title: Pan-cancer network analysis identifies combinations of rare somatic mutations across pathways and protein complexes.
abstract: Cancers exhibit extensive mutational heterogeneity, and the resulting long-tail phenomenon complicates the discovery of genes and pathways that are significantly mutated in cancer. We perform a pan-cancer analysis of mutated networks in 3,281 samples from 12 cancer types from The Cancer Genome Atlas (TCGA) using HotNet2, a new algorithm to find mutated subnetworks that overcomes the limitations of existing single-gene, pathway and network approaches. We identify 16 significantly mutated subnetworks that comprise well-known cancer signaling pathways as well as subnetworks with less characterized roles in cancer, including cohesin, condensin and others. Many of these subnetworks exhibit co-occurring mutations across samples. These subnetworks contain dozens of genes with rare somatic mutations across multiple cancers; many of these genes have additional evidence supporting a role in cancer. By illuminating these rare combinations of mutations, pan-cancer network analyses provide a roadmap to investigate new diagnostic and therapeutic opportunities across cancer types.
authors.affiliation: 1] Department of Computer Science, Brown University, Providence, Rhode Island, USA. [2] Center for Computational Molecular Biology, Brown University, Providence, Rhode Island, USA.
authors.forename: Mark D M
authors.initials: MD
authors.lastname: Leiserson
authors.affiliation: 1] Department of Computer Science, Brown University, Providence, Rhode Island, USA. [2] Center for Computational Molecular Biology, Brown University, Providence, Rhode Island, USA.
authors.forename: Fabio
authors.initials: F
authors.lastname: Vandin
authors.affiliation: 1] Department of Computer Science, Brown University, Providence, Rhode Island, USA. [2] Center for Computational Molecular Biology, Brown University, Providence, Rhode Island, USA.
authors.forename: Hsin-Ta
authors.initials: HT
authors.lastname: Wu
authors.affiliation: 1] Department of Computer Science, Brown University, Providence, Rhode Island, USA. [2] Center for Computational Molecular Biology, Brown University, Providence, Rhode Island, USA. [3] Department of Molecular Biology, Cell Biology and Biochemistry, Brown University, Providence, Rhode Island, USA.
authors.forename: Jason R
authors.initials: JR
authors.lastname: Dobson
authors.affiliation: Department of Computer Science, Brown University, Providence, Rhode Island, USA.
authors.forename: Jonathan V
authors.initials: JV
authors.lastname: Eldridge
authors.affiliation: Department of Computer Science, Brown University, Providence, Rhode Island, USA.
authors.forename: Jacob L
authors.initials: JL
authors.lastname: Thomas
authors.affiliation: Department of Computer Science, Brown University, Providence, Rhode Island, USA.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Papoutsaki
authors.affiliation: Department of Computer Science, Brown University, Providence, Rhode Island, USA.
authors.forename: Younhun
authors.initials: Y
authors.lastname: Kim
authors.affiliation: Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Beifang
authors.initials: B
authors.lastname: Niu
authors.affiliation: Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Michael
authors.initials: M
authors.lastname: McLellan
authors.affiliation: Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Lawrence
authors.affiliation: Research Unit on Biomedical Informatics, Department of Experimental and Health Sciences, University Pompeu Fabra, Barcelona, Spain.
authors.forename: Abel
authors.initials: A
authors.lastname: Gonzalez-Perez
authors.affiliation: Research Unit on Biomedical Informatics, Department of Experimental and Health Sciences, University Pompeu Fabra, Barcelona, Spain.
authors.forename: David
authors.initials: D
authors.lastname: Tamborero
authors.affiliation: Program of Computational Biology and Bioinformatics, Yale University, New Haven, Connecticut, USA.
authors.forename: Yuwei
authors.initials: Y
authors.lastname: Cheng
authors.affiliation: Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut, USA.
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Ryslik
authors.affiliation: 1] Research Unit on Biomedical Informatics, Department of Experimental and Health Sciences, University Pompeu Fabra, Barcelona, Spain. [2] Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain.
authors.forename: Nuria
authors.identifier: 0000000349258988
authors.initials: N
authors.lastname: Lopez-Bigas
authors.affiliation: 1] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA. [2] Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts, USA.
authors.forename: Gad
authors.initials: G
authors.lastname: Getz
authors.affiliation: 1] Genome Institute, Washington University in St. Louis, St. Louis, Missouri, USA. [2] Department of Medicine, Washington University in St. Louis, St. Louis, Missouri, USA. [3] Siteman Cancer Center, Washington University in St. Louis, St. Louis, Missouri, USA.
authors.forename: Li
authors.initials: L
authors.lastname: Ding
authors.affiliation: 1] Department of Computer Science, Brown University, Providence, Rhode Island, USA. [2] Center for Computational Molecular Biology, Brown University, Providence, Rhode Island, USA.
authors.forename: Benjamin J
authors.initials: BJ
authors.lastname: Raphael
mesh_terms: D000465:Algorithms; D019295:Computational Biology / Q000379:methods*; D030541:Databases, Genetic; D053263:Gene Regulatory Networks / Q000235:genetics*; D016678:Genome / Q000235:genetics*; D006801:Humans; D046912:Multiprotein Complexes / Q000235:genetics; D009154:Mutation; D009369:Neoplasms / Q000175:diagnosis / Q000235:genetics*; D015398:Signal Transduction / Q000235:genetics*
chemical_list: D046912:Multiprotein Complexes