We propose an approach to detection of essential genes/
proteins required for
cancer cell survival. A gene is considered essential if a mutation with high impact upon the function of encoded
protein causes death of the
cancer cell. We draw an analogy between essential
cancer proteins and well-known Abraham Wald's work on estimating the plane critical areas using data on survivability of aircraft encountering enemy fire. Wald reasoned that parts with no bullet holes on the airplanes returned to the airbase from a combat flight are the most crucial ones for the airplane functioning: a hit in one of these parts downs an airplane, so it does not return back for the survey. We have envisaged that the airplane surface is a
cancer genome and the bullets are somatic mutations with high impact upon
protein function. Similarly we propose that genes specifically essential for
tumor cell survival should carry less high-impact mutations in
cancer cells compared to polymorphisms found in normal cells. We 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. The Gene 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 the 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. Overall, 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.