Mouse models of testicular germ cell tumors

Carouge, Delphine; Nadeau, Joseph H.

doi:10.5772/38921

Cited by 4 publications

(7 citation statements)

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“…Even with these findings however, the majority of inherited TGCT susceptibility remains unknown. In the mouse, several TGCT susceptibility genes have been identified, including Kit , Kitlg , Pten , Dmrt1 , Eif2s2 and others (for a review, see [58]). Together these human and mouse genes implicate pathways and functions related to germ cell proliferation, PGC differentiation and cell cycle control in TGCT development.…”

Section: Discussionmentioning

confidence: 99%

Contrasting effects of Deadend1 (Dnd1) gain and loss of function mutations on allelic inheritance, testicular cancer, and intestinal polyposis

et al. 2013

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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.

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Section: Discussionmentioning

confidence: 99%

Contrasting effects of Deadend1 (Dnd1) gain and loss of function mutations on allelic inheritance, testicular cancer, and intestinal polyposis

et al. 2013

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“…refs. 28,66). In addition, maternal ko/+ heterozygosity significantly reduced the prevalence of affected +/+ wild-type sons, not only in the first generation (Table 1, cross 2a) but also for at least two subsequent generations (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…In mice and humans, TGCTs arise from primordial germ cells (PGCs), which are the embryonic precursors of gametes in adults (21,22). PGC transformation occurs during embryonic days 13.5-16.5 (E13.5-E16.5) when several critical events occur, including gonad determination, epigenetic reprogramming to replace most parent-of-origin molecular marks with those reflecting fetal sex, and meiotic arrest of PGCs in females and mitotic arrest in males (23)(24)(25)(26).Genetic variants that modify TGCT susceptibility provide insights into both the development of the PGC lineage and the regulation of TGCT pathogenesis (27,28). Studies of interactions between these modifier genes in mice reveal remarkable evidence for transgenerational genetic effects on TGCT risk (29).…”

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confidence: 99%

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Transgenerational epigenetic effects of theApobec1cytidine deaminase deficiency on testicular germ cell tumor susceptibility and embryonic viability

Nelson

Heaney

Tesar

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Environmental agents and genetic variants can induce heritable epigenetic changes that affect phenotypic variation and disease risk in many species. These transgenerational effects challenge conventional understanding about the modes and mechanisms of inheritance, but their molecular basis is poorly understood. The Deadend1 (Dnd1) gene enhances susceptibility to testicular germ cell tumors (TGCTs) in mice, in part by interacting epigenetically with other TGCT modifier genes in previous generations. Sequence homology to A1cf, the RNA-binding subunit of the ApoB editing complex, raises the possibility that the function of Dnd1 is related to Apobec1 activity as a cytidine deaminase. We conducted a series of experiments with a genetically engineered deficiency of Apobec1 on the TGCT-susceptible 129/Sv inbred background to determine whether dosage of Apobec1 modifies susceptibility, either alone or in combination with Dnd1, and either in a conventional or a transgenerational manner. In the paternal germ-lineage, Apobec1 deficiency significantly increased susceptibility among heterozygous but not wild-type male offspring, without subsequent transgenerational effects, showing that increased TGCT risk resulting from partial loss of Apobec1 function is inherited in a conventional manner. By contrast, partial deficiency in the maternal germ-lineage led to suppression of TGCTs in both partially and fully deficient males and significantly reduced TGCT risk in a transgenerational manner among wild-type offspring. These heritable epigenetic changes persisted for multiple generations and were fully reversed after consecutive crosses through the alternative germ-lineage. These results suggest that Apobec1 plays a central role in controlling TGCT susceptibility in both a conventional and a transgenerational manner.epigenetics | testicular cancer | gametogenesis | epistasis E stablishing the genetic basis and mode of inheritance for most traits and diseases has proven to be remarkably elusive (1). Susceptibility to testicular germ cell tumors (TGCTs) is illustrative (2). Testicular cancer is the most common malignancy affecting young men (3), more than 90% of testicular cancers result from TGCTs (4), TGCTs rank third in heritability among all cancers (5), and family history is the strongest known risk factor with a two-to sixfold increase among sons and a 5-to 19-fold increase among brothers of affected individuals (6-9). Despite the strong evidence for heritability, the only TGCT susceptibility factors identified in genome-wide association studies are the gr/gr deletion on the Y chromosome and autosomal variants in KITLG, SPRY4, BAK1, and DMRT1, which together account for less than 10% of risk (10-14). The substantial difference in prevalence between sons and brothers of cases and the epidemiological evidence for maternal estrogens, birth order, birth weight, and other factors (15-17) together raise the possibility that maternal conditions, epigenetic effects, and perhaps unconventional modes of inheritance also contribute to TG...

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“…Kitl, Dnd1, Stra8, Eif2s2, Apobec1, A1cf, Ago2, Trp53, and other mutations each influence the frequency of affected males by a factor of 52-3 when present in the heterozygous state. 45,46 In cases where homozygotes for these modifiers can be tested (i.e., where they do not result in embryonic lethality), exceptionally strong effects often emerge. For example, the Dnd1 Ter mutant allele increases TGCT penetrance from the baseline rate of $7% in wild-type 129/Sv males to 17% in Dnd1 Ter/þ heterozygotes and 94% in 49 demonstrating that the mutant allele modifies the likelihood of tumor development only in genetically predisposed individuals and is not simply a general driver of tumorigenesis.…”

Section: Modifiers Of Complex Traitsmentioning

confidence: 99%

From Peas to Disease: Modifier Genes, Network Resilience, and the Genetics of Health

Riordan

Nadeau

2017

The American Journal of Human Genetics

119

107

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Phenotypes are rarely consistent across genetic backgrounds and environments, but instead vary in many ways depending on allelic variants, unlinked genes, epigenetic factors, and environmental exposures. In the extreme, individuals carrying the same causal DNA sequence variant but on different backgrounds can be classified as having distinct conditions. Similarly, some individuals that carry disease alleles are nevertheless healthy despite affected family members in the same environment. These genetic background effects often result from the action of so-called ''modifier genes'' that modulate the phenotypic manifestation of target genes in an epistatic manner. While complicating the prospects for gene discovery and the feasibility of mechanistic studies, such effects are opportunities to gain a deeper understanding of gene interaction networks that provide organismal form and function as well as resilience to perturbation. Here, we review the principles of modifier genetics and assess progress in studies of modifier genes and their targets in both simple and complex traits. We propose that modifier effects emerge from gene interaction networks whose structure and function vary with genetic background and argue that these effects can be exploited as safe and effective ways to prevent, stabilize, and reverse disease and dysfunction.

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Mouse models of testicular germ cell tumors

Cited by 4 publications

References 162 publications

Contrasting effects of Deadend1 (Dnd1) gain and loss of function mutations on allelic inheritance, testicular cancer, and intestinal polyposis

Contrasting effects of Deadend1 (Dnd1) gain and loss of function mutations on allelic inheritance, testicular cancer, and intestinal polyposis

Transgenerational epigenetic effects of theApobec1cytidine deaminase deficiency on testicular germ cell tumor susceptibility and embryonic viability

From Peas to Disease: Modifier Genes, Network Resilience, and the Genetics of Health

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