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
Source: PubMed


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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    • "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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    • "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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