Integrated genomic analysis reveals aberrations in WNT signaling in germ cell tumors of childhood and adolescence.

Germ cell tumors (GCTs) are neoplasms of the testis, ovary and extragonadal sites that occur in infants, children, adolescents and adults. Post-pubertal (type II) malignant GCTs may present as seminoma, non-seminoma or mixed histologies. In contrast, pre-pubertal (type I) GCTs are limited to (benign) teratoma and (malignant) yolk sac tumor (YST). Epidemiologic and molecular data have shown that pre- and post-pubertal GCTs arise by distinct mechanisms. Dedicated studies of the genomic landscape of type I and II GCT in children and adolescents are lacking. Here we present an integrated genomic analysis of extracranial GCTs across the age spectrum from 0-24 years. Activation of the WNT pathway by somatic mutation, copy-number alteration, and differential promoter methylation is a prominent feature of GCTs in children, adolescents and young adults, and is associated with poor clinical outcomes. Significantly, we find that small molecule WNT inhibitors can suppress GCT cells both in vitro and in vivo. These results highlight the importance of WNT pathway signaling in GCTs across all ages and provide a foundation for future efforts to develop targeted therapies for these cancers.

Pediatric Germ Cell Tumors: A Developmental Perspective.

Germ cell tumors (GCTs) arising in infants, children, and adolescents present a set of special challenges. GCTs make up about 3% of malignancies in children aged 0-18 and nearly 15% of cancers in adolescents. Epidemiologic and molecular evidence suggests that GCTs in young children likely represent a distinct biologic group as compared to GCTs of older adolescents and adults. Despite this difference, pediatric GCTs are typically treated with cisplatin-based multiagent regimens similar to those used in adults. There is evidence that children are particularly vulnerable to late effects of conventional therapy, including ototoxicity, pulmonary abnormalities, and secondary malignancies, motivating the search for molecular targets for novel therapies. Evidence is accumulating that the genes and mechanisms controlling normal germ cell development are particularly relevant to the understanding of germ cell tumorigenesis. Perturbations in the epigenetic program of germ cell differentiation, with resulting effects on the regulation of pluripotency, may contribute to the marked histologic variability of GCTs. Perturbations in the KIT receptor signaling pathway have been identified via next-generation sequencing studies and in genome-wide association studies of testicular cancer susceptibility. Here, we review these and other biological insights that may fuel further translational and clinical research in childhood GCTs.