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

Marcel Kool; David T.W. Jones; Natalie Jäger; Paul A. Northcott; Trevor J. Pugh; Volker Hovestadt; Rosario M. Piro; L. Adriana Esparza; Shirley L. Markant; Marc Remke; Till Milde; Franck Bourdeaut; Marina Ryzhova; Dominik Sturm; Elke Pfaff; Sebastian Stark; Sonja Hutter; Huriye Sxeker-Cin; Pascal Johann; Sebastian Bender; Christin Schmidt; Tobias Rausch; David Shih; Jüri Reimand; Laura Sieber; Andrea Wittmann; Linda Linke; Hendrik Witt; Ursula D. Weber; Marc Zapatka; Rainer König; Rameen Beroukhim; Guillaume Bergthold; Peter Van Sluis; Richard Volckmann; Jan Koster; Rogier Versteeg; Sabine Schmidt; Stephan Wolf; Chris Lawerenz; Cynthia C. Bartholomae; Christof Von Kalle; Andreas Unterberg; Christel Herold-Mende; Silvia Hofer; Andreas E. Kulozik; Andreas Von Deimling; Wolfram Scheurlen; Jörg Felsberg; Guido Reifenberger; Martin Hasselblatt; John R. Crawford; Gerald A. Grant; Nada Jabado; Arie Perry; Cynthia Cowdrey; Sydney Croul; Gelareh Zadeh; Jan O. Korbel; Francois Doz; Olivier Delattre; Gary D. Bader; Martin G. McCabe; V. Peter Collins; Mark W. Kieran; Yoon Jae Cho; Scott L. Pomeroy; Olaf Witt; Benedikt Brors; Michael D. Taylor; Ulrich Schüller; Andrey Korshunov; Roland Eils; Robert J. Wechsler-Reya; Peter Lichter; Stefan M. Pfister

doi:10.1016/j.ccr.2014.02.004

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

Marcel Kool, David T.W. Jones, Natalie Jäger, Paul A. Northcott, Trevor J. Pugh, Volker Hovestadt, Rosario M. Piro, L. Adriana Esparza, Shirley L. Markant, Marc Remke, Till Milde, Franck Bourdeaut, Marina Ryzhova, Dominik Sturm, Elke Pfaff, Sebastian Stark, Sonja Hutter, Huriye Sxeker-Cin, Pascal Johann, Sebastian BenderChristin Schmidt, Tobias Rausch, David Shih, Jüri Reimand, Laura Sieber, Andrea Wittmann, Linda Linke, Hendrik Witt, Ursula D. Weber, Marc Zapatka, Rainer König, Rameen Beroukhim, Guillaume Bergthold, Peter Van Sluis, Richard Volckmann, Jan Koster, Rogier Versteeg, Sabine Schmidt, Stephan Wolf, Chris Lawerenz, Cynthia C. Bartholomae, Christof Von Kalle, Andreas Unterberg, Christel Herold-Mende, Silvia Hofer, Andreas E. Kulozik, Andreas Von Deimling, Wolfram Scheurlen, Jörg Felsberg, Guido Reifenberger, Martin Hasselblatt, John R. Crawford, Gerald A. Grant, Nada Jabado, Arie Perry, Cynthia Cowdrey, Sydney Croul, Gelareh Zadeh, Jan O. Korbel, Francois Doz, Olivier Delattre, Gary D. Bader, Martin G. McCabe, V. Peter Collins, Mark W. Kieran, Yoon Jae Cho, Scott L. Pomeroy, Olaf Witt, Benedikt Brors, Michael D. Taylor, Ulrich Schüller, Andrey Korshunov, Roland Eils, Robert J. Wechsler-Reya, Peter Lichter, Stefan M. Pfister

Research output: Contribution to journal › Article › peer-review

586 Scopus citations

Abstract

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.

