Genetic control of susceptibility to testicular cancer

Testicular germ cell tumors (TGCTs) are the most common solid tumors affecting young to middle aged men. It is the fifth most rapidly increasing type of cancer. Therefore, a better understanding is urgently needed of risk factors, early diagnosis, and treatment before metastasis. To date, there has not been a susceptibility gene identified in humans. We study a mouse model, the 129/Sv inbred mouse strain, in which TGCTs arise spontaneously by 3-weeks of age. Linkage studies with the 129/Sv strain, which has a low rate (1--5%) of TGCTs, reveal exceptional complexity in the genetic control of susceptibility. Various mutations that are inherited as Mendelian traits in laboratory mice affect susceptibility to spontaneous TGCTs on the 129/Sv genetic background. These genes, alone or in combination, provide important clues to the control of susceptibility and resistance to tumorigenesis. We undertook a systematic survey to test pairwise interactions of all known TGCT susceptibility loci, by comparing the frequency of TGCTs in double-mutant mice to identify combinations that show evidence of enhancer or suppressor effects. We identified three pairs of genes that enhanced the susceptibility of TGCTs and two pairs of genes that suppress the development of TGCTs. These mouse models can help simplify the complexity of TGCTs.; We can extrapolate from the findings in the mouse model to help identify candidate susceptibility genes in human. Recently, we identified the Ter mutation to be a premature stop codon in the Dnd1 gene that causes significantly increased susceptibility to TGCTs. The human ortholog of Dnd1 maps to Chr5q31. We performed an association study to test whether the human ortholog of Dnd1 contributes to susceptibility of TGCTs in human. We did not identify a mutation within the coding region in the cases, which indicates that Dnd1 may be a low frequency variant in human population.