Perturbation-response genes reveal signaling footprints in cancer gene expression

被引：488

作者：

Schubert, Michael ^{[1
]}

Klinger, Bertram ^{[2
,3
,4
]}

Kluenemann, Martina ^{[2
,3
,4
]}

Sieber, Anja ^{[2
,3
,4
]}

Uhlitz, Florian ^{[2
,3
,4
]}

Sauer, Sascha ^{[5
]}

Garnett, Mathew J. ^{[6
]}

Bluethgen, Nils ^{[2
,3
,4
]}

Saez-Rodriguez, Julio ^{[1
,7
]}

机构：

[1] European Mol Biol Lab, European Bioinformat Inst, Wellcome Genome Campus, Cambridge CB10 1SD, England

[2] Charite, Inst Pathol, Charitepl 1, D-10117 Berlin, Germany

[3] Humboldt Univ, IRI Life Sci, Philippstr 13,Haus 18, D-10115 Berlin, Germany

[4] Humboldt Univ, Inst Theoret Biol, Philippstr 13,Haus 18, D-10115 Berlin, Germany

[5] Berlin Inst Hlth, Berlin Inst Med Syst Biol, Max Delbruck Ctr Mol Med MDC, Robert Rossle Str 10, D-13092 Berlin, Germany

[6] Wellcome Trust Sanger Inst, Wellcome Genome Campus, Cambridge CB10 1SA, England

[7] Rhein Westfal TH Aachen, Fac Med, Joint Res Ctr Computat Biomed, D-52057 Aachen, Germany

来源：

NATURE COMMUNICATIONS | 2018年 / 9卷

基金：

英国惠康基金;

关键词：

ENCYCLOPEDIA; SIGNATURES; PATHWAYS; PI3K/AKT; DATABASE; TARGETS; GAIN; MAP;

D O I：

10.1038/s41467-017-02391-6

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Aberrant cell signaling can cause cancer and other diseases and is a focal point of drug research. A common approach is to infer signaling activity of pathways from gene expression. However, mapping gene expression to pathway components disregards the effect of post-translational modifications, and downstream signatures represent very specific experimental conditions. Here we present PROGENy, a method that overcomes both limitations by leveraging a large compendium of publicly available perturbation experiments to yield a common core of Pathway RespOnsive GENes. Unlike pathway mapping methods, PROGENy can (i) recover the effect of known driver mutations, (ii) provide or improve strong markers for drug indications, and (iii) distinguish between oncogenic and tumor suppressor pathways for patient survival. Collectively, these results show that PROGENy accurately infers pathway activity from gene expression in a wide range of conditions.

引用

页数：11

共 49 条

[1]

[Anonymous], NAT METHODS

[2] The Cancer Cell Line Encyclopedia enables predictive modelling of anticancer drug sensitivity [J].

Barretina, Jordi ;

Caponigro, Giordano ;

Stransky, Nicolas ;

Venkatesan, Kavitha ;

Margolin, Adam A. ;

Kim, Sungjoon ;

Wilson, Christopher J. ;

Lehar, Joseph ;

Kryukov, Gregory V. ;

Sonkin, Dmitriy ;

Reddy, Anupama ;

Liu, Manway ;

Murray, Lauren ;

Berger, Michael F. ;

Monahan, John E. ;

Morais, Paula ;

Meltzer, Jodi ;

Korejwa, Adam ;

Jane-Valbuena, Judit ;

Mapa, Felipa A. ;

Thibault, Joseph ;

Bric-Furlong, Eva ;

Raman, Pichai ;

Shipway, Aaron ;

Engels, Ingo H. ;

Cheng, Jill ;

Yu, Guoying K. ;

Yu, Jianjun ;

Aspesi, Peter, Jr. ;

de Silva, Melanie ;

Jagtap, Kalpana ;

Jones, Michael D. ;

Wang, Li ;

Hatton, Charles ;

Palescandolo, Emanuele ;

Gupta, Supriya ;

Mahan, Scott ;

Sougnez, Carrie ;

Onofrio, Robert C. ;

Liefeld, Ted ;

MacConaill, Laura ;

Winckler, Wendy ;

Reich, Michael ;

Li, Nanxin ;

Mesirov, Jill P. ;

Gabriel, Stacey B. ;

Getz, Gad ;

Ardlie, Kristin ;

Chan, Vivien ;

Myer, Vic E. .

NATURE, 2012, 483 (7391) :603-607

[3] 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

[4] Oncogenic pathway signatures in human cancers as a guide to targeted therapies [J].

Bild, AH ;

Yao, G ;

Chang, JT ;

Wang, QL ;

Potti, A ;

Chasse, D ;

Joshi, MB ;

Harpole, D ;

Lancaster, JM ;

Berchuck, A ;

Olson, JA ;

Marks, JR ;

Dressman, HK ;

West, M ;

Nevins, JR .

NATURE, 2006, 439 (7074) :353-357

[5] A framework for oligonucleotide microarray preprocessing [J].

Carvalho, Benilton S. ;

Irizarry, Rafael A. .

BIOINFORMATICS, 2010, 26 (19) :2363-2367

[6] Reactome: a database of reactions, pathways and biological processes [J].

Croft, David ;

O'Kelly, Gavin ;

Wu, Guanming ;

Haw, Robin ;

Gillespie, Marc ;

Matthews, Lisa ;

Caudy, Michael ;

Garapati, Phani ;

Gopinath, Gopal ;

Jassal, Bijay ;

Jupe, Steven ;

Kalatskaya, Irina ;

Mahajan, Shahana ;

May, Bruce ;

Ndegwa, Nelson ;

Schmidt, Esther ;

Shamovsky, Veronica ;

Yung, Christina ;

Birney, Ewan ;

Hermjakob, Henning ;

D'Eustachio, Peter ;

Stein, Lincoln .

NUCLEIC ACIDS RESEARCH, 2011, 39 :D691-D697

[7] STAR: ultrafast universal RNA-seq aligner [J].

Dobin, Alexander ;

Davis, Carrie A. ;

Schlesinger, Felix ;

Drenkow, Jorg ;

Zaleski, Chris ;

Jha, Sonali ;

Batut, Philippe ;

Chaisson, Mark ;

Gingeras, Thomas R. .

BIOINFORMATICS, 2013, 29 (01) :15-21

[8] Pathway-based personalized analysis of cancer [J].

Drier, Yotam ;

Sheffer, Michal ;

Domany, Eytan .

PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 2013, 110 (16) :6388-6393

[9] A biology-driven approach identifies the hypoxia gene signature as a predictor of the outcome of neuroblastoma patients [J].

Fardin, Paolo ;

Barla, Annalisa ;

Mosci, Sofia ;

Rosasco, Lorenzo ;

Verri, Alessandro ;

Versteeg, Rogier ;

Caron, Huib N. ;

Molenaar, Jan J. ;

Ora, Ingrid ;

Eva, Alessandra ;

Puppo, Maura ;

Varesio, Luigi .

MOLECULAR CANCER, 2010, 9

[10] The l1-l2 regularization framework unmasks the hypoxia signature hidden in the transcriptome of a set of heterogeneous neuroblastoma cell lines [J].

Fardin, Paolo ;

Barla, Annalisa ;

Mosci, Sofia ;

Rosasco, Lorenzo ;

Verri, Alessandro ;

Varesio, Luigi .

BMC GENOMICS, 2009, 10 :474

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