Scientific Publications

Genome Sequencing of SHH Medulloblastoma Predicts Genotype-Related Response to Smoothened Inhibition.

Publication TypeJournal Article
AuthorsKool, M., Jones DT, Jäger N., Northcott PA, Pugh TJ, Hovestadt V., Piro RM, Esparza LA, Markant SL, Remke M., Milde T., Bourdeaut F., Ryzhova M., Sturm D., Pfaff E., Stark S., Hutter S., Seker-Cin H., Johann P., Bender S., Schmidt C., Rausch T., Shih D., Reimand J., Sieber L., Wittmann A., Linke L., Witt H., Weber UD, Zapatka M., König R., Beroukhim R., Bergthold G., van Sluis P., Volckmann R., Koster J., Versteeg R., Schmidt S., Wolf S., Lawerenz C., Bartholomae CC, von Kalle C., Unterberg A., Herold-Mende C., Hofer S., Kulozik AE, von Deimling A., Scheurlen W., Felsberg J., Reifenberger G., Hasselblatt M., Crawford JR, Grant GA, Jabado N., Perry A., Cowdrey C., Croul S., Zadeh G., Korbel JO, Doz F., Delattre O., Bader GD, McCabe MG, Collins VP, Kieran MW, Cho YJ, Pomeroy SL, Witt O., Brors B., Taylor MD, Schüller U., Korshunov A., Eils R., Wechsler-Reya RJ, Lichter P., Pfister SM, and ICGC PedBrain Tumor Project
AbstractSmoothened (SMO) inhibitors recently entered clinical trials for sonic-hedgehog-driven medulloblastoma (SHH-MB). Clinical response is highly variable. To understand the mechanism(s) of primary resistance and identify pathways cooperating with aberrant SHH signaling, we sequenced and profiled a large cohort of SHH-MBs (n = 133). SHH pathway mutations involved PTCH1 (across all age groups), SUFU (infants, including germline), and SMO (adults). Children >3 years old harbored an excess of downstream MYCN and GLI2 amplifications and frequent TP53 mutations, often in the germline, all of which were rare in infants and adults. Functional assays in different SHH-MB xenograft models demonstrated that SHH-MBs harboring a PTCH1 mutation were responsive to SMO inhibition, whereas tumors harboring an SUFU mutation or MYCN amplification were primarily resistant.
Year of Publication2014
JournalCancer cell
Date Published (YYYY/MM/DD)2014/03/17
ISSN Number1535-6108