Proteomics, Post-translational Modifications, and Integrative Analyses Reveal Molecular Heterogeneity within Medulloblastoma Subgroups

被引：147

作者：

Archer, Tenley C. ^{[1
,2
,3
,4
]}

Ehrenberger, Tobias ^{[5
]}

Mundt, Filip ^{[4
,6
]}

Gold, Maxwell P. ^{[5
]}

Krug, Karsten ^{[4
]}

Mah, Clarence K. ^{[7
]}

Mahoney, Elizabeth L. ^{[1
,2
]}

Daniel, Colin J. ^{[8
]}

LeNail, Alexander ^{[5
]}

Ramamoorthy, Divya ^{[5
]}

Mertins, Philipp ^{[4
,18
,19
]}

Mani, D. R. ^{[4
]}

Zhang, Hailei ^{[4
]}

Gillette, Michael A. ^{[2
,4
,9
]}

Clauser, Karl ^{[4
]}

Noble, Michael ^{[4
]}

Tang, Lauren C. ^{[4
]}

Pierre-Francois, Jessica ^{[1
,2
]}

Silterra, Jacob ^{[4
]}

Jensen, James ^{[7
]}

Tamayo, Pablo ^{[7
,10
]}

Korshunov, Andrey ^{[11
,12
]}

Pfister, Stefan M. ^{[13
,14
,15
,16
]}

Kool, Marcel ^{[13
,14
,15
]}

Northcott, Paul A. ^{[14
,15
,17
]}

Sears, Rosalie C. ^{[8
]}

Lipton, Jonathan O. ^{[1
,2
,3
]}

Carr, Steven A. ^{[4
]}

Mesirov, Jill P. ^{[7
,10
]}

Pomeroy, Scott L. ^{[1
,2
,4
]}

Fraenkel, Ernest ^{[4
,5
]}

机构：

[1] Boston Childrens Hosp, Dept Neurol, Boston, MA 02115 USA

[2] Harvard Med Sch, Boston, MA 02115 USA

[3] Harvard Med Sch, Div Sleep Med, Boston, MA USA

[4] Eli & Edythe Broad Inst MIT & Harvard, Cambridge, MA 02142 USA

[5] MIT, Dept Biol Engn, 77 Massachusetts Ave, Cambridge, MA 02139 USA

[6] Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden

[7] Univ Calif San Diego, Dept Med, La Jolla, CA 92093 USA

[8] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA

[9] Massachusetts Gen Hosp, Div Pulm & Crit Care Med, Boston, MA 02114 USA

[10] Univ Calif San Diego, Moores Canc Ctr, La Jolla, CA 92093 USA

[11] German Canc Res Ctr, CCU Neuropathol, Heidelberg, Germany

[12] Heidelberg Univ, Dept Neuropathol, Heidelberg, Germany

[13] NCT Heidelberg KiTZ, Hopp Childrens Canc Ctr, Heidelberg, Germany

[14] German Canc Res Ctr, Div Pediat Neurooncol, Heidelberg, Germany

[15] German Canc Consortium DKTK, Heidelberg, Germany

[16] Heidelberg Univ Hosp, Dept Hematol & Oncol, Heidelberg, Germany

[17] St Jude Childrens Res Hosp, Dept Dev Neurobiol, 332 N Lauderdale St, Memphis, TN 38105 USA

[18] Max Delbruck Ctr Mol Med, Helmholtz Soc, Prote Platform, Berlin, Germany

[19] Berlin Inst Hlth, Berlin, Germany

来源：

CANCER CELL | 2018年 / 34卷 / 03期

基金：

瑞典研究理事会;

关键词：

PROTEOGENOMIC CHARACTERIZATION; OUTCOME PREDICTION; C-MYC; DNA; MUTATIONS; CELLS; PHOSPHORYLATION; CLASSIFICATION; TARGET; INHIBITION;

D O I：

10.1016/j.ccell.2018.08.004

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

There is a pressing need to identify therapeutic targets in tumors with low mutation rates such as the malignant pediatric brain tumor medulloblastoma. To address this challenge, we quantitatively profiled global proteomes and phospho-proteomes of 45 medulloblastoma samples. Integrated analyses revealed that tumors with similar RNA expression vary extensively at the post-transcriptional and post-translational levels. We identified distinct pathways associated with two subsets of SHH tumors, and found post-translational modifications of MYC that are associated with poor outcomes in group 3 tumors. We found kinases associated with subtypes and showed that inhibiting PRKDC sensitizes MYC-driven cells to radiation. Our study shows that proteomics enables a more comprehensive, functional readout, providing a foundation for future therapeutic strategies.

引用

页码：396 / +

页数：23

共 83 条

[61] The Emerging Role of Cdk5 in Cancer [J].

Pozo, Karine ;

Bibb, James A. .

TRENDS IN CANCER, 2016, 2 (10) :606-618

[62] Medulloblastoma exome sequencing uncovers subtype-specific somatic mutations [J].

