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

被引：570

作者：

Kool, Marcel ^{[1
]}

Jones, David T. W. ^{[1
]}

Jaeger, Natalie ^{[2
]}

Northcott, Paul A. ^{[1
]}

Pugh, Trevor J. ^{[3
]}

Hovestadt, Volker ^{[4
]}

Piro, Rosario M. ^{[2
]}

Esparza, L. Adriana ^{[5
]}

Markant, Shirley L. ^{[5
]}

Remke, Marc ^{[6
]}

Milde, Till ^{[7
]}

Bourdeaut, Franck ^{[8
,9
]}

Ryzhova, Marina ^{[10
]}

Sturm, Dominik ^{[1
]}

Pfaff, Elke ^{[1
]}

Stark, Sebastian ^{[1
]}

Hutter, Sonja ^{[1
]}

Seker-Cin, Huriye ^{[1
]}

Johann, Pascal ^{[1
]}

Bender, Sebastian ^{[1
]}

Schmidt, Christin ^{[1
]}

Rausch, Tobias ^{[11
]}

Shih, David ^{[6
]}

Reimand, Jueri ^{[12
]}

Sieber, Laura ^{[1
]}

Wittmann, Andrea ^{[1
]}

Linke, Linda ^{[1
]}

Witt, Hendrik ^{[1
,7
]}

Weber, Ursula D. ^{[4
]}

Zapatka, Marc ^{[4
]}

Koenig, Rainer ^{[2
,13
,14
]}

Beroukhim, Rameen ^{[3
,15
,16
,17
]}

Bergthold, Guillaume ^{[3
,15
,18
]}

van Sluis, Peter ^{[19
]}

Volckmann, Richard ^{[19
]}

Koster, Jan ^{[19
]}

Versteeg, Rogier ^{[19
]}

Schmidt, Sabine ^{[20
]}

Wolf, Stephan ^{[20
]}

Lawerenz, Chris ^{[21
]}

Bartholomae, Cynthia C. ^{[22
,23
]}

von Kalle, Christof ^{[22
,23
]}

Unterberg, Andreas ^{[22
,23
]}

Herold-Mende, Christel ^{[22
,23
]}

Hofer, Silvia ^{[24
]}

Kulozik, Andreas E. ^{[7
]}

von Deimling, Andreas ^{[25
,26
]}

Scheurlen, Wolfram ^{[27
]}

Felsberg, Joerg ^{[28
]}

Reifenberger, Guido ^{[28
]}

机构：

[1] German Canc Res Ctr, Div Pediat Neurooncol, D-69121 Heidelberg, Germany

[2] German Canc Res Ctr, Div Theoret Bioinformat, D-69121 Heidelberg, Germany

[3] Broad Inst MIT & Harvard, Cambridge, MA 02141 USA

[4] German Canc Res Ctr, Div Mol Genet, D-69121 Heidelberg, Germany

[5] Sanford Burnham Med Res Inst, La Jolla, CA 92037 USA

[6] Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON M5G 1L7, Canada

[7] Univ Heidelberg Hosp, Dept Pediat Oncol Hematol & Immunol, D-69120 Heidelberg, Germany

[8] Inst Curie, F-75005 Paris, France

[9] Inst Curie, INSERM, U830, F-75248 Paris, France

[10] NN Burdenko Inst Neurosurg, Dept Neuropathol, Moscow 125047, Russia

[11] EMBL, D-69117 Heidelberg, Germany

[12] Univ Toronto, Donnelly Ctr, Toronto, ON M5S 3E1, Canada

[13] Jena Univ Hosp, Ctr Sepsis Control & Care, Integrated Res & Treatment Ctr, D-07747 Jena, Germany

[14] HKI, Leibniz Inst Nat Prod Res & Infect Biol, D-07745 Jena, Germany

[15] Dana Farber Canc Inst, Dept Canc Biol, Boston, MA 02215 USA

[16] Brigham & Womens Hosp, Dept Med, Boston, MA 02115 USA

[17] Harvard Univ, Sch Med, Boston, MA 02115 USA

[18] Univ Paris 11, Gustave Roussy Canc Inst, CNRS Vectorol & Anticanc Therapeut, UMR 8203, F-94805 Villejuif, France

[19] Univ Amsterdam, Acad Med Ctr, Dept Oncogen, NL-1105 AZ Amsterdam, Netherlands

[20] German Canc Res Ctr, Genom & Prote Core Facil, D-69121 Heidelberg, Germany

[21] German Canc Res Ctr, Data Management Facil, D-69121 Heidelberg, Germany

[22] German Canc Res Ctr, Div Translat Oncol, D-69121 Heidelberg, Germany

[23] Natl Ctr Tumor Dis NCT, D-69121 Heidelberg, Germany

[24] Univ Zurich Hosp, Dept Oncol, CH-8006 Zurich, Switzerland

[25] Heidelberg Univ, Dept Neuropathol, D-69120 Heidelberg, Germany

[26] German Canc Res Ctr, Clin Cooperat Unit Neuropathol, D-69121 Heidelberg, Germany

[27] Nurnberg Childrens Hosp, Cnopfsche Kinderklin, D-90419 Nurnberg, Germany

[28] Univ Dusseldorf, Dept Neuropathol, D-40225 Dusseldorf, Germany

[29] Univ Hosp Munster, Inst Neuropathol, D-48149 Munster, Germany

[30] Univ Calif San Diego, Dept Pediat, La Jolla, CA 92093 USA

[31] Univ Calif San Diego, Dept Neurosci, La Jolla, CA 92093 USA

[32] Rady Childrens Hosp, San Diego, CA 92123 USA

[33] Duke Univ, Med Ctr, Dept Pediat, Div Pediat Hematol Oncol, Durham, NC 27710 USA

[34] Duke Univ, Med Ctr, Dept Surg, Durham, NC 27710 USA

[35] McGill Univ, Dept Pediat & Human Genet, Montreal, PQ H3H 1P3, Canada

[36] Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94143 USA

[37] Univ Calif San Francisco, Dept Lab Med, San Francisco, CA 94143 USA

[38] Univ Calif San Francisco, Dept Neurol Surg, Brain Tumor Res Ctr, San Francisco, CA 94143 USA

[39] Arthur & Sonia Labatt Brain Tumour Res Ctr, Dept Neuropathol, Toronto, ON M5G 1L7, Canada

[40] Univ Paris 05, F-75006 Paris, France

[41] Manchester Acad Hlth Sci Ctr, Manchester M13 9NT, Lancs, England

[42] Univ Cambridge, Dept Pathol, Cambridge CB2 1QP, England

[43] Dana Farber Canc Inst, Boston, MA 02215 USA

[44] Boston Childrens Hosp, Boston, MA 02215 USA

[45] Stanford Univ, Sch Med, Dept Neurol & Neurosurg, Stanford, CA 94305 USA

[46] German Canc Res Ctr, CCU Pediat Oncol, D-69121 Heidelberg, Germany

[47] Univ Munich, Ctr Neuropathol & Prion Res, D-81377 Munich, Germany

来源：

CANCER CELL | 2014年 / 25卷 / 03期

关键词：

HEDGEHOG PATHWAY INHIBITOR; TERT PROMOTER MUTATIONS; PEDIATRIC MEDULLOBLASTOMA; MOUSE MODELS; TUMORS; ADULT; ITRACONAZOLE; RESISTANCE; SUBGROUPS; GROWTH;

D O I：

10.1016/j.ccr.2014.02.004

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 gernnline, 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.

引用

页码：393 / 405

页数：13

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