Research article

Global analysis of aberrant pre-mRNA splicing in glioblastoma using exon expression arrays

Hannah C Cheung^1,2 , Keith A Baggerly^{* 3,4} , Spiridon Tsavachidis³ , Linda L Bachinski⁵ , Valerie L Neubauer⁵ , Tamara J Nixon⁵ , Kenneth D Aldape^4,6 , Gilbert J Cote^{* 1,4} and Ralf Krahe^{* 2,4,5}

¹Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030, USA

²Graduate Program in Genes and Development, University of Texas at Houston Graduate School of Biomedical Sciences, Houston, TX, 77030, USA

³Department of Bioinformatics and Computational Biology, University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030, USA

⁴Graduate Program in Human and Molecular Genetics, University of Texas at Houston Graduate School of Biomedical Sciences, Houston, TX, 77030, USA

⁵Department of Cancer Genetics, University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030, USA

⁶Department of Pathology, University of Texas M. D. Anderson Cancer Center, Houston, TX, 77030, USA

author email corresponding author email* Contributed equally

BMC Genomics 2008, 9:216doi:10.1186/1471-2164-9-216

Published:	12 May 2008

Abstract

Background

Tumor-predominant splice isoforms were identified during comparative in silico sequence analysis of EST clones, suggesting that global aberrant alternative pre-mRNA splicing may be an epigenetic phenomenon in cancer. We used an exon expression array to perform an objective, genome-wide survey of glioma-specific splicing in 24 GBM and 12 nontumor brain samples. Validation studies were performed using RT-PCR on glioma cell lines, patient tumor and nontumor brain samples.

Results

In total, we confirmed 14 genes with glioma-specific splicing; seven were novel events identified by the exon expression array (A2BP1, BCAS1, CACNA1G, CLTA, KCNC2, SNCB, and TPD52L2). Our data indicate that large changes (> 5-fold) in alternative splicing are infrequent in gliomagenesis (< 3% of interrogated RefSeq entries). The lack of splicing changes may derive from the small number of splicing factors observed to be aberrantly expressed.

Conclusion

While we observed some tumor-specific alternative splicing, the number of genes showing exclusive tumor-specific isoforms was on the order of tens, rather than the hundreds suggested previously by in silico mining. Given the important role of alternative splicing in neural differentiation, there may be selective pressure to maintain a majority of splicing events in order to retain glial-like characteristics of the tumor cells.