Abstract 1260: Alternative splicing studies for the identification of novel cancer markers and targets for antibody-based therapy
Authors: Anne-Sophie Casagrande, Florence Mahé, Emeline Throo, Vin Kotraiah, Diego Pallares, Matt Pando, Laurent Desire
Journal: Cancer Research (2012)

Abstract Alternative splicing plays a major role in gene regulation, both in normal tissues as well as in disease. In cancer, abnormal alternative splicing, resulting in the production of novel transcript variants, has an impact on cellular processes related to tumor progression, including inhibition of apoptosis, tumor invasion, metastasis and angiogenesis. The identification of consistent molecular changes underlying the initiation and the progression of cancers is critical to better understand the mechanisms underlying tumorigenesis. Such molecular changes represent promising candidates for diagnostic and therapeutic applications. Exonhit has developed the Genome Wide SpliceArray™, a new generation of microarray that extends transcriptomic profiling to the monitoring of alternative splicing, thereby increasing the discriminatory power of the analyses. Through this novel discovery platform, libraries of alternative splicing events that are deregulated in cancer have been generated in order to be interrogated for the identification of novel biomarkers, allowing to monitor disease status, progression/relapse, and specificity/selectivity of drug response. Here we describe the identification of novel markers and transmembrane targets, arising in different cancers due to alternative splicing. Alternatively spliced transcripts were isolated from breast, colon, and lung tumors and their corresponding adjacent normal tissues (20 each). Different splicing patterns were evidenced in tumoral versus normal tissues and from specificity analysis performed across a pool of 20 normal organs. Events of interest, focused on splicing events that generate potential novel amino acid sequences, were selected based on combination of statistical analysis of probe sets deregulations, protein knowledge and pathway analyses. The events were used to identify novel cell surface epitopes for antibody development with therapeutic or diagnostic usefulness and were subsequently validated by QPCR analysis. With our microarray profiling performed here, focusing on up-regulated genes with biomarker potential, we identified and successfully validated genes that exhibit differential splicing in different cancers compared to normal adjacent tissue. We concentrated our analyses on genes involved in key processes of cancer progression such as epithelial-to-mesenchymal transition (EMT) and extracellular matrix remodeling. Alternative RNA splicing offers a currently underexploited source of biological information for cancer research. Platforms dedicated to alternative splicing such as the SpliceArray™ can be integrated into discovery processes to allow identification of biomarkers and novel targets. Further, such platforms may also provide guidance in the selection and follow-up of patients in clinical trials. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1260. doi:1538-7445.AM2012-1260