Cancer-Specific Alternative Splicing is prevalent in the Human Genome

Qiang Xu1, Christopher Lee2, Molecular Biology Institute, Department of Chemistry and Biochemistry, UCLA;, Molecular Biology Institute, Department of Chemistry and Biochemistry, UCLA

One of the most prevalent and successful models in cancer research is that cancer involves changes in gene expression1. However, given recent indications that alternative splicing is a widespread mechanism of functional regulation in the human genome2-7, it is interesting to ask whether cancer might also involve changes in mRNA splicing. Cancer-associated splice variants have been reported for EGFR8, CD449 and other genes10-16, and may contribute to cancer (e.g. inhibiting apoptosis, CD79 17), or simply reflect missplicing in tumors18. Here we report a genome-wide analysis of alternative splicing in 2 million expressed sequence tags (ESTs), to identify splice forms that are strongly upregulated in tumors relative to normal tissues. We found strong evidence (p<0.01) of cancer-specific splice variants in 316 human genes. 80% of the cancer-specific splice forms we detected are confirmed by human-curated mRNA sequences, demonstrating that our results are not due to random mis-splicing in tumors. Moreover, the majority of these genes have functions associated with cancer, suggesting that their altered splicing may play a functional role in cancer. Surprisingly, our data show that for a large number (190 in this study) of cancer-associated genes cloned originally from tumors, there exists a previously uncharacterized splice form of the gene that appears to be predominant in normal tissue. Discovery of the normal forms of these genes, and comparison with the cancer-specific forms, should shed a useful new light on the action of these known cancer genes.