Pediatric Malignant Germ Cell Tumors Show Characteristic Transcriptome Profiles

Abstract

Malignant germ cell tumors (GCT) of childhood are rare and heterogeneous neoplasms thought to arise from primordial germ cells. They vary substantially in their natural history and show important clinical differences from their adult counterparts. To address the biological basis for these observations, we have undertaken a comprehensive analysis of global gene expression patterns in pediatric malignant GCTs and compared these findings with published data on adult testicular GCTs (TGCT). Our study included 27 primary tumors and assessed the principal malignant histologic types of pediatric GCT, yolk sac tumor (YST; n = 18), and seminoma (n = 9). Analysis of Affymetrix U133A GeneChip data was performed using the statistical software environment R, including gene set enrichment analysis, with cross-validation at the RNA and protein level. Unsupervised analysis showed complete separation of YSTs and seminomas by global gene expression profiles and identified a robust set of 657 discriminatory transcripts. There was no segregation of tumors of the same histology arising at different sites or at different ages within the pediatric range. In contrast, there was segregation of pediatric malignant GCTs and adult malignant TGCTs, most notably for the YSTs. The pediatric seminomas were significantly enriched for genes associated with the self-renewing pluripotent phenotype, whereas the pediatric YSTs were significantly enriched for genes associated with a differentiation and proliferation phenotype. We conclude that histologic type is the key discriminator in pediatric malignant GCTs and that the observed clinical differences between malignant GCTs of children and adults are mirrored by significant differences in global gene expression.

Mutation in the type IB bone morphogenetic protein receptor alk6b impairs germ-cell differentiation and causes germ-cell tumors in zebrafish

“…For these reasons, alternative therapies for GCT are needed. In a recent analysis of childhood GCTs, expression of BMP2 and BMP4 was associated with differentiation state of the tumors (43). Together with our demonstration that BMP signaling directly mediates differentiation of germ cells in vivo, these results suggest that exploration of the BMP pathway and its effects on differentiation of GCTs may provide an alternative route to therapy of GCTs.…”

DNA methylation in germ cell tumour aetiology: current understanding and outstanding questions

“…Like the consistent cytogenetic abnormalities described earlier, this contrasts the separation of infantile and YSTs from older children as proposed by others (Veltman et al 2003, Oosterhuis & Looijenga 2005. Whether the differential gene expression profiles observed between paediatric and adult GCTs, particularly in YSTs, can be explained by DNA methylation changes remains to be determined (Palmer et al 2008, Jeyapalan et al 2011.…”

“…Increased expression of DNMT3B has been reported in EC cell lines compared with cell lines derived from other somatic cancers (Beyrouthy et al 2009) and in paediatric YSTs compared with seminomatous tumours (Palmer et al 2008, Jeyapalan et al 2011. A number of genes preferentially methylated in YSTs were found to be targets for DNMT3B consistent with a role for this enzyme in establishing the methylator phenotype of GCTs (Jeyapalan et al 2011).…”

“…Gene expression analysis has suggested that childhood GCTs may have different expression profiles compared to their adult counterparts; the separation was especially striking between adult and paediatric YSTs (Palmer et al 2008). However, this difference was identified by comparing data from different published studies and so would be subject to the potential for batch effect variation (nonbiological experimental variation to which array-based experiments are very vulnerable (Johnson et al 2007)).…”

Age‐related biological features of germ cell tumors

“…Seminomas (or germinomas, collectively referring to testicular seminomas, ovarian dysgerminomas and extragonadal germinomas) are composed of uniform sheets of tumour cells that resemble undifferentiated PGCs. By contrast, nonseminomas exhibit varying degrees of differentiation that resemble particular cell lineages or stages of embryonic development and include teratomas, embryonal carcinomas (ECs), yolk sac tumours (YSTs) and choriocarcinomas (CHCs) (Palmer et al, 2008). In addition to these, mixed malignant GCTs also exist which are composed of more than one histological subtype.…”