Defining a Cancer Dependency Map

Abstract

SUMMARY 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 standard deviations 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.

Interrogation of Mammalian Protein Complex Structure, Function, and Membership Using Genome-Scale Fitness Screens

“…Depletion of individual subunits required for complex function would be predicted to produce similar phenotypic effects on fitness (Figure 1A, right ). To assess this premise systematically in human cells, we analyzed recently-generated datasets from large-scale RNAi- and CRISPR-Cas9- based fitness screening efforts of hundreds of cancer cell lines via Project Achilles (https://portals.broadinstitute.org/achilles) (Cowley et al, 2014; Meyers et al, 2017; Tsherniak et al, 2017). Over 600 cancer cell lines representing 23 different lineages were screened across the RNAi and CRISPR-Cas9 datasets, representing an extremely diverse set of cellular contexts (Figure S1A, Table S1).…”

“…We and others have observed that cancer cell lines exhibit highly variable genetic dependencies for cellular fitness (Bertomeu et al, 2018; Blomen et al, 2015; Hart et al, 2015; Hart et al, 2017a; McDonald et al, 2017; Meyers et al, 2017; Tsherniak et al, 2017; Wang et al, 2015; Wang et al, 2017b) in a manner that reflects the diverse genomic and transcriptomic alterations a cell may accumulate during tumorigenesis. Project Achilles (Broad Institute of MIT and Harvard) seeks to systematically map genetic vulnerabilities across large collections of cancer cell lines, including the Cancer Cell Line Encyclopedia (CCLE) (Barretina et al, 2012), and has recently performed genome-scale perturbation screens in 501 cancer cell lines using RNA interference (RNAi) (Tsherniak et al, 2017) and in 342 cancer cell lines using CRISPR-Cas9 (Meyers et al, 2017).…”

“…Project Achilles (Broad Institute of MIT and Harvard) seeks to systematically map genetic vulnerabilities across large collections of cancer cell lines, including the Cancer Cell Line Encyclopedia (CCLE) (Barretina et al, 2012), and has recently performed genome-scale perturbation screens in 501 cancer cell lines using RNA interference (RNAi) (Tsherniak et al, 2017) and in 342 cancer cell lines using CRISPR-Cas9 (Meyers et al, 2017). Because the genomic and transcriptomic state of each cancer cell line gives rise to a unique overall fitness response upon perturbation of each gene, these datasets may provide an opportunity derive gene-gene functional relationships and to construct a modular network of cell function.…”

Basic Science in Oncology: Year 2017 Overview

“…Выявлены генетические элементы, ас-социированные с поддержанием жизнеспособности опухолевых клеток [49]. Сходная по своему направле-нию работа опубликована в этом же номере журнала Cell другим коллективом учёных [50].…”

A primer on recent developments in cancer immunotherapy, with a focus on neoantigen vaccines

“…melanoma [112] , the vast majority being "passenger" mutants not associated with cell transformation. Efforts to expand and/or refine the list of functional cancer genes may help in this regard [122,123] . Current vaccine strategy employs several epitopes to address tumor heterogeneity and reduce acquisition of resistance, while also compensating for the imperfect predictive value of pMHC binding tools.…”