodes the transmembrane-bound and soluble ligand of the kit receptor. Some (Sl and SlJ) but not all (Sld) mutations of the Steel locus increase TGCT incidence in heterozygous mutant mice. Because Sl and SlJ are large deletions that affect multiple transcripts and Sld is an intragenic deletion of the kit ligand (Kitl) from which only the soluble protein is produced, it was uncertain whether Kitl or a neighboring gene is a modifier of TGCT susceptibility. We tested the effect of the small Steel grizzle-belly (Slgb) deletion on TGCT susceptibility to determine whether Kitl is a TGCT modifier gene. An increase in TGCT incidence was observed in Slgb/+ heterozygotes, and fine mapping of the deletion breakpoints revealed that Kitl is the only conventional gene deleted by the mutation, suggesting that Kitl is the TGCT modifier gene at the Steel locus. Additionally, we propose that soluble KITL in Sld/+ heterozygous mutant mice complements a dosage effect of transmembrane-associated kit ligand on TGCT susceptibility and that the kit receptor (Kit) is haplosufficient for primordial germ cell development.

Trans-generational epistasis between Dnd1Ter and other modifier genes controls susceptibility to testicular germ cell tumors.

The genetic basis for susceptibility to testicular germ cell tumors (TGCTs) has been remarkably elusive. Although TGCTs are the most common cancer in young men and have an unusually strong familial risk, only one low-frequency susceptibility gene has been identified for this highly multigenic trait. In tests to determine whether pairs of genetic variants act epistatically to modulate susceptibility in the 129/Sv mouse model of spontaneous TGCTs, we discovered an unusual mode of inheritance that involved interactions between different genes in different generations. Any of six genetic variants, in either the female or male parent interacted with the Dnd1(Ter) mutation in male offspring to significantly increase both the frequency of affected Ter/+ males and the proportion of bilateral cases. Trans-generational epistasis is a novel mode of epigenetic inheritance that could account for the difficulty of finding TGCT susceptibility genes in humans and might represent a mechanism for transmitting information about genetic and environmental conditions from parents to offspring through the germline.

Enhancers and suppressors of testicular cancer susceptibility in single- and double-mutant mice.

Susceptibility to spontaneous testicular germ cell tumors (TGCTs), a common cancer affecting young men, shows unusual genetic complexity. Despite remarkable progress in the genetics analysis of susceptibility to many cancers, TGCT susceptibility genes have not yet been identified. Various mutations that are inherited as Mendelian traits in laboratory mice affect susceptibility to spontaneous TGCTs on the 129/Sv inbred genetic background. We compared the frequency of spontaneous TGCTs in single- and double-mutant mice to identify combinations that show evidence of enhancer or suppressor effects. The lower-than-expected TGCT frequencies in mice with partial deficiencies of TRP53 and MGF-SLJ and in 129.MOLF-Chr19 (M19) consomic mice that were heterozygous for the A(y) mutation suggest that either these genes complement each other to restore normal functionality in TGCT stem cells or together these genes activate mechanisms that suppress incipient TGCTs. By contrast, the higher-than-expected TGCT frequencies in Mgf(Sl-J)-M19 compound heterozygous mice suggest that these mutations exacerbate each other's effects. Together, these results provide clues to the genetic and molecular basis for susceptibility to TGCTs in mice and perhaps in humans.

Genetic control of susceptibility to spontaneous testicular germ cell tumors in mice.

Testicular germ cell tumors (TGCTs) are the most common cancer affecting young men. TGCT is a polygenic trait and genes that control susceptibility for TGCT development have not yet been identified. The 129/Sv inbred strain of mice is an important experimental model to study the genetics and development of TGCTs. We review several novel approaches that were developed to study the susceptibility of TGCTs in the 129/Sv mouse model and its application in humans. These approaches showed that several spontaneous and engineered mutations interact with 129/Sv-derived susceptibility genes to enhance or suppress susceptibility; two of these mutations (Ter and Trp53) revealed novel linkages for susceptibility genes in sensitized polygenic trait analysis. Linkage analysis with a chromosome substitution strains suggests that as many as 100 genes control susceptibility. Bilateral TGCTs result from the coincidental occurrence of unilateral tumors. These results highlight the important contributions that this mouse model can make to studies of TGCT susceptibility in humans.