An Integrated Approach to Uncover Drivers of Cancer

被引：382

作者：

Akavia, Uri David ^{[1
,2
]}

Litvin, Oren ^{[1
,2
]}

Kim, Jessica ^{[3
,4
]}

Sanchez-Garcia, Felix ^{[1
]}

Kotliar, Dylan ^{[1
]}

Causton, Helen C. ^{[1
]}

Pochanard, Panisa ^{[3
,4
]}

Mozes, Eyal ^{[1
]}

Garraway, Levi A. ^{[3
,4
]}

Pe'er, Dana ^{[1
,2
]}

机构：

[1] Columbia Univ, Dept Biol Sci, New York, NY 10027 USA

[2] Columbia Univ, Ctr Computat Biol & Bioinformat, New York, NY 10032 USA

[3] Harvard Univ, Sch Med, Dana Farber Canc Inst, Dept Med Oncol, Boston, MA 02115 USA

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

来源：

CELL | 2010年 / 143卷 / 06期

基金：

美国国家卫生研究院;

关键词：

GENE-EXPRESSION; MELANOMA; MITF; IDENTIFICATION; TRANSFORMATION; INTERFERENCE; REGULATORS; NETWORKS; MODULES; PROTEIN;

D O I：

10.1016/j.cell.2010.11.013

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

Systematic characterization of cancer genomes has revealed a staggering number of diverse aberrations that differ among individuals, such that the functional importance and physiological impact of most tumor genetic alterations remain poorly defined. We developed a computational framework that integrates chromosomal copy number and gene expression data for detecting aberrations that promote cancer progression. We demonstrate the utility of this framework using a melanoma data set. Our analysis correctly identified known drivers of melanoma and predicted multiple tumor dependencies. Two dependencies, TBC1D16 and RAB27A, confirmed empirically, suggest that abnormal regulation of protein trafficking contributes to proliferation in melanoma. Together, these results demonstrate the ability of integrative Bayesian approaches to identify candidate drivers with biological, and possibly therapeutic, importance in cancer.

引用

页码：1005 / 1017

页数：13

共 42 条

[1] Genetic regulators of large-scale transcriptional signatures in cancer [J].

Adler, AS ;

Lin, MH ;

Horlings, H ;

Nuyten, DSA ;

van de Vijver, MJ ;

Chang, HY .

NATURE GENETICS, 2006, 38 (04) :421-430

[2] Assessing the significance of chromosomal aberrations in cancer: Methodology and application to glioma [J].

Beroukhim, Rameen ;

Getz, Gad ;

Nghiemphu, Leia ;

Barretina, Jordi ;

Hsueh, Teli ;

Linhart, David ;

Vivanco, Igor ;

Lee, Jeffrey C. ;

Huang, Julie H. ;

Alexander, Sethu ;

Du, Jinyan ;

Kau, Tweeny ;

Thomas, Roman K. ;

Shah, Kinial ;

Soto, Horacio ;

Perner, Sven ;

Prensner, John ;

Debiasi, Ralph M. ;

Demichelis, Francesca ;

Hatton, Charlie ;

Rubin, Mark A. ;

Garraway, Levi A. ;

Nelson, Stan F. ;

Liau, Linda ;

Mischel, Paul S. ;

Cloughesy, Tim F. ;

Meyerson, Matthew ;

Golub, Todd A. ;

Lander, Eric S. ;

Mellinghoff, Ingo K. ;

Sellers, William R. .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2007, 104 (50) :20007-20012

[3] The landscape of somatic copy-number alteration across human cancers [J].

Beroukhim, Rameen ;

Mermel, Craig H. ;

Porter, Dale ;

Wei, Guo ;

Raychaudhuri, Soumya ;

Donovan, Jerry ;

Barretina, Jordi ;

Boehm, Jesse S. ;

Dobson, Jennifer ;

Urashima, Mitsuyoshi ;

Mc Henry, Kevin T. ;

Pinchback, Reid M. ;

Ligon, Azra H. ;

Cho, Yoon-Jae ;

Haery, Leila ;

Greulich, Heidi ;

Reich, Michael ;

Winckler, Wendy ;

Lawrence, Michael S. ;

Weir, Barbara A. ;

Tanaka, Kumiko E. ;

Chiang, Derek Y. ;

Bass, Adam J. ;

Loo, Alice ;

Hoffman, Carter ;

Prensner, John ;

Liefeld, Ted ;

Gao, Qing ;

Yecies, Derek ;

Signoretti, Sabina ;

Maher, Elizabeth ;

Kaye, Frederic J. ;

Sasaki, Hidefumi ;

Tepper, Joel E. ;

Fletcher, Jonathan A. ;

Tabernero, Josep ;

Baselga, Jose ;

Tsao, Ming-Sound ;

Demichelis, Francesca ;

Rubin, Mark A. ;

Janne, Pasi A. ;

Daly, Mark J. ;

Nucera, Carmelo ;

Levine, Ross L. ;

Ebert, Benjamin L. ;

Gabriel, Stacey ;

Rustgi, Anil K. ;

Antonescu, Cristina R. ;

Ladanyi, Marc ;

Letai, Anthony .

