Researchers have performed a comprehensive genetic analysis and identified potential drug targets for paediatric germ cell tumours (GCTs).
Germ cell tumours
GCTs are relatively rare in paediatric patients. The incidence rates are 5.3 and 4.4 per million in girls and boys, respectively. Typically, GCTs exhibit a bimodal age distribution, with two peaks in infancy and young adolescence. The survival rate of patients is high (>90%). In some cases, however, GCTs are refractory to treatment. As a result, novel approaches are required for chemotherapy-resistant GCTs. In addition, as many survivors suffer late complication induced by cytotoxic agents, the development of new targeted therapies may be more appropriate.
GCTs develop from primordial germ cells (PGCs), which develop in the embryonic yolk sac. As PGCs migrate to the gonads, they undergo DNA methylation erasure. Key pathways involved include KIT and CXCR4. After migration, PGCs re-establish their DNA methylation and differentiate into sperm or egg. Migrating PGCs are chromosomally unstable. While some aberrated PGCs are removed via apoptosis, a minority of these cells can survive and give rise to GCTs.
Comprehensive genetic analysis
In a study, published in Communications Biology, researchers profile genetic and epigenetic characteristics of each subtype of paediatric GCTs. Specifically, the team analysed 51 GCT samples (25 female and 26 male), including 6 germinomas, 2 embryonal carcinomas, 4 immature teratomas, 3 mature teratomas, 30 yolk sac tumours and 6 mixed germ cell tumours.
The team found that germinomas showed upregulation of pluripotent genes and global hypomethylation. Additionally, pluripotent genes were also highly expressed in embryonal carcinomas. Endodermal genes, such as GATA6 and FOXA2, were overexpressed in yolk sac tumours. The binding sites of these genes were hypomethylated. Interestingly, the team found that yolk sac tumours in infants and older children expressed different DNA methylation patterns. They also found that teratomas had a higher expression of ectodermal genes.
These results demonstrate that paediatric GCTs have characteristic genomic aberrations based on their developmental processes. The team suggest that KIT, TNFRSF8 and ERBB4 may be suitable targets for the treatment of germinomas, embryonal carcinomas and yolk sac tumours, respectively. They emphasise that molecular targets detected via genomic/epigenomic analyses may provide promising therapeutic options for refractory GCTs. They believe that their findings warrant further analysis to confirm efficacy of targeted molecular agents.
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