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.

Emerging insights into the molecular and cellular basis of glioblastoma

“…To this end, genome-wide tools capable of loss-and gain-offunction studies will likely be invaluable in interrogating phenotypes particularly relevant to glioblastoma. Large-scale pooled shRNA screening of a panel of glioblastoma cell lines as part of a larger panel of multiple lineages led to the identification of a list of candidate dependencies (Cheung et al 2011). These approaches should use panels of highly faithful models-murine and human-that recapitulate the salient in vivo behaviors of interest.…”

FACT Proteins, SUPT16H and SSRP1, Are Transcriptional Suppressors of HIV-1 and HTLV-1 That Facilitate Viral Latency

“…To calculate a gene-specific enrichment score based on the rank distribution of each individual RNAi reagent among all three screens performed by our group (Silencer Select, esiRNA, and SMARTpool), we used the RNAi gene enrichment ranking (RIGER) method that denotes the likelihood that the selected gene plays a role in the phenotype of interest (35,36). We generated the average RIGER score (RIGER3) from three RIGER integrative approaches (the second best, weighted sum, and Kolmogorov-Smirnov) and ranked genes from the most likely host dependence factors to host restriction factors were lysed for IP assays using an anti-FLAG or a mIgG antibody.…”

In vivo multiplexed interrogation of amplified genes identifies GAB2 as an ovarian cancer oncogene

“…We and others have performed large scale, lossof-function short hairpin RNA (shRNA) screens to identify essential cancer genes and recently reported PAX8 and ID4 as ovarian cancer dependencies (4,5). In other cancer types, both genome-wide and targeted loss-of-function studies were used to identify novel tumor suppressors in hepatocellular carcinoma (6) and epigenetic regulators in lymphomas (7).…”