Dataset Information

Defining a Cancer Dependency Map.

ABSTRACT: Most human epithelial tumors harbor numerous alterations, making it difficult to predict which genes are required for tumor survival. To systematically identify cancer dependencies, we analyzed 501 genome-scale loss-of-function screens performed in diverse human cancer cell lines. We developed DEMETER, an analytical framework that segregates on- from off-target effects of RNAi. 769 genes were differentially required in subsets of these cell lines at a threshold of six SDs from the mean. We found predictive models for 426 dependencies (55%) by nonlinear regression modeling considering 66,646 molecular features. Many dependencies fall into a limited number of classes, and unexpectedly, in 82% of models, the top biomarkers were expression based. We demonstrated the basis behind one such predictive model linking hypermethylation of the UBB ubiquitin gene to a dependency on UBC. Together, these observations provide a foundation for a cancer dependency map that facilitates the prioritization of therapeutic targets.

SUBMITTER: Tsherniak A

PROVIDER: S-EPMC5667678 | biostudies-literature | 2017 Jul

REPOSITORIES: biostudies-literature

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Publications

Defining a Cancer Dependency Map.

Tsherniak Aviad A Vazquez Francisca F Montgomery Phil G PG Weir Barbara A BA Kryukov Gregory G Cowley Glenn S GS Gill Stanley S Harrington William F WF Pantel Sasha S Krill-Burger John M JM Meyers Robin M RM Ali Levi L Goodale Amy A Lee Yenarae Y Jiang Guozhi G Hsiao Jessica J Gerath William F J WFJ Howell Sara S Merkel Erin E Ghandi Mahmoud M Garraway Levi A LA Root David E DE Golub Todd R TR Boehm Jesse S JS Hahn William C WC

Cell 20170701 3

Most human epithelial tumors harbor numerous alterations, making it difficult to predict which genes are required for tumor survival. To systematically identify cancer dependencies, we analyzed 501 genome-scale loss-of-function screens performed in diverse human cancer cell lines. We developed DEMETER, an analytical framework that segregates on- from off-target effects of RNAi. 769 genes were differentially required in subsets of these cell lines at a threshold of six SDs from the mean. We found ...[more]

PMID: 28753430

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Project description:Cancer Dependency Map (CDM) genes comprise an extensive series of genome-scale RNAi-based loss-of-function tests; hence, it served as a method based on the CRISPR-Cas9 technique that could assist scientists in investigating potential gene functions. These CDM genes have a role in tumor cell survival and proliferation, suggesting that they may be used as new therapeutic targets for some malignant tumors. So far, there have been less research on the involvement of CDM genes in breast cancer, and only a tiny percentage of CDM genes have been studied. In this study, information of patients with breast cancer was extracted from The Cancer Genome Atlas (TCGA), from which differentially expressed CDM genes in breast cancer were determined. A variety of bioinformatics techniques were used to assess the functions and prognostic relevance of these confirmed CDM genes. In all, 290 CDM genes were found differentially expressed. Six CDM genes (SRF, RAD51, PMF1, EXOSC3, EXOC1, and TSEN54) were found to be associated with the prognosis of breast cancer samples. Based on the expression of the identified CDM genes and their coefficients, a prognosis model was constructed for prediction, according to which patients with breast cancer were separated into two risk groups. Those with high risk had substantially poorer overall survival (OS) than patients in the other risk group in the TCGA training set, TCGA testing set, and an external cohort from Gene Expression Omnibus (GEO) database. The area under the receiver operating characteristic (ROC) curve for this prognostic signature was, respectively, 0.717 and 0.635 for TCGA training and testing sets, demonstrating its reliability in predicting the prognosis of patients with breast cancer. We next created a nomogram using the six CDM genes discovered to create a therapeutically useful model. The Human Protein Atlas database was used to acquire all immunohistochemistry staining images of the discovered CDM genes. The proportions of tumor-infiltrating immune cells, as well as the expression levels of checkpoint genes, varied substantially between the two risk groups, according to the analyses of immune response. In conclusion, the findings of this research may aid in the understanding of the prognostic value and biological roles of CDM genes in breast cancer.

Dataset Information

Defining a Cancer Dependency Map.

Publications

Defining a Cancer Dependency Map.

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