Abstract
Genes mutated in congenital malformation syndromes are frequently implicated in oncogenesis1,2, 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 effect3. Screening of 30 spermatocytic seminomas4,5 for oncogenic mutations in 17 genes identified 2 mutations in FGFR3 (both 1948A>G, encoding K650E, which causes thanatophoric dysplasia in the germline)6 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 cancer7,8. 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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Acknowledgements
We thank the Oxford Fertility Clinic and anonymous sperm donors for help with obtaining samples; L. Andersen, T. Chin-A-Woeng, K. Clark, K. Cook, A. Fenwick, A. Herlihy, H. Kistrup, J. Lim, J.-E. Nielsen, L. Thompson and N. Ward for expert technical support and advice; associates of the Rajpert-De Meyts and Wilkie labs for discussions; staff in numerous pathology departments in Denmark and Lund (Sweden), and G. Turner and I. Roberts, for histopathological support and samples; L. Legeai-Mallet for providing control genomic samples; G. Spagnoli for the MAGE-A4 antibody; M. de Gobbi for information on TaqMan primers for DNA quantification; and S. Robertson for comments on the manuscript. This work was funded by the Danish Cancer Society (DP08147 to E.R.-D.M.) and the Wellcome Trust (078666 to A.O.M.W.).
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A.G. designed and performed experiments, analyzed data and wrote the paper; R.M.S.H., I.B.T. and I.A.O. performed experiments; G.K.J. collected tumor samples and constructed tissue arrays; S.J.M., S.P.P. and G.A.T.M. developed analytical tools and analyzed data; E.R.-D.M. collected tumor samples, designed and performed experiments; A.O.M.W. designed experiments, analyzed data and wrote the paper.
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Supplementary Note, Supplementary Figures 1 and 2 and Supplementary Tables 1, 3, 5 and 6 (PDF 1989 kb)
Supplementary Table 2
Results of immunohistochemical staining, mutation screening and SNP genotyping in 30 spermatocytic seminomas (SS). (XLS 6152 kb)
Supplementary Table 4
Mutation levels of the 9 possible substitutions at FGFR3 K650 codon (AAG) in sperm and blood samples, estimated by massively parallel sequencing. (XLS 83 kb)
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Goriely, A., Hansen, R., Taylor, I. et al. Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors. Nat Genet 41, 1247–1252 (2009). https://doi.org/10.1038/ng.470
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DOI: https://doi.org/10.1038/ng.470
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