title: Predicting cancer-specific vulnerability via data-driven detection of synthetic lethality.
abstract: Synthetic lethality occurs when the inhibition of two genes is lethal while the inhibition of each single gene is not. It can be harnessed to selectively treat cancer by identifying inactive genes in a given cancer and targeting their synthetic lethal (SL) partners. We present a data-driven computational pipeline for the genome-wide identification of SL interactions in cancer by analyzing large volumes of cancer genomic data. First, we show that the approach successfully captures known SL partners of tumor suppressors and oncogenes. We then validate SL predictions obtained for the tumor suppressor VHL. Next, we construct a genome-wide network of SL interactions in cancer and demonstrate its value in predicting gene essentiality and clinical prognosis. Finally, we identify synthetic lethality arising from gene overactivation and use it to predict drug efficacy. These results form a computational basis for exploiting synthetic lethality to uncover cancer-specific susceptibilities.
authors.affiliation: The Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv 6997801, Israel. Electronic address: livnatje@post.tau.ac.il.
authors.forename: Livnat
authors.initials: L
authors.lastname: Jerby-Arnon
authors.affiliation: Cancer Research UK, The Beatson Institute for Cancer Research, Switchback Road, Glasgow G61 1BD, Scotland, UK.
authors.forename: Nadja
authors.initials: N
authors.lastname: Pfetzer
authors.affiliation: The Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv 6997801, Israel.
authors.forename: Yedael Y
authors.initials: YY
authors.lastname: Waldman
authors.affiliation: Cancer Research UK, The Beatson Institute for Cancer Research, Switchback Road, Glasgow G61 1BD, Scotland, UK.
authors.forename: Lynn
authors.initials: L
authors.lastname: McGarry
authors.affiliation: Cancer Research UK, The Beatson Institute for Cancer Research, Switchback Road, Glasgow G61 1BD, Scotland, UK.
authors.forename: Daniel
authors.initials: D
authors.lastname: James
authors.affiliation: Cancer Research UK, The Beatson Institute for Cancer Research, Switchback Road, Glasgow G61 1BD, Scotland, UK.
authors.forename: Emma
authors.initials: E
authors.lastname: Shanks
authors.affiliation: Center for the Science of Therapeutics, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Brinton
authors.initials: B
authors.lastname: Seashore-Ludlow
authors.affiliation: The Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv 6997801, Israel.
authors.forename: Adam
authors.initials: A
authors.lastname: Weinstock
authors.affiliation: The Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel.
authors.forename: Tamar
authors.initials: T
authors.lastname: Geiger
authors.affiliation: Center for the Science of Therapeutics, Broad Institute of Harvard and MIT, 7 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Clemons
authors.affiliation: Cancer Research UK, The Beatson Institute for Cancer Research, Switchback Road, Glasgow G61 1BD, Scotland, UK.
authors.forename: Eyal
authors.initials: E
authors.lastname: Gottlieb
authors.affiliation: The Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv 6997801, Israel; The Sackler School of Medicine, Tel Aviv University, Tel Aviv 6997801, Israel. Electronic address: ruppin@post.tau.ac.il.
authors.forename: Eytan
authors.initials: E
authors.lastname: Ruppin
mesh_terms: D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor; D019295:Computational Biology / Q000379:methods*; D057225:Data Mining / Q000379:methods*; D016147:Genes, Tumor Suppressor; D006801:Humans; D009369:Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000473:pathology; D009857:Oncogenes; D034741:RNA, Small Interfering / Q000378:metabolism; D057188:Workflow
chemical_list: D034741:RNA, Small Interfering