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Pediatric Malignant Germ Cell Tumors Show Characteristic Transcriptome Profiles

¹ MRC Cancer Cell Unit, Hutchison/MRC Research Center; ² Department of Paediatric Oncology, Addenbrooke's Hospital; ³ Computational Biology Group, Department of Oncology, University of Cambridge, Cambridge Research Institute, Cambridge, United Kingdom; ⁴ Department of Pathology, Institute of Clinical Science, Royal Group of Hospitals, Belfast, United Kingdom; and ⁵ Clinic of Pediatrics, Dortmund, Germany

Requests for reprints: Roger D. Palmer, MRC Cancer Cell Unit, Hutchison/MRC Research Center, Box 197, Hills Road, Cambridge, CB2 0XZ, United Kingdom. Phone: 44-1223-763279; Fax: 44-1223-763284; E-mail: rdp{at}hutchison-mrc.cam.ac.uk.

Key Words: germ cell tumor • yolk sac • seminoma • child • gene expression • pathway analysis

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. [Cancer Res 2008;68(11):4239–47]