Testicular cancers (testicular germ cell tumors, TGCTs) are the most common cancers in young males and the incidence has doubled over the last 50 years. TGCT susceptibility genes have not been identified in humans although the first genetic linkage has recently been reported. I have developed a novel mouse strain, the 129.MOLF-Chr 19 consomic strain, in which more than 70% of the males develop spontaneous congenital TGCTs. In this 129 strain, the intact Chromosome (Chr) 19 is replaced with a homologous chromosome from the MOLF strain. The dramatic increase in TGCT in the consomic strain reflects critical differences in the function of gene(s) encoded by the MOLF-derived Chr 19. In spite of the high frequency of TGCTs in the 129.MOLF-Chr 19 strain, this strain is fertile. Thus, this strain is very useful for the study of the genetics as well as the biology of TGCT development. To delineate the TGCT-causing genes on Chr 19, congenic mouse strains carrying large segments of MOLF Chr 19 on a 129 background have been made. The TGCT frequency of these congenics indicate that multiple TGCT susceptibility genes are present on MOLF Chr 19. The genes are present in proximal, middle and distal regions of Chr 19. Evidence indicates that overall, the multiple regions from the MOLF Chr 19 act additively to contribute to tumorigenesis. However, some regions appear to interact epistatically to contribute to tumorigenesis and tumors develop only when two different regions are present in the mouse strain. My goal is to identify and characterize these TGCT causing genes and their interactions. First, the boundaries of the TGCT loci will be defined. Second, the genes within the intervals will be identified. This step will entail examination of the genome databases, gene expression analysis, sequence analysis and the creation of transgenic mouse strains to confirm gene identity. Third, we will assess whether a known tumor suppressor which maps to Chr 19, the PTEN gene, is a candidate TGCT predisposing gene. Fourth, we will establish techniques to investigate the biological and molecular differences in primordial germ cells (PGCs) isolated from normal compared to TGCT-predisposed mouse strains. TGCTs arise from PGCs that become transformed and subsequently give rise to TGCT. The consomic and congenic strains with varying TGCT predisposition are valuable resources for the dissection of the biology of PGC transformation.

R01CA093754

2003-07-01

2010-04-30