DE NOVO POINT MUTATIONS and Copy Number Variations CNVs

Monday, October 26, 2009

Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors

Letter abstract
Nature Genetics Published online: 25 October 2009 doi:10.1038/ng.470
Activating mutations in FGFR3 and HRAS reveal a shared genetic origin for congenital disorders and testicular tumors
Anne Goriely1, Ruth M S Hansen1, Indira B Taylor1, Inge A Olesen2, Grete Krag Jacobsen3, Simon J McGowan4, Susanne P Pfeifer5, Gilean A T McVean5, Ewa Rajpert-De Meyts2 & Andrew O M Wilkie1
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.Top of page
Weatherall Institute of Molecular Medicine, University of Oxford, John Radcliffe Hospital, Oxford, UK.
Department of Growth & Reproduction, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
Department of Pathology, Copenhagen University Hospital (Rigshospitalet), Copenhagen, Denmark.
Computational Biology Research Group, Oxford, UK.
Department of Statistics, University of Oxford, Oxford, UK.
Correspondence to: Andrew O M Wilkie1 e-mail: awilkie@hammer.imm.ox.ac.uk

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