Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition.

Journal Article (Journal Article)

Smoothened (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.

Full Text

Duke Authors

Cited Authors

  • Kool, M; Jones, DTW; 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, Y-J; Pomeroy, SL; Witt, O; Brors, B; Taylor, MD; Schüller, U; Korshunov, A; Eils, R; Wechsler-Reya, RJ; Lichter, P; Pfister, SM; ICGC PedBrain Tumor Project,

Published Date

  • March 17, 2014

Published In

Volume / Issue

  • 25 / 3

Start / End Page

  • 393 - 405

PubMed ID

  • 24651015

Pubmed Central ID

  • PMC4493053

Electronic International Standard Serial Number (EISSN)

  • 1878-3686

Digital Object Identifier (DOI)

  • 10.1016/j.ccr.2014.02.004


  • eng

Conference Location

  • United States