The pioneer and differentiation factor FOXA2 is a key driver of yolk-sac tumour formation and a new biomarker for paediatric and adult yolk-sac tumours.pdf

Yolk-sac tumors (YSTs), a testis cancer subtype, occurs in newborns and infants as well as in young adults of age 14 - 44 years.<b> </b>In clinics, adult patients with YSTs face a poor prognosis, since these tumors are often therapy-resistant and count for the majority of GCT related deaths. So far, the molecular and (epi)genetic mechanisms that control development of YST are far from being understood. We deciphered the molecular and (epi)genetic mechanisms regulating YST formation by meta-analyzing high-throughput data of gene and microRNA expression, DNA methylation, and mutational burden. We validated our findings by qRT-PCR and immunohistochemical analyses of pediatric and adult YSTs.On a molecular level, pediatric and adult YSTs were nearly indistinguishable, but were considerably different from embryonal carcinomas, the stem cell precursor of YSTs. We identified <i>FOXA2</i> as a putative key driver of YST formation, subsequently inducing <i>AFP</i>, <i>GPC3</i>, <i>APOA1/APOB</i>, <i>ALB</i> and <i>GATA3/4/6 </i>expression. In YSTs, WNT-, BMP- and MAPK-signaling-related genes were upregulated, while pluripotency- and germ cell-associated genes were downregulated. Expression of these key factors might be regulated by DNA methylation or microRNAs. Additionally, our results highlight FOXA2 as a promising new biomarker for pediatric and adult YSTs.