Identifying alternative hyper-splicing signatures in MG-thymoma by exon arrays

Lilach Soreq*, Adi Gilboa-Geffen, Sonia Berrih-Aknin, Paul Lacoste, Ariel Darvasi, Eyal Soreq, Hagai Bergman, Hermona Soreq

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


Background: The vast majority of human genes (>70%) are alternative spliced. Although alternative pre-mRNA processing is modified in multiple tumors, alternative hyper-splicing specific to particular tumor types are still lacking. Here we report the use of Affymetrix Human Exon Arrays to spot hyper-splicing events characteristic of myasthenia gravis (MG)-thymoma, thymic tumors which develop in patients with MG and discriminate them from colon cancer changes. Methodology/Principal Findings: We combined GO term to parent threshold-based and threshold-independent ad-hoc functional statistics with in-depth analysis of key modified transcripts to highlight vaious exon-specific changes. These denote alternative splicing in MG-thymoma tumors compared to healthy human thymus and to in-house and Affymetrix datasets from colon cancer and healthy tissues. By using both global and specific, term-to-parent Gene Oncology (GO) statistical comparisons, our functional integrative ad-hoc method allowed the detection of disease-relevant splicing events. Conclusions/Significance: Hyper-spliced transcripts spanned several categories, including the tumorogenic ERBB4 tyrosine kinase receptor and the connective tissue growth factor CTGF, as well as the immune function-related histocompatibility gene HLA-DRB1 and interleukin (IL) 19, two muscle-specific collagens and one myosin heavy chain gene; intriguingly, a putative new exon was discovered in the MG-involved acethylcholinesterase ACHE gene. Corresponding changes in splicesome composition were indicated by co-decreases in the splicing factors ASF/ SF2 and SC35. Parallel tumor-associated changes occured in colon cancer as well, but the majority of the apparent hyper-splicing events were particular to MG-thymoma and could be validated by Flourescent In-Situ Hybridization (FISH), Reverse Transcription-Polymerase Chain Reaction (RT-PCR) and mass spectrometry (MS) followed by peptide sequencing. Our findings demonstrate a particular alternative hyper-splicing signature for transcripts over-expressed in MG-thymoma, supporting the hypothesis that alternative hyper-splicing contributes to shaping the biological functions of these and other specialized tumors and opening new venues for the development of diagnosis and treatment approaches.

Original languageAmerican English
Article numbere2392
JournalPLoS ONE
Issue number6
StatePublished - 11 Jun 2008


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