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.
Highlights
Germ cell tumors (GCT) are a rare and complex group of heterogenous neoplasms that comprise both benign and malignant histologies [1]
Many epidemiologic and clinical differences exist between GCTs arising in adulthood and those arising in childhood, with tumors in adolescents showing a degree of overlap with GCTs in both age groups [1]
Our data indicate that the key discriminating factor between malignant GCTs arising across the pediatric age range, irrespective of the site of origin, is the histologic diagnosis
Summary
Germ cell tumors (GCT) are a rare and complex group of heterogenous neoplasms that comprise both benign and malignant histologies [1] Despite their heterogeneity, they are all presumed to arise from totipotent primordial germ cells (PGC). Many epidemiologic and clinical differences exist between GCTs arising in adulthood and those arising in childhood (defined in United Kingdom as 0–16 years of age), with tumors in adolescents showing a degree of overlap with GCTs in both age groups [1]. Because of these differences, GCTs of identical histology are treated differently depending on patient age and country of residence. It is essential to obtain a greater understanding of the biology of pediatric malignant GCTs, not least so that children can be given the most appropriate treatment
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