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

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• 作者：Marcel Kool¹ ; ^{m.kool@dkfz.de" class="auth_mail} ; David T.W. Jones¹ ; Natalie Jä ; ger² ; Paul A. Northcott¹ ; Trevor J. Pugh³ ; Volker Hovestadt⁴ ; Rosario M. Piro² ; L. Adriana Esparza⁵ ; Shirley L. Markant⁵ ; Marc Remke⁶ ; Till Milde⁷ ; Franck Bourdeaut⁸ ; ⁹ ; Marina Ryzhova¹⁰ ; Dominik Sturm¹ ; Elke Pfaff¹ ; Sebastian Stark¹ ; Sonja Hutter¹ ; Huriye 艦eker-Cin¹ ; Pascal Johann¹ ; Sebastian Bender¹ ; Christin Schmidt¹ ; Tobias Rausch¹¹ ; David Shih⁶ ; Jü ; ri Reimand¹² ; Laura Sieber¹ ; Andrea Wittmann¹ ; Linda Linke¹ ; Hendrik Witt¹ ; ⁷ ; Ursula D. Weber⁴ ; Marc Zapatka⁴ ; Rainer Kö ; nig² ; ¹³ ; ¹⁴ ; Rameen Beroukhim³ ; ¹⁵ ; ¹⁶ ; Guillaume Bergthold³ ; ¹⁵ ; ¹⁷ ; Peter van Sluis¹⁸ ; Richard Volckmann¹⁸ ; Jan Koster¹⁸ ; Rogier Versteeg¹⁸ ; Sabine Schmidt¹⁹ ; Stephan Wolf¹⁹ ; Chris Lawerenz²⁰ ; Cynthia C. Bartholomae²¹ ; Christof von Kalle²¹ ; Andreas Unterberg²¹ ; Christel Herold-Mende²¹ ; Silvia Hofer²² ; Andreas E. Kulozik⁷ ; Andreas von Deimling²³ ; ²⁴ ; Wolfram Scheurlen²⁵ ; Jö ; rg Felsberg²⁶ ; Guido Reifenberger²⁶ ; Martin Hasselblatt²⁷ ; John R. Crawford²⁸ ; ²⁹ ; Gerald A. Grant³⁰ ; ³¹ ; Nada Jabado³² ; Arie Perry³³ ; Cynthia Cowdrey³⁴ ; Sydney Croul³⁵ ; Gelareh Zadeh³⁵ ; Jan O. Korbel¹¹ ; Francois Doz⁸ ; ³⁶ ; Olivier Delattre⁸ ; ⁹ ; Gary D. Bader¹² ; Martin G. McCabe³⁷ ; V. Peter Collins³⁸ ; Mark W. Kieran³⁹ ; Yoon-Jae Cho⁴⁰ ; Scott L. Pomeroy⁴¹ ; Olaf Witt⁴² ; Benedikt Brors² ; Michael D. Taylor⁶ ; Ulrich Schü ; ller⁴³ ; Andrey Korshunov¹ ; ²³ ; ²⁴ ; Roland Eils² ; Robert J. Wechsler-Reya⁵ ; ⁴⁴ ; Peter Lichter⁴ ; ⁴⁴ ; Stefan M. Pfister¹ ; ⁷ ; ⁴⁴ ; on behalf of the ICGC PedBrain Tumor Project
• 刊名：Cancer Cell
• 出版年：17 March, 2014
• 年：2014
• 卷：25
• 期：3
• 页码：393-405
• 全文大小：3748 K

文摘

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Summary

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聽= 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.