Discovery of novel splice forms and functional analysis of cancer-specific alternative splicing in human expressed sequences

Abstract

We report here a genome-wide analysis of alternative splicing in 2 million human expressed sequence tags (ESTs), to identify splice forms that are upregulated in tumors relative to normal tissues. We found strong evidence (P < 0.01) of cancer-speci®c splice variants in 316 human genes. In total, 78% of the cancer-speci®c splice forms we detected are con®rmed by human-curated mRNA sequences, indicating that our results are not due to random mis-splicing in tumors; 73% of the genes showed the same cancer-speci®c splicing changes in tissuematched tumor versus normal datasets, indicating that the vast majority of these changes are associated with tumorigenesis, not tissue speci®city. We have con®rmed our EST results in an independent set of experimental data provided by human-curated mRNAs (P-value 10 ±5.7 ). Moreover, the majority of the genes we detected have functions associated with cancer (P-value 0.0007), suggesting that their altered splicing may play a functional role in cancer. Analysis of the types of cancer-speci®c splicing shifts suggests that many of these shifts act by disrupting a tumor suppressor function. 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.

Coupling between alternative polyadenylation and alternative splicing is limited to terminal introns

“…It is known that splicing defects play a role in many human diseases, 50,51 including numerous types of cancer. [52][53][54][55] Similarly, APA has a demonstrated regulatory role in human disease. 30,[56][57][58][59] Thus, coordinated APA and upstream AS could generate alternatively spliced mRNA isoforms with unique 3 0 UTRs that dictate mRNA half-lives and protein product functions (Fig.…”

The PRMT1 gene expression pattern in colon cancer

“…Approximately, 10 -30% of alternatively spliced human genes have tissue-specific variants (Xu et al, 2002), whereas 316 genes have been shown to have cancer-specific variants (Xu and Lee, 2003). Production of alternative transcripts may be a consequence of disease such as cancer (Mercatante and Kole, 2000).…”

Knockdown of polypyrimidine tract-binding protein suppresses ovarian tumor cell growth and invasiveness in vitro

“…Mounting evidence suggests that altered splicing is associated with and possibly involved in tumor progression and/or metastasis (Venables, 2004). Recent computational analyses, based on alignments of expressed sequence tags to human RefSeq mRNAs or human genomic DNA, revealed that many alternatively spliced variants were significantly associated with cancer, and the majority of these genes have functions related to cancer (Wang et al, 2003;Xu and Lee, 2003). In general, the direct causes behind the alteration of pre-mRNA splicing can be divided into two categories: mutations in cis-elements and changes in trans-acting factors.…”