title: Characterizing genomic alterations in cancer by complementary functional associations.
abstract: Systematic efforts to sequence the cancer genome have identified large numbers of mutations and copy number alterations in human cancers. However, elucidating the functional consequences of these variants, and their interactions to drive or maintain oncogenic states, remains a challenge in cancer research. We developed REVEALER, a computational method that identifies combinations of mutually exclusive genomic alterations correlated with functional phenotypes, such as the activation or gene dependency of oncogenic pathways or sensitivity to a drug treatment. We used REVEALER to uncover complementary genomic alterations associated with the transcriptional activation of β-catenin and NRF2, MEK-inhibitor sensitivity, and KRAS dependency. REVEALER successfully identified both known and new associations, demonstrating the power of combining functional profiles with extensive characterization of genomic alterations in cancer genomes.
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Jong Wook
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Bioinformatics and Systems Biology Program, University of California at San Diego, La Jolla, California, USA.|Department of Cellular and Molecular Medicine, University of California at San Diego, La Jolla, California, USA.|Stem Cell Program and Institute for Genomic Medicine, University of California at San Diego, La Jolla, California, USA.
authors.forename: Olga B
authors.initials: OB
authors.lastname: Botvinnik
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Omar
authors.initials: O
authors.lastname: Abudayyeh
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Chet
authors.initials: C
authors.lastname: Birger
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: Rosenbluh
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Yashaswi
authors.initials: Y
authors.lastname: Shrestha
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Radiation Oncology, Cleveland Clinic, Cleveland, Ohio, USA.
authors.forename: Mohamed E
authors.initials: ME
authors.lastname: Abazeed
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Harvard Medical School, Boston, Massachusetts, USA.|Department of Medicine, Dana Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Peter S
authors.initials: PS
authors.lastname: Hammerman
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: DiCara
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: David J
authors.initials: DJ
authors.lastname: Konieczkowski
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Cory M
authors.initials: CM
authors.lastname: Johannessen
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Arthur
authors.initials: A
authors.lastname: Liberzon
authors.affiliation: Department of Electrical and Computer Engineering, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Amir Reza
authors.initials: AR
authors.lastname: Alizad-Rahvar
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Pediatric Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Boston Children's Hospital, Boston, Massachusetts, USA.|Bioinformatics Graduate Program, Boston University, Boston, Massachusetts, USA.
authors.forename: Gabriela
authors.initials: G
authors.lastname: Alexe
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Aguirre
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Mahmoud
authors.identifier: 0000-0003-1897-2265
authors.initials: M
authors.lastname: Ghandi
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Heidi
authors.initials: H
authors.lastname: Greulich
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Francisca
authors.initials: F
authors.lastname: Vazquez
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Weir
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Eliezer M
authors.initials: EM
authors.lastname: Van Allen
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Aviad
authors.identifier: 0000-0002-3797-1877
authors.initials: A
authors.lastname: Tsherniak
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: Diane D
authors.initials: DD
authors.lastname: Shao
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Program in Biophysics, Harvard University, Boston, Massachusetts, USA.
authors.forename: Travis I
authors.initials: TI
authors.lastname: Zack
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: Noble
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Program in Biophysics, Harvard University, Boston, Massachusetts, USA.
authors.forename: Rameen
authors.initials: R
authors.lastname: Beroukhim
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.
authors.forename: Levi A
authors.initials: LA
authors.lastname: Garraway
authors.affiliation: Department of Electrical and Computer Engineering, University of Alberta, Edmonton, Alberta, Canada.
authors.forename: Masoud
authors.initials: M
authors.lastname: Ardakani
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.
authors.forename: Chiara
authors.initials: C
authors.lastname: Romualdi
authors.affiliation: Department of Biology, University of Padova, Padova, Italy.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Sales
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: David A
authors.initials: DA
authors.lastname: Barbie
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Jesse S
authors.identifier: 0000-0002-6795-6336
authors.initials: JS
authors.lastname: Boehm
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.|Department of Medicine, Brigham and Women's Hospital, Boston, Massachusetts, USA.|Center for Cancer Genome Discovery, Dana-Farber Cancer Institute, Boston, Massachusetts, USA.
authors.forename: William C
authors.initials: WC
authors.lastname: Hahn
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Medicine, University of California San Diego, La Jolla, California, USA.|Moores Cancer Center, University of California San Diego, La Jolla, California, USA.
authors.forename: Jill P
authors.initials: JP
authors.lastname: Mesirov
authors.affiliation: Eli and Edythe Broad Institute of Harvard and Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.|Department of Medicine, University of California San Diego, La Jolla, California, USA.|Moores Cancer Center, University of California San Diego, La Jolla, California, USA.
authors.forename: Pablo
authors.identifier: 0000-0002-9360-4668
authors.initials: P
authors.lastname: Tamayo
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D002874:Chromosome Mapping / Q000379:methods*; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D052138:Genes, Neoplasm / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics; D015894:Genome, Human / Q000235:genetics; D055106:Genome-Wide Association Study / Q000379:methods*; D006801:Humans; D009154:Mutation / Q000235:genetics; D009363:Neoplasm Proteins / Q000235:genetics*; D009369:Neoplasms / Q000175:diagnosis / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics
chemical_list: D014408:Biomarkers, Tumor; D009363:Neoplasm Proteins