Kinase analysis of penile squamous cell carcinoma on multiple platforms to identify potential therapeutic targets
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Eddy S. Yang1,*, Christopher D. Willey1,*, Amitkumar Mehta2,*, Michael R. Crowley3, David K. Crossman3, Dongquan Chen4, Joshua C. Anderson1, Gurudatta Naik2, Deborah L. Della Manna1, Tiffiny S. Cooper1, Guru Sonpavde2
1Department of Radiation Oncology, University of Alabama, Birmingham (UAB), Birmingham, Alabama, USA
2Department of Medicine, Section of Oncology, UAB School of Medicine, Birmingham, Alabama, USA
3Department of Genetics, UAB School of Medicine, Birmingham, Alabama, USA
4Department of Medicine, Division of Preventive Medicine, Biostatistics and Bioinformatics Shared Facility, UAB Comprehensive Cancer Center, Birmingham, Alabama, USA
*These authors have equal credit
Guru Sonpavde, email: [email protected]
Keywords: penile squamous cell carcinoma, kinases, DNA, RNA, protein
Received: August 23, 2016 Accepted: January 23, 2017 Published: February 21, 2017
Penile squamous cell carcinoma (PSCC) is an orphan malignancy with poorly understood biology and suboptimal systemic therapy. Given that kinases may be drivers and readily actionable, we performed comprehensive multiplatform analysis of kinases in PSCC tumor and normal tissue. Fresh frozen tumors were collected from 11 patients with PSCC. After macrodissection to demarcate tumor from normal tissue, the samples underwent multiplatform analysis of kinases. Next Generation Sequencing (NGS) of 517 kinase genes was performed using Agilent Kinome capture and run on the Illumina MiSeq at PE150bp. The NanoString nCounter® platform analyzed the expression of 519 kinase genes. Kinase activity of tissue lysates was measured using PamStation®12 high-content phospho-peptide substrate microarray system. Network mapping was done with GeneGo MetaCore™ and upstream kinase prediction was performed with BioNavigator and the Kinexus database. Ingenuity pathway analysis was performed to integrate elevated kinase activity and gene over-expression with coexisting missense mutations at DNA level. Top pathways upregulated in both the kinase activity and gene expression platforms were PTEN, STAT3, GNRH, IL-8 and B cell receptor signaling. Potentially relevant missense mutations were seen in 176 kinase genes, with the top altered pathways overlapping with gene overexpression being GNRH, NF-kB and STAT3 signaling. ERBB2, ERBB3 and SYK were altered on NGS and also exhibited elevated kinase activity. To summarize, multiplatform comprehensive analysis of kinases discovered potential drivers of PSCC and actionable therapeutic targets. Translational studies are necessary to validate the functional relevance of our data to make advances in this rare malignancy.
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