Pugh, Trevor J. ;

Weeraratne, Shyamal Dilhan ;

Archer, Tenley C. ;

Krummel, Daniel A. Pomeranz ;

Auclair, Daniel ;

Bochicchio, James ;

Carneiro, Mauricio O. ;

Carter, Scott L. ;

Cibulskis, Kristian ;

Erlich, Rachel L. ;

Greulich, Heidi ;

Lawrence, Michael S. ;

Lennon, Niall J. ;

McKenna, Aaron ;

Meldrim, James ;

Ramos, Alex H. ;

Ross, Michael G. ;

Russ, Carsten ;

Shefler, Erica ;

Sivachenko, Andrey ;

Sogoloff, Brian ;

Stojanov, Petar ;

Tamayo, Pablo ;

Mesirov, Jill P. ;

Amani, Vladimir ;

Teider, Natalia ;

Sengupta, Soma ;

Francois, Jessica Pierre ;

Northcott, Paul A. ;

Taylor, Michael D. ;

Yu, Furong ;

Crabtree, Gerald R. ;

Kautzman, Amanda G. ;

Gabriel, Stacey B. ;

Getz, Gad ;

Jaeger, Natalie ;

Jones, David T. W. ;

Lichter, Peter ;

Pfister, Stefan M. ;

Roberts, Thomas M. ;

Meyerson, Matthew ;

Pomeroy, Scott L. ;

Cho, Yoon-Jae .

NATURE, 2012, 488 (7409) :106-110

[63] Oncotator: Cancer Variant Annotation Tool [J].

Ramos, Alex H. ;

Lichtenstein, Lee ;

Gupta, Manaswi ;

Lawrence, Michael S. ;

Pugh, Trevor J. ;

Saksena, Gordon ;

Meyerson, Matthew ;

Getz, Gad .

HUMAN MUTATION, 2015, 36 (04) :E2423-E2429

[64] Isobaric Labeling-Based Relative Quantification in Shotgun Proteomics [J].

Rauniyar, Navin ;

Yates, John R., III .

JOURNAL OF PROTEOME RESEARCH, 2014, 13 (12) :5293-5309

[65] iRefIndex: A consolidated protein interaction database with provenance [J].

Razick, Sabry ;

Magklaras, George ;

Donaldson, Ian M. .

BMC BIOINFORMATICS, 2008, 9 (1)

[66] Novel mutations target distinct subgroups of medulloblastoma [J].

Robinson, Giles ;

Parker, Matthew ;

Kranenburg, Tanya A. ;

Lu, Charles ;

Chen, Xiang ;

Ding, Li ;

Phoenix, Timothy N. ;

Hedlund, Erin ;

Wei, Lei ;

Zhu, Xiaoyan ;

Chalhoub, Nader ;

Baker, Suzanne J. ;

Huether, Robert ;

Kriwacki, Richard ;

Curley, Natasha ;

Thiruvenkatam, Radhika ;

Wang, Jianmin ;

Wu, Gang ;

Rusch, Michael ;

Hong, Xin ;

Becksfort, Jared ;

Gupta, Pankaj ;

Ma, Jing ;

Easton, John ;

Vadodaria, Bhavin ;

Onar-Thomas, Arzu ;

Lin, Tong ;

Li, Shaoyi ;

Pounds, Stanley ;

Paugh, Steven ;

Zhao, David ;

Kawauchi, Daisuke ;

Roussel, Martine F. ;

Finkelstein, David ;

Ellison, David W. ;

Lau, Ching C. ;

Bouffet, Eric ;

Hassall, Tim ;

Gururangan, Sridharan ;

Cohn, Richard ;

Fulton, Robert S. ;

Fulton, Lucinda L. ;

Dooling, David J. ;

Ochoa, Kerri ;

Gajjar, Amar ;

Mardis, Elaine R. ;

Wilson, Richard K. ;

Downing, James R. ;

Zhang, Jinghui ;

Gilbertson, Richard J. .

NATURE, 2012, 488 (7409) :43-48

[67] Vismodegib Exerts Targeted Efficacy Against Recurrent Sonic Hedgehog-Subgroup Medulloblastoma: Results From Phase II Pediatric Brain Tumor Consortium Studies PBTC-025B and PBTC-032 [J].

Robinson, Giles W. ;

Orr, Brent A. ;

Wu, Gang ;

Gururangan, Sridharan ;

Lin, Tong ;

Qaddoumi, Ibrahim ;

Packer, Roger J. ;

Goldman, Stewart ;

Prados, Michael D. ;

Desjardins, Annick ;

Chintagumpala, Murali ;

Takebe, Naoko ;

Kaste, Sue C. ;

Rusch, Michael ;

Allen, Sariah J. ;

Onar-Thomas, Arzu ;

Stewart, Clinton F. ;

Fouladi, Maryam ;

Boyett, James M. ;

Gilbertson, Richard J. ;

Curran, Tom ;

Ellison, David W. ;

Gajjar, Amar .

JOURNAL OF CLINICAL ONCOLOGY, 2015, 33 (24) :2646-U106

[68] Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: a cohort study [J].

Schwalbe, Edward C. ;

Lindsey, Janet C. ;

Nakjang, Sirintra ;

Crosier, Stephen ;

Smith, Amanda J. ;

Hicks, Debbie ;

Rafiee, Gholamreza ;

Hill, Rebecca M. ;

Iliasova, Alice ;

Stone, Thomas ;

Pizer, Barry ;

Michalski, Antony ;

Joshi, Abhijit ;

Wharton, Stephen B. ;

Jacques, Thomas S. ;

Bailey, Simon ;

Williamson, Daniel ;

Clifford, Steven C. .

LANCET ONCOLOGY, 2017, 18 (07) :958-971

[69] Critical limitations of consensus clustering in class discovery [J].

Senbabaoglu, Yasin ;

Michailidis, George ;

Li, Jun Z. .

SCIENTIFIC REPORTS, 2014, 4

[70] Cytoscape: A software environment for integrated models of biomolecular interaction networks [J].

Shannon, P ;

Markiel, A ;

Ozier, O ;

Baliga, NS ;

Wang, JT ;

Ramage, D ;

Amin, N ;

Schwikowski, B ;

Ideker, T .

GENOME RESEARCH, 2003, 13 (11) :2498-2504

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