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


CONCLUSIONS
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.
Cheung
Hannah C
HC
Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas M, D, Anderson Cancer Center, Houston, TX 77030, USA. hcheung@mdanderson.org
Baggerly
Keith A
KA
Tsavachidis
Spiridon
S
Bachinski
Linda L
LL
Neubauer
Valerie L
VL
Nixon
Tamara J
TJ
Aldape
Kenneth D
KD
Cote
Gilbert J
GJ
Krahe
Ralf
R
D017398:Alternative Splicing; D001483:Base Sequence; D001932:Brain Neoplasms / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D017931:DNA Primers / Q000235:genetics; D044127:Epigenesis, Genetic; D005091:Exons; D020869:Gene Expression Profiling; D005909:Glioblastoma / Q000235:genetics* / Q000378:metabolism*; D005910:Glioma / Q000235:genetics / Q000378:metabolism; D006801:Humans; D020411:Oligonucleotide Array Sequence Analysis; D012322:RNA Precursors / Q000235:genetics* / Q000378:metabolism*; D012334:RNA, Neoplasm / Q000235:genetics* / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
D017931:DNA Primers; D012322:RNA Precursors; D012334:RNA, Neoplasm; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1