Novel robust biomarkers for human bladder cancer based on activation of intracellular signaling pathways
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Ksenia Lezhnina1,2, Olga Kovalchuk3,4, Alexander A. Zhavoronkov,2,5,6, Mikhail B. Korzinkin1, Anastasia A. Zabolotneva7, Peter V. Shegay8, Dmitry G. Sokov9, Nurshat M. Gaifullin10,11, Igor G. Rusakov8, Alexander M. Aliper1,2, Sergey A. Roumiantsev2, Boris Y. Alekseev8, Nikolay M. Borisov12 and Anton A. Buzdin1,2,7
1 Pathway Pharmaceuticals, Wan Chai, Hong Kong, Hong Kong SAR
2 Laboratory of Bioinformatics, D. Rogachyov Federal Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
3 Department of Biological Sciences, University of Lethbridge, 4401 University Drive, Lethbridge, AB, T1K 3M4
4 Canada Cancer and Aging Research Laboratories, Lethbridge, AB, Canada
5 Insilico Medicine, Inc, ETC, Johns Hopkins University, Baltimore, MD
6 Faculty of Biological and Medical Physics, Moscow Institute of Physics and Technology
7 Group for Genomic Regulation of Cell Signaling Systems, Shemyakn-Ovchinnikov Institute of Bioorganic Chemistry, Moscow, Russia
8 P.A. Herzen Moscow Oncological Research Institute, Moscow, Russia
9 Moscow 1st Oncological Hospital, Moscow, Russia
10 Lomonosov Moscow State University, Faculty of Fundamental Medicine, Moscow, Russia
11 Russian medical postgraduate academy,Moscow, Russia
12 Laboratory of Systems Biology, A.I. Burnasyan Federal Medical Biophysical Center, Moscow, Russia
Anton A. Buzdin, email:
Keywords: Bladder cancer, Intracellular signaling pathway activation, Gene expression, Transcriptome profiling, Molecular markers, AUC
Received: August 21, 2014 Accepted: September 15, 2014 Published: September 16, 2014
We recently proposed a new bioinformatic algorithm called OncoFinder for quantifying the activation of intracellular signaling pathways. It was proved advantageous for minimizing errors of high-throughput gene expression analyses and showed strong potential for identifying new biomarkers. Here, for the first time, we applied OncoFinder for normal and cancerous tissues of the human bladder to identify biomarkers of bladder cancer. Using Illumina HT12v4 microarrays, we profiled gene expression in 17 cancer and seven non-cancerous bladder tissue samples. These experiments were done in two independent laboratories located in Russia and Canada. We calculated pathway activation strength values for the investigated transcriptomes and identified signaling pathways that were regulated differently in bladder cancer (BC) tissues compared with normal controls. We found, for both experimental datasets, 44 signaling pathways that serve as excellent new biomarkers of BC, supported by high area under the curve (AUC) values. We conclude that the OncoFinder approach is highly efficient in finding new biomarkers for cancer. These markers are mathematical functions involving multiple gene products, which distinguishes them from “traditional” expression biomarkers that only assess concentrations of single genes.
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