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Synthetic sickness or lethality points at candidate combination therapy targets in glioblastoma

MPS-Authors
http://pubman.mpdl.mpg.de/cone/persons/resource/persons50545

Szczurek,  E.
Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons50432

Misra,  N.
Gene Structure and Array Design (Stefan Haas), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

http://pubman.mpdl.mpg.de/cone/persons/resource/persons50613

Vingron,  M.
Gene regulation (Martin Vingron), Dept. of Computational Molecular Biology (Head: Martin Vingron), Max Planck Institute for Molecular Genetics, Max Planck Society;

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Szczurek et al.pdf
(Publisher version), 441KB

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Citation

Szczurek, E., Misra, N., & Vingron, M. (2013). Synthetic sickness or lethality points at candidate combination therapy targets in glioblastoma. International Journal of Cancer, 133(9), 2123-2132. doi:10.1002/ijc.28235.


Cite as: http://hdl.handle.net/11858/00-001M-0000-0014-7BA5-B
Abstract
Synthetic lethal interactions in cancer hold the potential for successful combined therapies, which would avoid the difficulties of single molecule-targeted treatment. Identification of interactions that are specific for human tumors is an open problem in cancer research. This work aims at deciphering synthetic sick or lethal interactions directly from somatic alteration, expression and survival data of cancer patients. To this end, we look for pairs of genes and their alterations or expression levels that are "avoided" by tumors and "beneficial" for patients. Thus, candidates for synthetic sickness or lethality (SSL) interaction are identified as such gene pairs whose combination of states is under-represented in the data. Our main methodological contribution is a quantitative score that allows ranking of the candidate SSL interactions according to evidence found in patient survival. Applying this analysis to glioblastoma data, we collect 1,956 synthetic sick or lethal partners for 85 abundantly altered genes, most of which show extensive copy number variation across the patient cohort. We rediscover and interpret known interaction between TP53 and PLK1, as well as provide insight into the mechanism behind EGFR interacting with AKT2, but not AKT1 nor AKT3. Cox model analysis determines 274 of identified interactions as having significant impact on overall survival in glioblastoma, which is more informative than a standard survival predictor based on patient's age.