Doctor of Philosophy, Case Western Reserve University, 2013, Genetics

Testicular germ cell tumours (TGCTs), which comprise 95% of all testicular cancers, are a group of neoplasms that affect young men. In the last 40 years, the incidence of this cancer has steadily risen throughout the world. Despite the strong heritability of the disease, few genetic or epigenetic risk factors have been identified. Metastases are a prominent feature of the human disease and are responsible for most of the morbidity and mortality associated with TGCTs. The 129 strain family of mice develop spontaneous TGCTs and are a useful organism to study this disease, but the applicability to human disease is subject to debate. We discovered that the mouse model also develops spontaneous metastases in approximately 11% of affected males, suggesting that TGCTs in mice may be more relevant to human TGCTs than previously thought. Moreover, metastasis rates remain consistent between 129 strains with TGCT modifier genes, even when TGCT rates vary. This suggests that the TGCT genetic susceptibility found in 129 strain mice may include a predisposition to metastasis. In order to further characterize one of these genetic modifiers, Dnd1Ter, we created Dnd1 knockout mice and have found several new functions for DND1. Surprisingly, we found that complete loss of DND1 is embryonically lethal, and that intercrossing animals with Dnd1KO alleles reveals a Dnd1 segregation bias. We have also shown that the most powerful TGCT modifier gene in mice, Dnd1Ter, is not a loss of function allele. Loss of a copy of Dnd1 does not affect TGCT rates, but the presence of the Dnd1Ter allele significantly increases TGCT rates. This increase is dose-dependent; a second copy of Dnd1Ter further increases TGCT rates. We have also found that the pro-oncogenic effects of Dnd1Ter are not limited to testicular cancer; it also increases polyp numbers and burden in an APCMIN mouse model of intestinal polyposis. These results show that the mouse model of TGCTs may allow for experimental inv (open full item for complete abstract)

Committee: Joseph Nadeau (Advisor); Helen Salz (Advisor); Hua Lou (Committee Chair); Ronald Conlon (Committee Member); Zhenghe (John) Wang (Committee Member); Ruth Keri (Committee Member) Subjects: Biomedical Research; Developmental Biology; Genetics