Original language	English (US)
Pages (from-to)	393-405
Number of pages	13
Journal	Cancer Cell
Volume	25
Issue number	3
DOIs	https://doi.org/10.1016/j.ccr.2014.02.004
State	Published - Mar 17 2014
Externally published	Yes

ASJC Scopus subject areas

Oncology
Cancer Research

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10.1016/j.ccr.2014.02.004

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Kool, M., Jones, D. T. W., Jäger, N., Northcott, P. A., Pugh, T. J., Hovestadt, V., Piro, R. M., Esparza, L. A., Markant, S. L., Remke, M., Milde, T., Bourdeaut, F., Ryzhova, M., Sturm, D., Pfaff, E., Stark, S., Hutter, S., Sxeker-Cin, H., Johann, P., ... Pfister, S. M. (2014). Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition. Cancer Cell, 25(3), 393-405. https://doi.org/10.1016/j.ccr.2014.02.004

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, Sxeker-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 2014, 'Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition', Cancer Cell, vol. 25, no. 3, pp. 393-405. https://doi.org/10.1016/j.ccr.2014.02.004

@article{d00cc4cd94814b7ebb1c1c284d6ecc95,

title = "Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition",

abstract = "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.",

author = "Marcel Kool and Jones, {David T.W.} and Natalie J{\"a}ger and Northcott, {Paul A.} and Pugh, {Trevor J.} and Volker Hovestadt and Piro, {Rosario M.} and Esparza, {L. Adriana} and Markant, {Shirley L.} and Marc Remke and Till Milde and Franck Bourdeaut and Marina Ryzhova and Dominik Sturm and Elke Pfaff and Sebastian Stark and Sonja Hutter and Huriye Sxeker-Cin and Pascal Johann and Sebastian Bender and Christin Schmidt and Tobias Rausch and David Shih and J{\"u}ri Reimand and Laura Sieber and Andrea Wittmann and Linda Linke and Hendrik Witt and Weber, {Ursula D.} and Marc Zapatka and Rainer K{\"o}nig and Rameen Beroukhim and Guillaume Bergthold and {Van Sluis}, Peter and Richard Volckmann and Jan Koster and Rogier Versteeg and Sabine Schmidt and Stephan Wolf and Chris Lawerenz and Bartholomae, {Cynthia C.} and {Von Kalle}, Christof and Andreas Unterberg and Christel Herold-Mende and Silvia Hofer and Kulozik, {Andreas E.} and {Von Deimling}, Andreas and Wolfram Scheurlen and J{\"o}rg Felsberg and Guido Reifenberger and Martin Hasselblatt and Crawford, {John R.} and Grant, {Gerald A.} and Nada Jabado and Arie Perry and Cynthia Cowdrey and Sydney Croul and Gelareh Zadeh and Korbel, {Jan O.} and Francois Doz and Olivier Delattre and Bader, {Gary D.} and McCabe, {Martin G.} and Collins, {V. Peter} and Kieran, {Mark W.} and Cho, {Yoon Jae} and Pomeroy, {Scott L.} and Olaf Witt and Benedikt Brors and Taylor, {Michael D.} and Ulrich Sch{\"u}ller and Andrey Korshunov and Roland Eils and Wechsler-Reya, {Robert J.} and Peter Lichter and Pfister, {Stefan M.}",

note = "Funding Information: For technical support and expertise, we thank the people from the DKFZ Genomics and Proteomics Core Facility, Malaika Knopf from the NCT Heidelberg, and GATC Biotech AG for sequencing services. This work was principally supported by the PedBrain Tumor Project ( http://www.pedbraintumor.org ) contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (Bundesministerium f{\"u}r Bildung und Forschung, grant numbers 01KU1201A, MedSys 0315416C, and NGFNplus 01GS0883). Additional support came from the Dutch Cancer Foundations KWF (2010-4713) and KIKA (to M.K.), and the Brain Tumor Charity (to V.P.C.). G.R. received a research grant from Roche and honoraria for advisory boards from Merck Serono and Roche. R.B. and O.W. are consultants for and received grant funding from Novartis. ",

year = "2014",

month = mar,

day = "17",

doi = "10.1016/j.ccr.2014.02.004",

language = "English (US)",

volume = "25",

pages = "393--405",

journal = "Cancer Cell",

issn = "1535-6108",

publisher = "Cell Press",

number = "3",

}

TY - JOUR

T1 - Genome sequencing of SHH medulloblastoma predicts genotype-related response to smoothened inhibition

AU - Kool, Marcel

AU - Jones, David T.W.

