Abstract
BackgroundCertain mutations in the Deadend1 (Dnd1) gene are the most potent modifiers of testicular germ cell tumor (TGCT) susceptibility in mice and rats. In the 129 family of mice, the Dnd1Ter mutation significantly increases occurrence of TGCT-affected males. To test the hypothesis that he Dnd1Ter allele is a loss-of-function mutation; we characterized the consequences of a genetically-engineered loss-of-function mutation in mice, and compared these results with those for Dnd1Ter.ResultsWe found that intercrossing Dnd1+/KO heterozygotes to generate a complete loss-of-function led to absence of Dnd1KO/KO homozygotes and significantly reduced numbers of Dnd1+/KO heterozygotes. Further crosses showed that Dnd1Ter partially rescues loss of Dnd1KO mice. We also found that loss of a single copy of Dnd1 in Dnd1KO/+ heterozygotes did not affect baseline occurrence of TGCT-affected males and that Dnd1Ter increased TGCT risk regardless whether the alternative allele was loss-of-function (Dnd1KO) or wild-type (Dnd1+). Finally, we found that the action of Dnd1Ter was not limited to testicular cancer, but also significantly increased polyp number and burden in the Apc+/Min model of intestinal polyposis.ConclusionThese results show that Dnd1 is essential for normal allelic inheritance and that Dnd1Ter has a novel combination of functions that significantly increase risk for both testicular and intestinal cancer.
Highlights
Certain mutations in the Deadend1 (Dnd1) gene are the most potent modifiers of testicular germ cell tumor (TGCT) susceptibility in mice and rats
Loss of Dnd1 homozygotes and heterozygotes Unexpected results were found for Dnd1+/KO intercrosses that were intended to produce Dnd1+/KO heterozygotes and Dnd1KO/KO homozygotes as well as Dnd1+/+ wild-type controls for TGCT surveys
The current study suggests that Dnd1Ter is not a lossof-function allele, but instead affects TGCT risk and embryonic development in distinct ways from Dnd1KO, a true loss-of-function mutation
Summary
Certain mutations in the Deadend (Dnd1) gene are the most potent modifiers of testicular germ cell tumor (TGCT) susceptibility in mice and rats. To test the hypothesis that he Dnd1Ter allele is a loss-of-function mutation; we characterized the consequences of a genetically-engineered loss-of-function mutation in mice, and compared these results with those for Dnd1Ter. Testicular germ cell tumors (TGCTs) are the most common cancer affecting young men. Testicular germ cell tumors (TGCTs) are the most common cancer affecting young men They are disproportionately represented in men aged 20–40, comprising ~60% of all cancers in this age group [1], while accounting for only 1.0-1.5 % of all cancers [2]. Genetic factors contribute significantly to TGCT susceptibility as exemplified by a 4- to 15-fold increased risk in the sons and germ cell development and differentiation are largely unknown. The TERT SNP is associated with adenocarcinoma [20]
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