Updating germ cell tumor pathogenesis - The ability of seminomas for FOXA2-driven extra-embryonic differentiation

Testicular germ cell tumors are the most common solid malignancies in young men of age 14 - 44 years. It is generally accepted that both, seminomas and non-seminomas, arise from a common precursor, the germ cell neoplasia in situ, which itself is the result of a defective (primordial) germ cell development. The stem cell-like population of the non-seminomas, the embryonal carcinoma, is capable of differentiation into cells all three germ layers (teratomas) and extra-embryonic tissues (yolk-sac tumors, choriocarcioma). In contrast, seminoma are thought to have a limited differentiation potential. Nevertheless, several studies pointed at their ability to undergo reprogramming to an embryonal carcinoma or differentiation into other non-seminomatous entities. Here, we demonstrate that in approximately 5 % of seminomas, the yolk-sac tumor driver gene FOXA2 is detectable on protein level, indicative of an occult yolk-sac tumor subpopulation that putatively arose from seminoma cells, since presence of other GCT entities could be excluded. Presence of these subpopulations might render the tumor more aggressive and argue for an adjustment of the therapeutic concept. We used our data to update the model of germ cell tumor pathogenesis, especially regarding the developmental potential of seminomas. Additionally, we suggest to include detection of FOXA2 into standard routine diagnosis of seminomas.