Goriely, A. et al. Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors. Nature Genet. 41, 1247-1252

Nature Genetics (Impact Factor: 29.35). 11/2009; 41(11):1247-52. DOI: 10.1038/ng.470
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Genes mutated in congenital malformation syndromes are frequently implicated in oncogenesis, but the causative germline and somatic mutations occur in separate cells at different times of an organism's life. Here we unify these processes to a single cellular event for mutations arising in male germ cells that show a paternal age effect. Screening of 30 spermatocytic seminomas for oncogenic mutations in 17 genes identified 2 mutations in FGFR3 (both 1948A>G, encoding K650E, which causes thanatophoric dysplasia in the germline) and 5 mutations in HRAS. Massively parallel sequencing of sperm DNA showed that levels of the FGFR3 mutation increase with paternal age and that the mutation spectrum at the Lys650 codon is similar to that observed in bladder cancer. Most spermatocytic seminomas show increased immunoreactivity for FGFR3 and/or HRAS. We propose that paternal age-effect mutations activate a common 'selfish' pathway supporting proliferation in the testis, leading to diverse phenotypes in the next generation including fetal lethality, congenital syndromes and cancer predisposition.

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    • "In addition, expression of Cyclin D2 (CCND2) is detectable in CIS cells and various TGCTs but undetectable in human male germ cells during normal conditions (Houldsworth, Reuter, Bosl, & Chaganti, 1997). Furthermore, the Ras oncogene family (H-Ras, K-Ras, and N-Ras) is often mutated in human TGCTs including spermatocytic seminomas (Goriely et al., 2009; Moul, Theune, & Chang, 1992). Lastly, expression of the cell cycle repressor PTEN is not detectable in teratomas, 56% of seminomas, and 86% of embryonal carcinomas (Andreassen et al., 2013; Di Vizio et al., 2005). "
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    ABSTRACT: Sperm have a vital role in the continuity of a species by contributing genetic information to the next generation. Production of these specialized gametes in numbers sufficient to confer normal fertility occurs via cycling of the spermatogenic lineage, a process referred to as spermatogenesis. Continuity relies on the activities of a self-renewing reservoir of spermatogonial stem cells (SSCs) from which progenitors will arise that transiently amplify in number before committing to a pathway of terminal differentiation. A primary population of SSCs is established during neonatal development from a pool of quiescent gonocyte precursors that forms in embryogenesis. Disruption of this process has dire consequences on maintenance of a cycling spermatogenic lineage in adulthood. At present, the molecular mechanisms underlying initial formation of the SSC pool are largely undefined. However, several transcription factors and posttranscriptional regulators have been identified as important regulators of SSC self-renewal from studies with mutant mouse models and experimental manipulation within primary cultures of mouse SSCs. Importantly, loss of function of these self-renewal factors may be underlying causes of infertility. Furthermore, disruption in the establishment of the SSC state within gonocytes or misregulation of self-renewal may manifest as testicular germ cell tumors in postnatal life.
    Current Topics in Developmental Biology 01/2014; 107C:235-267. DOI:10.1016/B978-0-12-416022-4.00009-3 · 4.68 Impact Factor
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    • "In contrast to wild-type SrAp, the mutant SrAp occasionally produce extra stem-cell lineages leading to the clonal expansion and a relative enrichment of mutant SrAp in local areas within the testis, thereby explaining the formation of mutation clusters and high mutation frequencies with ageing (19–21). The selective advantage is likely the result of changes in the growth factor receptor-RAS and related signaling pathways caused by the mutant protein (19,21,25). "
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    ABSTRACT: There are certain de novo germline mutations associated with genetic disorders whose mutation rates per generation are orders of magnitude higher than the genome average. Moreover, these mutations occur exclusively in the male germ line and older men have a higher probability of having an affected child than younger ones, known as the paternal age-effect. The classic example of a genetic disorder exhibiting a PAE is achondroplasia, caused predominantly by a single nucleotide substitution (c.1138G>A) in FGFR3. To elucidate what mechanisms might be driving the high frequency of this mutation in the male germline, we examined the spatial distribution of the c.1138G>A substitution in a testis from an 80-year old unaffected man. Using a technology based on bead-emulsion amplification, we were able to measure mutation frequencies in 192 individual pieces of the dissected testis with a false positive rate lower than 2.7x10(-6). We observed that most mutations are clustered in a few pieces with 95% of all mutations occurring in 27% of the total testis. Using computational simulations, we rejected the model proposing an elevated mutation rate per cell division at this nucleotide site. Instead we determined that the observed mutation distribution fits a germline selection model, where mutant spermatogonial stem cells have a proliferative advantage over unmutated cells. Combined with data on several other PAE mutations, our results support the idea that the PAE, associated with a number of Mendelian disorders, may be explained primarily by a selective mechanism.
    Human Molecular Genetics 06/2013; 22(20). DOI:10.1093/hmg/ddt260 · 6.39 Impact Factor
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    • "Changes in the expression of somatic factors in cryptorchid testes in humans have been detected using whole genome studies as previously mentioned, and interestingly, many of these differentially expressed genes such as NY-ESO, FGFR3, UTF1, and DSG2 are aberrantly expressed in seminomas (Waheeb and Hofmann, 2011). One study found that ERK1/2 – an intermediate of the GDNF pathway that leads to activation of FOS and other target genes, was increasingly phosphorylated in more than half of 26 seminomas potentially altering expression of downstream targets of the RAS/ERK1/2 pathway including FOS and ATF (Goriely et al., 2009). Taken in conjunction with the finding that GDNF overexpression in mice leads to the formation of seminomas in advanced age, it is conceivable to suggest that changes in somatic cells in the testis can lead to the deregulation of the SSC somatic niche (Clark, 2007; Kristensen et al., 2008). "
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    ABSTRACT: The failure of testicular descent or cryptorchidism is the most common defect in newborn boys. The descent of the testes during development is controlled by insulin-like 3 peptide and steroid hormones produced in testicular Leydig cells, as well as by various genetic and developmental factors. While in some cases the association with genetic abnormalities and environmental causes has been shown, the etiology of cryptorchidism remains uncertain. Cryptorchidism is an established risk factor for infertility and testicular germ cell tumors (TGCT). Experimental animal models suggest a causative role for an abnormal testicular position on the disruption of spermatogenesis however the link between cryptorchidism and TGCT is less clear. The most common type of TGCT in cryptorchid testes is seminoma, believed to be derived from pluripotent prenatal germ cells. Recent studies have shown that seminoma cells and their precursor carcinoma in situ cells express a number of spermatogonial stem cell (SSC) markers suggesting that TGCTs might originate from adult stem cells. We review here the data on changes in the SSC somatic cell niche observed in cryptorchid testes of mouse models and in human patients. We propose that the misregulation of growth factors' expression may alter the balance between SSC self-renewal and differentiation and shift stem cells toward neoplastic transformation.
    Frontiers in Endocrinology 03/2013; 4:32. DOI:10.3389/fendo.2013.00032
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