Bringing Down Cancer Aircraft: Searching For Essential Hypomutated Proteins In Skin Melanoma

Abstract

Abstract\n\nBackgroundWe propose an approach to detection of essential proteins required for cancer cell survival. Gene is considered essential if mutation with high functional impact upon function of encoded protein causes death of cancer cell. We draw an analogy between essential cancer proteins and well-known Abraham Walds work on estimating the plane critical areas using data on survivability of aircraft encountering enemy fire. Wald reasoned that parts hit least on the returned planes are critical and should be protected more. Similarly we propose that genes essential for tumor cell should carry less high-impact mutations in cancer compared to polymorphisms found in normal cells.\n\nResultsWe used data on mutations from the Cancer Genome Atlas and polymorphisms found in healthy humans (from 1000 Genomes Project) to predict 91 protein-coding genes essential for melanoma. These genes were selected according to several criteria including negative selection, expression in melanocytes and decrease in the proportion of high-impact mutations in cancer compared with normal cells.\n\nGene ontology analysis revealed enrichment of essential proteins related to membrane and cell periphery. We speculate that this could be a sign of immune system-driven negative selection of cancer neo-antigens. Another finding is overrepresentation of semaphorin receptors, which can mediate distinctive signaling cascades and are involved in various aspects of tumor development. Cytokine receptors CCR5 and CXCR1 were also identified as cancer essential proteins and this is confirmed by other studies.\n\nConclusionsOverall our goal was to illustrate the idea of detecting proteins whose sequence integrity and functioning is important for cancer cell survival. Hopefully, this prediction of essential cancer proteins may point to new targets for anti-tumor therapies.