title: A Landscape of Pharmacogenomic Interactions in Cancer.
abstract: 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.
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Francesco
authors.initials: F
authors.lastname: Iorio
authors.affiliation: Institute for Systems Biology, Seattle, WA 98109, USA; Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands.
authors.forename: Theo A
authors.initials: TA
authors.lastname: Knijnenburg
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands.
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Vis
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Graham R
authors.initials: GR
authors.lastname: Bignell
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK; Faculty of Medicine, Joint Research Centre for Computational Biomedicine, RWTH Aachen University, Aachen 52057, Germany.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Menden
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Michael
authors.initials: M
authors.lastname: Schubert
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands; Department of EEMCS, Delft University of Technology, Delft 2628 CD, the Netherlands.
authors.forename: Nanne
authors.initials: N
authors.lastname: Aben
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Emanuel
authors.initials: E
authors.lastname: Gonçalves
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Syd
authors.initials: S
authors.lastname: Barthorpe
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Howard
authors.initials: H
authors.lastname: Lightfoot
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK; Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Thomas
authors.initials: T
authors.lastname: Cokelaer
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Greninger
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands.
authors.forename: Ewald
authors.initials: E
authors.lastname: van Dyk
authors.affiliation: Genetically Defined Diseases and Genomics, Bristol-Myers Squibb Research and Development, Hopewell, NJ 08534, USA.
authors.forename: Han
authors.initials: H
authors.lastname: Chang
authors.affiliation: Genetically Defined Diseases and Genomics, Bristol-Myers Squibb Research and Development, Hopewell, NJ 08534, USA.
authors.forename: Heshani
authors.initials: H
authors.lastname: de Silva
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet 08908, Barcelona, Catalonia, Spain.
authors.forename: Holger
authors.initials: H
authors.lastname: Heyn
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Xianming
authors.initials: X
authors.lastname: Deng
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Regina K
authors.initials: RK
authors.lastname: Egan
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Qingsong
authors.initials: Q
authors.lastname: Liu
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Tatiana
authors.initials: T
authors.lastname: Mironenko
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Xeni
authors.initials: X
authors.lastname: Mitropoulos
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Richardson
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Jinhua
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Tinghu
authors.initials: T
authors.lastname: Zhang
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet 08908, Barcelona, Catalonia, Spain.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Moran
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet 08908, Barcelona, Catalonia, Spain.
authors.forename: Sergi
authors.initials: S
authors.lastname: Sayols
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Maryam
authors.initials: M
authors.lastname: Soleimani
authors.affiliation: Research Program on Biomedical Informatics, IMIM Hospital del Mar Medical Research Institute and Universitat Pompeu Fabra, Barcelona 08003, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Tamborero
authors.affiliation: Research Program on Biomedical Informatics, IMIM Hospital del Mar Medical Research Institute and Universitat Pompeu Fabra, Barcelona 08003, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Catalonia, Spain.
authors.forename: Nuria
authors.initials: N
authors.lastname: Lopez-Bigas
authors.affiliation: Genetically Defined Diseases and Genomics, Bristol-Myers Squibb Research and Development, Hopewell, NJ 08534, USA.
authors.forename: Petra
authors.initials: P
authors.lastname: Ross-Macdonald
authors.affiliation: Cancer Epigenetics and Biology Program (PEBC), Bellvitge Biomedical Research Institute (IDIBELL), L'Hospitalet 08908, Barcelona, Catalonia, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), 08010 Barcelona, Catalonia, Spain; Department of Physiological Sciences II of the School of Medicine, University of Barcelona, L'Hospitalet 08908, Barcelona, Catalonia, Spain.
authors.forename: Manel
authors.initials: M
authors.lastname: Esteller
authors.affiliation: Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA 02215, USA; Department of Biological Chemistry & Molecular Pharmacology, Harvard Medical School, Boston, MA 02215, USA.
authors.forename: Nathanael S
authors.initials: NS
authors.lastname: Gray
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA; Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA.
authors.forename: Daniel A
authors.initials: DA
authors.lastname: Haber
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Stratton
authors.affiliation: Center for Cancer Research, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA 02129, USA.
authors.forename: Cyril H
authors.initials: CH
authors.lastname: Benes
authors.affiliation: Division of Molecular Carcinogenesis, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands; Department of EEMCS, Delft University of Technology, Delft 2628 CD, the Netherlands; Cancer Genomics Netherlands, Uppsalalaan 8, Utrecht 3584CT, the Netherlands.
authors.forename: Lodewyk F A
authors.initials: LFA
authors.lastname: Wessels
authors.affiliation: European Molecular Biology Laboratory, European Bioinformatics Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK; Faculty of Medicine, Joint Research Centre for Computational Biomedicine, RWTH Aachen University, Aachen 52057, Germany.
authors.forename: Julio
authors.initials: J
authors.lastname: Saez-Rodriguez
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK. Electronic address: um1@sanger.ac.uk.
authors.forename: Ultan
authors.initials: U
authors.lastname: McDermott
authors.affiliation: Wellcome Trust Sanger Institute, Wellcome Genome Campus, Cambridge CB10 1SA, UK. Electronic address: mg12@sanger.ac.uk.
authors.forename: Mathew J
authors.initials: MJ
authors.lastname: Garnett
mesh_terms: D000704:Analysis of Variance; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D019175:DNA Methylation; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D018628:Gene Dosage; D006801:Humans; D008957:Models, Genetic; D009154:Mutation; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics; D009857:Oncogenes; D057285:Precision Medicine
chemical_list: D000970:Antineoplastic Agents