AU - Jäger, Natalie

AU - Northcott, Paul A.

AU - Pugh, Trevor J.

AU - Hovestadt, Volker

AU - Piro, Rosario M.

AU - Esparza, L. Adriana

AU - Markant, Shirley L.

AU - Remke, Marc

AU - Milde, Till

AU - Bourdeaut, Franck

AU - Ryzhova, Marina

AU - Sturm, Dominik

AU - Pfaff, Elke

AU - Stark, Sebastian

AU - Hutter, Sonja

AU - Sxeker-Cin, Huriye

AU - Johann, Pascal

AU - Bender, Sebastian

AU - Schmidt, Christin

AU - Rausch, Tobias

AU - Shih, David

AU - Reimand, Jüri

AU - Sieber, Laura

AU - Wittmann, Andrea

AU - Linke, Linda

AU - Witt, Hendrik

AU - Weber, Ursula D.

AU - Zapatka, Marc

AU - König, Rainer

AU - Beroukhim, Rameen

AU - Bergthold, Guillaume

AU - Van Sluis, Peter

AU - Volckmann, Richard

AU - Koster, Jan

AU - Versteeg, Rogier

AU - Schmidt, Sabine

AU - Wolf, Stephan

AU - Lawerenz, Chris

AU - Bartholomae, Cynthia C.

AU - Von Kalle, Christof

AU - Unterberg, Andreas

AU - Herold-Mende, Christel

AU - Hofer, Silvia

AU - Kulozik, Andreas E.

AU - Von Deimling, Andreas

AU - Scheurlen, Wolfram

AU - Felsberg, Jörg

AU - Reifenberger, Guido

AU - Hasselblatt, Martin

AU - Crawford, John R.

AU - Grant, Gerald A.

AU - Jabado, Nada

AU - Perry, Arie

AU - Cowdrey, Cynthia

AU - Croul, Sydney

AU - Zadeh, Gelareh

AU - Korbel, Jan O.

AU - Doz, Francois

AU - Delattre, Olivier

AU - Bader, Gary D.

AU - McCabe, Martin G.

AU - Collins, V. Peter

AU - Kieran, Mark W.

AU - Cho, Yoon Jae

AU - Pomeroy, Scott L.

AU - Witt, Olaf

AU - Brors, Benedikt

AU - Taylor, Michael D.

AU - Schüller, Ulrich

AU - Korshunov, Andrey

AU - Eils, Roland

AU - Wechsler-Reya, Robert J.

AU - Lichter, Peter

AU - Pfister, Stefan M.

N1 - Funding Information: For technical support and expertise, we thank the people from the DKFZ Genomics and Proteomics Core Facility, Malaika Knopf from the NCT Heidelberg, and GATC Biotech AG for sequencing services. This work was principally supported by the PedBrain Tumor Project ( http://www.pedbraintumor.org ) contributing to the International Cancer Genome Consortium, funded by German Cancer Aid (109252) and by the German Federal Ministry of Education and Research (Bundesministerium für Bildung und Forschung, grant numbers 01KU1201A, MedSys 0315416C, and NGFNplus 01GS0883). Additional support came from the Dutch Cancer Foundations KWF (2010-4713) and KIKA (to M.K.), and the Brain Tumor Charity (to V.P.C.). G.R. received a research grant from Roche and honoraria for advisory boards from Merck Serono and Roche. R.B. and O.W. are consultants for and received grant funding from Novartis.

PY - 2014/3/17

Y1 - 2014/3/17

N2 - 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.

AB - 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.

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UR - http://www.scopus.com/inward/citedby.url?scp=84896096387&partnerID=8YFLogxK

U2 - 10.1016/j.ccr.2014.02.004

DO - 10.1016/j.ccr.2014.02.004

M3 - Article

C2 - 24651015

AN - SCOPUS:84896096387

SN - 1535-6108

VL - 25

SP - 393

EP - 405

JO - Cancer Cell

JF - Cancer Cell

IS - 3

ER -

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

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