Wu, G., Diaz, A.K., Paugh, B.S., Rankin, S.L., Ju, B., Li, Y., Zhu, X., Qu, C., Chen, X., Zhang, J., Easton, J., Edmonson, M., Ma, X., Lu, C., Nagahawatte, P., Hedlund, E., Rusch, M., Pounds, S., Lin, T., Onar-Thomas, A., Huether, R., Kriwacki, R., Parker, M., Gupta, P., Becksfort, J., Wei, L., Mulder, H.L., Boggs, K., Vadodaria, B., Yergeau, D., Russell, J.C., Ochoa, K., Fulton, R.S., Fulton, L.L., Jones, C., Boop, F.A., Broniscer, A., Wetmore, C., Gajjar, A., Ding, L., Mardis, E.R., Wilson, R.K., Taylor, M.R., Downing, J.R., Ellison, D.W., Zhang, J., Baker, S.J. (2014) The genomic landscape of diffuse intrinsic pontine glioma and pediatric non-brainstem high-grade glioma. Nature Genetics. 46:444-50.
Pediatric high-grade glioma (HGG) is a devastating disease with a less than 20% survival rate 2 years after diagnosis. We analyzed 127 pediatric HGGs, including diffuse intrinsic pontine gliomas (DIPGs) and non-brainstem HGGs (NBS-HGGs), by whole-genome, whole-exome and/or transcriptome sequencing. We identified recurrent somatic mutations in ACVR1 exclusively in DIPGs (32%), in addition to previously reported frequent somatic mutations in histone H3 genes, TP53 and ATRX, in both DIPGs and NBS-HGGs. Structural variants generating fusion genes were found in 47% of DIPGs and NBS-HGGs, with recurrent fusions involving the neurotrophin receptor genes NTRK1, NTRK2 and NTRK3 in 40% of NBS-HGGs in infants. Mutations targeting receptor tyrosine kinase-RAS-PI3K signaling, histone modification or chromatin remodeling, and cell cycle regulation were found in 68%, 73% and 59% of pediatric HGGs, respectively, including in DIPGs and NBS-HGGs. This comprehensive analysis provides insights into the unique and shared pathways driving pediatric HGG within and outside the brainstem.