Alternative splicing studies for the identification of novel cancer markers

• Published in: European journal of cancer (1990) Vol. 47; p. S13
• Main Authors: Casagrande, A-S, Kotraiah, V, Toema, D, Kong, D, Mahe, F, Pando, M, Desire, L
• Format: Journal Article
• Language: English
• Published: 01.10.2011
• Subjects: Alternative splicing; Antibodies; biomarkers; Cancer; Cell surface; Colon; DNA probes; Drug development; Drug discovery; Drug resistance; Epitopes; Genomes; Lung; RNA; Statistical analysis; Transcription; Tumor cell lines; Tumors
• ISSN: 0959-8049

Background: Abnormal alternative splicing occurs in cancer, resulting in the production of novel transcript variants. Understanding the diverse mechanisms by which splicing dysregulation contributes to human disease will opened up new perspectives for drug development, biomarkers identification and drug response monitoring. ExonHit has generated a novel discovery platform, the Genome Wide SpliceArray, and is currently building libraries of alternative splicing events that are deregulated in cancer and in cases of therapy resistance. These libraries can be interrogated for the identification of novel biomarkers, allowing to monitor disease status, progression/relapse, and specificity/selectivity of drug response. Here, the SpliceArray platform was used for the profiling of different cancers to identify novel markers that are either commonly regulated across multiple cancers or specific of a given cancer type. Materials and Methods: Transcripts alternatively spliced were isolated from breast, colon, and lung tumors and their corresponding adjacent normal tissues. Different splicing patterns were evidenced in tumoral versus normal tissues and from specificity analysis performed across a pool of 20 normal organs. Based on combination of statistical analysis of probe sets deregulations, and protein knowledge, most relevant events were selected as alternatively spliced transcripts. Finally, focusing on splicing events that generate potential novel amino acid sequences, we conducted a QPCR expression analysis to validate the specificity of the selected events identified by the probe sets that emerged from the genome-wide splicing analysis in these 3 cancers. Results: These validated events will be used to identify novel cell surface epitopes for antibody development with therapeutic and/or diagnostic usefulness. Applying this same approach, we profiled two types of Imatinib-resistant leukemia cell lines to identify pathways/genes or splicing events potentially involved in drug resistance affecting genes with biomarker potential. Conclusion: Our results demonstrate that alternative RNA splicing offers a currently underexploited source of biological information for studying the cancer diversity. Platforms dedicated to alternative splicing can be integrated into discovery processes to allow identification of novel cancer makers, diagnostics and targets for drug discovery.