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

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 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.

Epigenetic modifications and self-renewal regulation of mouse germline stem cells

“…They also showed increased expression of CD44, a cancer stem cell antigen [53]. Importantly, our results in mice were very recently confirmed in human studies, where activating mutations in H-Ras were found in human germ cell tumors [54]. In addition, cyclin D2 is known to be expressed at very early stages of human GCTs.…”

Missing heritability: paternal age effect mutations and selfish spermatogonia

“…The best-characterized PAE mutations encode mutant proteins with gain-of-function properties and share other distinctive features: near-exclusive paternal origin, high apparent germline mutation rate (up to 1,000-fold above background), and elevated paternal age (by 2-5 years, compared to the population average). Well-documented examples are in the fibroblast growth factor receptor 2 (FGFR2), FGFR3, RET, protein tyrosine phosphatase, non-receptor type 11 (PTPN11) and HRAS genes, heterozygous substitutions of which cause congenital skeletal disorders, sometimes with additional predisposition to cancer 4 .…”

“…1). This clonal growth, which is likely to take place in the testes of all men, leads to the relative enrichment of mutant sperm over time -accounting for the distinctive paternal age effect of these mutations -and in extreme cases, to the formation of testicular tumours 4 .…”

“…All well-established PAE mutations activate one pathway, involving growth factor receptor-RAS signalling 4,7 . This is likely to reflect a crucial role of this pathway in controlling the fate choice (self-renewal versus differentiation to produce mature sperm) of spermatogonial cells; additional pathways involved in the proliferation and survival of spermatogonia might also be vulnerable to such 'selfish' mutations.…”

“…Direct measurements [4][5][6] in normal sperm and testes are laborious, and segregation of normal and mutant alleles in sperm of heterozygotes for PAE mutations is not expected to deviate from 50:50. Recently, the first direct study of new mutations in the human germ line, obtained by whole-genome sequencing Figure 1 | Illustrative depiction of how enrichment of functionally significant paternal age effect mutations could occur.…”