NATURE, 2010, 463 (7283) :899-905

[4] Patterns of Gene Expression and Copy-Number Alterations in von-Hippel Lindau Disease-Associated and Sporadic Clear Cell Carcinoma of the Kidney [J].

Beroukhim, Rameen ;

Brunet, Jean-Philippe ;

Di Napoli, Arianna ;

Mertz, Kirsten D. ;

Seeley, Apryle ;

Pires, Maira M. ;

Linhart, David ;

Worrell, Robert A. ;

Moch, Holger ;

Rubin, Mark A. ;

Sellers, William R. ;

Meyerson, Matthew ;

Linehan, W. Marston ;

Kaelin, William G., Jr. ;

Signoretti, Sabina .

CANCER RESEARCH, 2009, 69 (11) :4674-4681

[5] Functional Identification of Tumor-Suppressor Genes through an In Vivo RNA Interference Screen in a Mouse Lymphoma Model [J].

Bric, Anka ;

Miething, Cornelius ;

Bialucha, Carl Uli ;

Scuoppo, Claudio ;

Zender, Lars ;

Krasnitz, Alexander ;

Xuan, Zhenyu ;

Zuber, Johannes ;

Wigler, Michael ;

Hicks, James ;

McCombie, Richard W. ;

Hemann, Michael T. ;

Hannon, Gregory J. ;

Powers, Scott ;

Lowe, Scott W. .

CANCER CELL, 2009, 16 (04) :324-335

[6] The transcriptional network for mesenchymal transformation of brain tumours [J].

Carro, Maria Stella ;

Lim, Wei Keat ;

Alvarez, Mariano Javier ;

Bollo, Robert J. ;

Zhao, Xudong ;

Snyder, Evan Y. ;

Sulman, Erik P. ;

Anne, Sandrine L. ;

Doetsch, Fiona ;

Colman, Howard ;

Lasorella, Anna ;

Aldape, Ken ;

Califano, Andrea ;

Iavarone, Antonio .

NATURE, 2010, 463 (7279) :318-U68

[7] Microphthalmia-associated transcription factor regulates RAB27A gene expression and controls melanosome transport [J].

Chiaverini, Christine ;

Beuret, Laurent ;

Flori, Enrica ;

Busca, Roser ;

Abbe, Patricia ;

Bille, Karine ;

Bahadoran, Philippe ;

Ortonne, Jean-Paul ;

Bertolotto, Corine ;

Ballotti, Robert .

JOURNAL OF BIOLOGICAL CHEMISTRY, 2008, 283 (18) :12635-12642

[8] Malignant melanoma: genetics and therapeutics in the genomic era [J].

Chin, Lynda ;

Garraway, Levi A. ;

Fisher, David E. .

GENES & DEVELOPMENT, 2006, 20 (16) :2149-2182

[9] Critical role of CDK2 for melanoma growth linked to its melanocyte-specific transcriptional regulation by MITF [J].

Du, JY ;

Widlund, HR ;

Horstmann, MA ;

Ramaswamy, S ;

Ross, K ;

Huber, WE ;

Nishimura, EK ;

Golub, TR ;

Fisher, DE .

CANCER CELL, 2004, 6 (06) :565-576

[10] Phase IIB Trial of Oral Midostaurin (PKC412), the FMS-Like Tyrosine Kinase 3 Receptor (FLT3) and Multi-Targeted Kinase Inhibitor, in Patients With Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome With Either Wild-Type or Mutated FLT3 [J].

Fischer, Thomas ;

Stone, Richard M. ;

DeAngelo, Daniel J. ;

Galinsky, Ilene ;

Estey, Elihu ;

Lanza, Carlo ;

Fox, Edward ;

Ehninger, Gerhard ;

Feldman, Eric J. ;

Schiller, Gary J. ;

Klimek, Virginia M. ;

Nimer, Stephen D. ;

Gilliland, D. Gary ;

Dutreix, Catherine ;

Huntsman-Labed, Alice ;

Virkus, Jodi ;

Giles, Francis J. .

JOURNAL OF CLINICAL ONCOLOGY, 2010, 28 (28) :4339-4345

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