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Bringing Down Cancer Aircraft: Searching for Essential Hypomutated Proteins in Skin Melanoma.

Pyatnitskiy M, Karpov D, Poverennaya E, Lisitsa A, Moshkovskii S - PLoS ONE (2015)

Bottom Line: 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.The Gene Ontology analysis revealed enrichment of essential proteins related to membrane and cell periphery.Another finding is the overrepresentation of semaphorin receptors, which can mediate distinctive signaling cascades and are involved in various aspects of tumor development.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biomedical Chemistry, 119121, Pogodinskaya str, 10, Moscow, Russia.

ABSTRACT
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.

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Related in: MedlinePlus

Analogy between bullet-free plane critical areas and hypomutated proteins essential for cancer.Undamaged areas on the returned planes are critical for the aircraft performance. Similarly we propose that proteins with reduced number of deleterious somatic mutations compared to germline are essential for cancer cell survival.
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pone.0142819.g001: Analogy between bullet-free plane critical areas and hypomutated proteins essential for cancer.Undamaged areas on the returned planes are critical for the aircraft performance. Similarly we propose that proteins with reduced number of deleterious somatic mutations compared to germline are essential for cancer cell survival.

Mentions: Our study represents an alternative approach to analysis of cancer genome data. The idea is inspired by a well-known fact from the history of applied statistics, namely Abraham Wald's aircraft problem [6]. Wald proposed to search for aircraft vulnerability zones by estimation of the bullet-free patches on airplanes which returned to the airbase from a combat flight. Indeed, it is the bullet-free areas on the machine surface are essential for the aircraft performance. If bullets hit those areas, then the machines crashed and the data on aircraft vulnerability became unobservable (Fig 1, left panel). So the bullet-free zones on the returned aircrafts were essential for the plane functioning and hence needed more armor.


Bringing Down Cancer Aircraft: Searching for Essential Hypomutated Proteins in Skin Melanoma.

Pyatnitskiy M, Karpov D, Poverennaya E, Lisitsa A, Moshkovskii S - PLoS ONE (2015)

Analogy between bullet-free plane critical areas and hypomutated proteins essential for cancer.Undamaged areas on the returned planes are critical for the aircraft performance. Similarly we propose that proteins with reduced number of deleterious somatic mutations compared to germline are essential for cancer cell survival.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4643971&req=5

pone.0142819.g001: Analogy between bullet-free plane critical areas and hypomutated proteins essential for cancer.Undamaged areas on the returned planes are critical for the aircraft performance. Similarly we propose that proteins with reduced number of deleterious somatic mutations compared to germline are essential for cancer cell survival.
Mentions: Our study represents an alternative approach to analysis of cancer genome data. The idea is inspired by a well-known fact from the history of applied statistics, namely Abraham Wald's aircraft problem [6]. Wald proposed to search for aircraft vulnerability zones by estimation of the bullet-free patches on airplanes which returned to the airbase from a combat flight. Indeed, it is the bullet-free areas on the machine surface are essential for the aircraft performance. If bullets hit those areas, then the machines crashed and the data on aircraft vulnerability became unobservable (Fig 1, left panel). So the bullet-free zones on the returned aircrafts were essential for the plane functioning and hence needed more armor.

Bottom Line: 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.The Gene Ontology analysis revealed enrichment of essential proteins related to membrane and cell periphery.Another finding is the overrepresentation of semaphorin receptors, which can mediate distinctive signaling cascades and are involved in various aspects of tumor development.

View Article: PubMed Central - PubMed

Affiliation: Institute of Biomedical Chemistry, 119121, Pogodinskaya str, 10, Moscow, Russia.

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus