title: A novel independence test for somatic alterations in cancer shows that biology drives mutual exclusivity but chance explains most co-occurrence.
abstract: In cancer, mutually exclusive or co-occurring somatic alterations across genes can suggest functional interactions. Existing tests for such patterns make the unrealistic assumption of identical gene alteration probabilities across tumors. We present Discrete Independence Statistic Controlling for Observations with Varying Event Rates (DISCOVER), a novel test that is more sensitive than other methods and controls its false positive rate. A pan-cancer analysis using DISCOVER finds no evidence for widespread co-occurrence, and most co-occurrences previously detected do not exceed expectation by chance. Many mutual exclusivities are identified involving well-known genes related to cell cycle and growth factor signaling, as well as lesser known regulators of Hedgehog signaling.
authors.affiliation: Department of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands.
authors.forename: Sander
authors.initials: S
authors.lastname: Canisius
authors.affiliation: Department of Medical Oncology, Erasmus University Medical Center, Rotterdam, The Netherlands.
authors.forename: John W M
authors.initials: JW
authors.lastname: Martens
authors.affiliation: Department of Molecular Carcinogenesis, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, 1066 CX, The Netherlands. l.wessels@nki.nl.|Faculty of EEMCS, Delft University of Technology, Delft, The Netherlands. l.wessels@nki.nl.|Cancer Genomics Netherlands, Amsterdam, The Netherlands. l.wessels@nki.nl.
authors.forename: Lodewyk F A
authors.initials: LF
authors.lastname: Wessels
mesh_terms: D000465:Algorithms; D019295:Computational Biology; D015972:Gene Expression Regulation, Neoplastic; D053823:Hedgehog Proteins / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D009154:Mutation / Q000235:genetics; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology; D015398:Signal Transduction
chemical_list: D053823:Hedgehog Proteins
keywords: Co-occurrence; Computational biology; Mutual exclusivity