Low-amplitude copy number gains shape cancer through known and novel oncogenes with associated therapeutic vulnerabilities.

Large chromosomal copy number gains are ubiquitous throughout cancer types. However, which genes drive their selective advantage is not well established, and therefore they are hardly utilized in clinical practice. Our analysis of copy number patterns in pan-cancer datasets suggests that the selective advantage of copy number gains is largely driven by known oncogenes. Analysis of CRISPR screening data identifies a list of 101 genes that are likely to mediate the effect of these gains, which is highly enriched in annotated oncogenes but also contains genes that have not been implicated in cancer so far. Moreover, we show that specific gains are associated with drug sensitivity or resistance, with a strong enrichment of gains of oncogenes with increased sensitivity to inhibitors targeting these specific genes. Finally, we provide examples where gains can function as relevant clinical biomarkers for diagnosis and treatment. Thus, large copy number gains exert their selective advantage through known and novel oncogenes, and their systematic analysis could advance precision oncology.