title: Systematic investigation of genetic vulnerabilities across cancer cell lines reveals lineage-specific dependencies in ovarian cancer.
abstract: A comprehensive understanding of the molecular vulnerabilities of every type of cancer will provide a powerful roadmap to guide therapeutic approaches. Efforts such as The Cancer Genome Atlas Project will identify genes with aberrant copy number, sequence, or expression in various cancer types, providing a survey of the genes that may have a causal role in cancer. A complementary approach is to perform systematic loss-of-function studies to identify essential genes in particular cancer cell types. We have begun a systematic effort, termed Project Achilles, aimed at identifying genetic vulnerabilities across large numbers of cancer cell lines. Here, we report the assessment of the essentiality of 11,194 genes in 102 human cancer cell lines. We show that the integration of these functional data with information derived from surveying cancer genomes pinpoints known and previously undescribed lineage-specific dependencies across a wide spectrum of cancers. In particular, we found 54 genes that are specifically essential for the proliferation and viability of ovarian cancer cells and also amplified in primary tumors or differentially overexpressed in ovarian cancer cell lines. One such gene, PAX8, is focally amplified in 16% of high-grade serous ovarian cancers and expressed at higher levels in ovarian tumors. Suppression of PAX8 selectively induces apoptotic cell death of ovarian cancer cells. These results identify PAX8 as an ovarian lineage-specific dependency. More generally, these observations demonstrate that the integration of genome-scale functional and structural studies provides an efficient path to identify dependencies of specific cancer types on particular genes and pathways.
authors: Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA 02115, USA.
authors: Hiu Wing
authors: HW
authors: Cheung
authors: Glenn S
authors: GS
authors: Cowley
authors: Barbara A
authors: BA
authors: Weir
authors: Jesse S
authors: JS
authors: Boehm
authors: Scott
authors: S
authors: Rusin
authors: Justine A
authors: JA
authors: Scott
authors: Alexandra
authors: A
authors: East
authors: Levi D
authors: LD
authors: Ali
authors: Patrick H
authors: PH
authors: Lizotte
authors: Terence C
authors: TC
authors: Wong
authors: Guozhi
authors: G
authors: Jiang
authors: Jessica
authors: J
authors: Hsiao
authors: Craig H
authors: CH
authors: Mermel
authors: Gad
authors: G
authors: Getz
authors: Jordi
authors: J
authors: Barretina
authors: Shuba
authors: S
authors: Gopal
authors: Pablo
authors: P
authors: Tamayo
authors: Joshua
authors: J
authors: Gould
authors: Aviad
authors: A
authors: Tsherniak
authors: Nicolas
authors: N
authors: Stransky
authors: Biao
authors: B
authors: Luo
authors: Yin
authors: Y
authors: Ren
authors: Ronny
authors: R
authors: Drapkin
authors: Sangeeta N
authors: SN
authors: Bhatia
authors: Jill P
authors: JP
authors: Mesirov
authors: Levi A
authors: LA
authors: Garraway
authors: Matthew
authors: M
authors: Meyerson
authors: Eric S
authors: ES
authors: Lander
authors: David E
authors: DE
authors: Root
authors: William C
authors: WC
authors: Hahn
mesh_terms: D000429:Alcohol Oxidoreductases; D001483:Base Sequence; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study; D006801:Humans; D009857:Oncogenes; D010051:Ovarian Neoplasms / Q000235:genetics* / Q000473:pathology; D000072636:PAX8 Transcription Factor; D051761:Paired Box Transcription Factors / Q000235:genetics; D012334:RNA, Neoplasm / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics
chemical_list: D000072636:PAX8 Transcription Factor; C083325:PAX8 protein, human; D051761:Paired Box Transcription Factors; D012334:RNA, Neoplasm; D034741:RNA, Small Interfering; D000429:Alcohol Oxidoreductases; C021496:lactate-malate transhydrogenase