Differential developmental expression of transcription factors GATA-4 and GATA-6, their cofactor FOG-2 and downstream target genes in testicular carcinoma in situ and germ cell tumors

Abstract

Objective: Testicular germ cell cancer is the most common malignancy among young males. The preinvasive precursor, carcinoma in situ testis (CIS), presumably originates from arrested and transformed fetal gonocytes. Given that GATA transcription factors have essential roles in embryonic and testicular development, we explored the expression of GATA-4, GATA-6, cofactor friend of GATA (FOG)-2, and downstream target genes during human testis development and addressed the question whether changes in this pathway may contribute to germ cell neoplasms. Methods: Fetal testis, testicular CIS, and overt tumor samples were analyzed by immunohistochemistry for GATA-4, GATA-6, FOG-2, steroidogenic factor 1 (NR5A1/SF1), anti-Mü llerian hormone/Mü llerianinhibiting substance (AMH), and inhibin-a (INHa). Results: GATA-4 was not expressed in normal germ cells, except for a subset of gonocytes at the 15th gestational week. The CIS cells expressed GATA-4 and GATA-6 heterogeneously, whereas most of the CIS cells expressed GATA-4 cofactor FOG-2. GATA target gene SF-1 was expressed heterogeneously in CIS cells, whereas INHa and AMH were mostly negative. Seminomas and yolk sac tumors were positive for GATA-4 and GATA-6, but mostly negative for FOG-2 and the GATA target genes. In contrast, pluripotent embryonal carcinomas and choriocarcinomas were GATA-4 and GATA-6 negative. Conclusions: Differential expression of the GATA-4 target genes suggested cell-specific functions of GATA-4 in the germ and somatic cells. The GATA-4 expression in early fetal gonocytes, CIS, and seminoma cells but the absence in more mature germ cells is consistent with the early fetal origin of CIS cells and suggests that GATA-4 is involved in early germ cell differentiation.

Recent Advances in Understanding the Etiology and Pathogenesis of Pediatric Germ Cell Tumors

“…For study marked with *there is no distinction of the childhood tumors into histologic subtypes, and DG/SEM/GER and YST are rated collectively. 5,[23][24][25][26][27][28][29]33,37,38,40,[42][43][44][45][46][47][48][49]51,54 DG indicates dysgerminoma; GER, germinoma; IHC, immunohistochemistry; IT, immature teratoma; MT, mature teratoma; SEM, seminoma; SNP, single nucleotide polymorphism; YST, yolk sac tumor.…”

“…In tumor cells the varying expression of GATA4 in differentiated and nondifferentiated (pluripotent) tumor cells may be explained by cell-specific function in germ cells and somatic cells. 38 After many years of studying expression of genes oneby-one at the protein level, the advent of high throughput array methods allowed genome-wide evaluation of entire transcriptome. Several such studies have been performed in adolescent and adult GCTs (reviewed in Alagaratnam et al 2011 39 ).…”

Molecular Characteristics of Malignant Ovarian Germ Cell Tumors and Comparison With Testicular Counterparts: Implications for Pathogenesis

“…For example, the DGs express GATA4 but not GATA6 (285), whereas seminoma express both (313). Another example is KIT mutation, reported in around 30% of both DG and seminoma analyzed (55, 156, 177).…”

GATA6 (GATA binding protein 6)

“…Using in situ hybridization and immunohistochemical staining, GATA6 was evaluated in pediatric germ cell tumors and was found to be expressed in a majority of yolk sac tumors. GATA6 expression was also evident in distinct cell types comprising teratomas, including gut and airway epithelia (Siltanen et al, 2003), but was variable in carcinoma in situ of the testis and absent from embryonal carcinomas and choriocarcinomas (Salonen et al, 2010). Prognosis The prognostic role of GATA6 in germ cell tumors is unknown.…”