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

Abstract

Yolk‐sac tumours (YSTs), a germ cell tumour subtype, occur in newborns and infants as well as in young adults of age 14‐44 years. In clinics, adult patients with YSTs face a poor prognosis, as these tumours are often therapy‐resistant and count for many germ cell tumour 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‐analysing high‐throughput data of gene and microRNA expression, DNA methylation and mutational burden. We validated our findings by qRT‐PCR and immunohistochemical analyses of paediatric and adult YSTs. On a molecular level, paediatric and adult YSTs were nearly indistinguishable, but were considerably different from embryonal carcinomas, the stem cell precursor of YSTs. We identified FOXA2 as a putative key driver of YST formation, subsequently inducing AFP , GPC3 , APOA1/APOB , ALB and GATA3/4/6 expression. In YSTs, WNT‐, BMP‐ and MAPK signalling‐related genes were up‐regulated, while pluripotency‐ and (primordial) germ cell‐associated genes were down‐regulated. Expression of FOXA2 and related key factors seems to be regulated by DNA methylation, histone methylation / acetylation and microRNAs. Additionally, our results highlight FOXA2 as a promising new biomarker for paediatric and adult YSTs.

Primary mediastinal germ cell tumours: an immunohistochemical and molecular diagnostic approach

“…The aim of this study was to provide a diagnostic algorithm for PMGCTs 21 with the careful use of immunohistochemical markers in small biopsy samples, and to focus on emerging markers such as Lin‐28 homologue A (LIN28), sex‐determining region Y‐box 2 (SOX2), sex‐determining region Y‐box 17 (SOX17), and forkhead box protein A2 (FOXA2) 22–24 . Our results contribute to the hitherto sparse PMGCT immunohistochemical studies 11,25,26 .…”

“…In OCT3/4‐negative tumours, staining for FOXA2, GPC3 and AFP can confirm YST, and β‐hCG staining combined with GATA3 staining can confirm CC. FOXA2 is a recently described marker that is extremely useful and highly specific for the detection of small YST components 22 . Mature TERs can be usually diagnosed on the basis of their typical morphology.…”

“…Therefore, FOXA2 and GPC3 are more sensitive and specific markers for YST than AFP. Recently, FOXA2 expression in YST cell lines and strong nuclear staining in YST tissue specimens have demonstrated that it is a reliable marker protein 22 . Furthermore, FOXA2 is more specific for distinguishing YST from CC, because CC can be positive for GPC3, and its nuclear staining is easier to identify than cytoplasmic staining for GPC3 54 .…”

“…FOXA2 is a recently described marker that is extremely useful and highly specific for the detection of small YST components. 22 Mature TERs can be usually diagnosed on the basis of their typical morphology. In difficult cases, e.g.…”

Targeting CLDN6 in germ cell tumors by an antibody-drug-conjugate and studying therapy resistance of yolk-sac tumors to identify and screen specific therapeutic options

“…With regard to molecular profiling of YST, we previously observed high molecular similarities between YST and hepatocytes as well as hepatocellular carcinomas (HCC) regarding expression of endodermal factors like FOXA2 , SOX17 , APOA1 / A2 / B , ALB, FGA / B / G, and GATA3 / 4 / 6 (Ang et al 2018 ; D’Amour et al 2005 ; Wruck et al 2021 ). Additionally, we found similarities in signaling pathway activities when comparing YST and HCC (enhanced WNT and BMP signalling) (Ang et al 2018 ; D’Amour et al 2005 ; Wruck et al 2021 ). Based on these observations, we hypothesized that drugs used to treat HCC might also be suitable for the treatment of YST and, thus, screened drugs already in use or in clinical trials in the field of HCC therapy.…”