A Landscape of Pharmacogenomic Interactions in Cancer

被引：1449

作者：

Iorio, Francesco ^{[1
,2
]}

Knijnenburg, Theo A. ^{[3
,4
]}

Vis, Daniel J. ^{[4
]}

Bignell, Graham R. ^{[2
]}

Menden, Michael P. ^{[1
,5
]}

Schubert, Michael ^{[1
]}

Aben, Nanne ^{[4
,6
]}

Goncalves, Emanuel ^{[1
]}

Barthorpe, Syd ^{[2
]}

Lightfoot, Howard ^{[2
]}

Cokelaer, Thomas ^{[1
,2
,18
]}

Greninger, Patricia ^{[7
]}

van Dyk, Ewald ^{[4
]}

Chang, Han ^{[8
]}

de Silva, Heshani ^{[8
]}

Heyn, Holger ^{[9
]}

Deng, Xianming ^{[10
,11
,19
]}

Egan, Regina K. ^{[7
]}

Liu, Qingsong ^{[10
,11
]}

Mironenko, Tatiana ^{[2
]}

Mitropoulos, Xeni ^{[7
]}

Richardson, Laura ^{[2
]}

Wang, Jinhua ^{[10
,11
]}

Zhang, Tinghu ^{[10
,11
]}

Moran, Sebastian ^{[9
]}

Sayols, Sergi ^{[9
,20
]}

Soleimani, Maryam ^{[2
]}

Tamborero, David ^{[12
,13
]}

Lopez-Bigas, Nuria ^{[12
,13
,14
]}

Ross-Macdonald, Petra ^{[8
]}

Esteller, Manel ^{[9
,14
,15
]}

Gray, Nathanael S. ^{[10
,11
]}

Haber, Daniel A. ^{[7
,16
]}

Stratton, Michael R. ^{[2
]}

Benes, Cyril H. ^{[7
]}

Wessels, Lodewyk F. A. ^{[4
,6
,17
]}

Saez-Rodriguez, Julio ^{[1
,5
]}

McDermott, Ultan ^{[2
]}

Garnett, Mathew J. ^{[2
]}

机构：

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

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

[3] Inst Syst Biol, Seattle, WA 98109 USA

[4] Netherlands Canc Inst, Div Mol Carcinogenesis, Plesmanlaan 121, NL-1066 CX Amsterdam, Netherlands

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

[6] Delft Univ Technol, Dept EEMCS, NL-2628 CD Delft, Netherlands

[7] Harvard Med Sch, Massachusetts Gen Hosp, Ctr Canc Res, Charlestown, MA 02129 USA

[8] Bristol Myers Squibb Res & Dev, Genetically Defined Dis & Genom, Hopewell, NJ 08534 USA

[9] Bellvitge Biomed Res Inst IDIBELL, PEBC, Barcelona CATALONIA, Spain

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

[11] Harvard Med Sch, Dept Biol Chem & Mol Pharmacol, Boston, MA 02215 USA

[12] IMIM Hosp del Mar Med Res Inst, Res Program Biomed Informat, Barcelona 08003, Spain

[13] Univ Pompeu Fabra, Barcelona 08003, Spain

[14] ICREA, Barcelona 08010, Catalonia, Spain

[15] Univ Barcelona, Sch Med, Dept Physiol Sci 2, Barcelona 08908, Catalonia, Spain

[16] Howard Hughes Med Inst, Chevy Chase, MD 20815 USA

[17] Canc Genom Netherlands, Uppsalalaan 8, NL-3584 CT Utrecht, Netherlands

[18] Inst Pasteur, USR IP CNRS 3756, C3BI, Bioinformat & Biostat Hub, F-75015 Paris, France

[19] Xiamen Univ, Sch Life Sci, Innovat Ctr Cell Signaling Network, Xiamen 361102, Peoples R China

[20] Inst Mol Biol, D-55128 Mainz, Germany

来源：

CELL | 2016年 / 166卷 / 03期

基金：

欧盟第七框架计划; 英国惠康基金; 欧洲研究理事会;

关键词：

DRUG-SENSITIVITY; IDENTIFICATION; GENE; MUTATIONS; DISCOVERY; PATTERNS;

D O I：

10.1016/j.cell.2016.06.017

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

070307 [化学生物学]; 071010 [生物化学与分子生物学];

摘要：

Systematic studies of cancer genomes have provided unprecedented insights into the molecular nature of cancer. Using this information to guide the development and application of therapies in the clinic is challenging. Here, we report how cancer-driven alterations identified in 11,289 tumors from 29 tissues (integrating somatic mutations, copy number alterations, DNA methylation, and gene expression) can be mapped onto 1,001 molecularly annotated human cancer cell lines and correlated with sensitivity to 265 drugs. We find that cell lines faithfully recapitulate oncogenic alterations identified in tumors, find that many of these associate with drug sensitivity/resistance, and highlight the importance of tissue lineage in mediating drug response. Logic-based modeling uncovers combinations of alterations that sensitize to drugs, while machine learning demonstrates the relative importance of different data types in predicting drug response. Our analysis and datasets are rich resources to link genotypes with cellular phenotypes and to identify therapeutic options for selected cancer sub-populations.

引用

页码：740 / 754

页数：15

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