A compendium of Amplification-Related Gain Of Sensitivity (ARGOS) genes in human cancer

Abstract

Chromosomal gains are among the most frequent somatic genetic alterations occurring in cancer. While the effect of sustained oncogene expression has been characterized, the impact of copy-number gains affecting collaterally-amplified “bystander” genes on cellular fitness remains less understood. To investigate this, we built a comprehensive map of dosage compensations across human cancers by integrating expression and copy number profiles from over 8,000 TCGA tumors and CCLE cell lines. Further, we analyzed the effect of gene overexpression across 17 human cancer ORF screens to provide an overview of genes that prove toxic to cancer cells when overexpressed. Combining these two independent approaches we propose a class of ‘Amplification-Related Gain Of Sensitivity’ (ARGOS) genes. These genes are located in commonly amplified regions of the genome, have lower expression levels than expected by their copy-number status, and are toxic to cancer cells when overexpressed. We experimentally validatedCDKN1AandRBM14as high-confidence pan-cancer ARGOS genes in lung and breast cancer cell line models. We additionally suggest that RBM14’s mechanism of toxicity involves altered DNA damage response and innate immune signaling processes following gene overexpression. Finally, we provide a comprehensive catalog of compensated, toxic, and ARGOS genes as a community resource.

Recurrent breakpoints in theBRD4locus reduce toxicity associated with gene amplification

“…We next determined the log-fold changes in cell growth following overexpression of BRD4-long and BRD4-short isoforms across different cell lines for a period of 2-3 weeks and in the absence of any additional selection pressures (Figure 3A). In 10/16 cell lines (62.5%), global BRD4 overexpression decreased cell growth (as evidenced by negative log-fold changes), supporting its role as a "toxic" gene in cancer 29 . For the remaining cell lines, gene overexpression had a neutral effect on cell proliferation (Figure 3B).…”

“…In recent efforts, our group and others have characterized the effect of collateral amplifications occurring across multiple tumor types, identifying genes that cause proliferation defects when overexpressed due to their close genomic proximity to an amplified oncogene. Such amplifications introduce genetic vulnerabilities and may present novel therapeutic avenues 29,[34][35][36] . Our current study provides evidence of BRD4 focal deletions serving as a mechanism of gene-dosage compensation following gene amplification.…”

“…The analysis of ORF screen data was performed as previously described 29 . Briefly, we looked at data from 16 independent screens conducted at the Broad Institute of MIT and Harvard, were cells were infected with the ORFeome pLX_317 barcoded library, which contains 16,100 barcoded ORFs over-expressing 12,753 genes.…”