Abstract
Cancer cells usually depend on the aberrant function of one or few driver genes to initiate and promote their malignancy, an attribute known as oncogene addiction. However, cancer cells might become dependent on the normal cellular functions of certain genes that are not oncogenes but ensure cell survival (non-oncogene addiction). The downregulation or silencing of DNA repair genes and the consequent genetic and epigenetic instability is key to promote malignancy, but the activation of the DNA-damage response (DDR) has been shown to become a type of non-oncogene addiction that critically supports tumour survival. In the present study, a systematic evaluation of DNA repair addiction at the pan-cancer level was performed using data derived from The Cancer Dependency Map and The Cancer Genome Atlas (TCGA). From 241 DDR genes, 59 were identified as commonly essential in cancer cell lines. However, large differences were observed in terms of dependency scores in 423 cell lines and transcriptomic alterations across 18 cancer types. Among these 59 commonly essential genes, 14 genes were exclusively associated with better overall patient survival and 19 with worse overall survival. Notably, a specific molecular signature among the latter, characterized by DDR genes like UBE2T, RFC4, POLQ, BRIP1, and H2AFX showing the weakest dependency scores, but significant upregulation was strongly associated with worse survival. The present study supports the existence and importance of non-oncogenic addiction to DNA repair in cancer and may facilitate the identification of prognostic biomarkers and therapeutic opportunities.
Highlights
Tumours develop through a multistage process driven by the acquisition of genetic and epigenetic abnormalities, many of them become dependent on one or few genes to promote malignancy
I integrated data derived from The Cancer Dependency Map and transcriptomic data derived from The Cancer Genome Atlas (TCGA) to characterize the non-oncogene addiction to DNA repair across the pan-cancer scale
In order to obtain an updated list, a literature search was done and the most comprehensive list found was used as a starting point[6]. This list comprised 276 DNA Damage Repair (DDR) genes annotated in ten different DNA repair pathways, but genes involved in the nucleotide pool maintenance were excluded in this study as that is not truly a pathway
Summary
Tumours develop through a multistage process driven by the acquisition of genetic and epigenetic abnormalities, many of them become dependent on one or few genes to promote malignancy As many of these genes were originally identified as oncogenes, this attribute was named oncogene a ddiction[1]. Given the importance of both oncogene and non-oncogene addiction, different groups have developed a variety of approaches to identify and prioritize cancer dependencies and vulnerabilities to exploit them therapeutically. Two large pan-cancer CRISPR-Cas[9] screens were independently performed with the same goal, containing data from over 1000 screens of more than 900 cell lines[12,13] Based on both approaches, a combined CRISPR-shRNA dependency score was later developed, providing a more sensitive measure to identify essential genes[14]. This approach may facilitate the identification of prognostic biomarkers and therapeutic opportunities by targeting this non-oncogene addiction
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