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 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 the FGFR3 mutation increases with paternal age, with a similar mutation spectrum at the K650 codon to that 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.

Schwerd et al. report a novel homozygous missense substitution in the cytokine co-receptor GP130 encoded by IL6ST. This is associated with defective IL-6, IL-11, OSM, and IL-27 signaling and causes immunodeficiency and skeletal abnormalities with similarities to STAT3 hyper-IgE syndrome.

The RAS proto-oncogene Harvey rat sarcoma viral oncogene homolog (HRAS) encodes a small GTPase that transduces signals from cell surface receptors to intracellular effectors to control cellular behavior. Although somatic HRAS mutations have been described in many cancers, germline mutations cause Costello syndrome (CS), a congenital disorder associated with predisposition to malignancy. Based on the epidemiology of CS and the occurrence of HRAS mutations in spermatocytic seminoma, we proposed that activating HRAS mutations become enriched in sperm through a process akin to tumorigenesis, termed selfish spermatogonial selection. To test this hypothesis, we quantified the levels, in blood and sperm samples, of HRAS mutations at the p.G12 codon and compared the results to changes at the p.A11 codon, at which activating mutations do not occur. The data strongly support the role of selection in determining HRAS mutation levels in sperm, and hence the occurrence of CS, but we also found differences from the mutation pattern in tumorigenesis. First, the relative prevalence of mutations in sperm correlates weakly with their in vitro activating properties and occurrence in cancers. Second, specific tandem base substitutions (predominantly GC>TT/AA) occur in sperm but not in cancers; genomewide analysis showed that this same mutation is also overrepresented in constitutional pathogenic and polymorphic variants, suggesting a heightened vulnerability to these mutations in the germline. We developed a statistical model to show how both intrinsic mutation rate and selfish selection contribute to the mutational burden borne by the paternal germline.paternal age effect | male mutation bias | RASopathy | testis