PMID- 18545673
OWN - NLM
STAT- MEDLINE
DCOM- 20080820
LR  - 20240326
IS  - 1932-6203 (Electronic)
IS  - 1932-6203 (Linking)
VI  - 3
IP  - 6
DP  - 2008 Jun 11
TI  - Identifying alternative hyper-splicing signatures in MG-thymoma by exon arrays.
PG  - e2392
LID - 10.1371/journal.pone.0002392 [doi]
LID - e2392
AB  - BACKGROUND: The vast majority of human genes (>70%) are alternatively spliced. 
      Although alternative pre-mRNA processing is modified in multiple tumors, 
      alternative hyper-splicing signatures 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 various 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 
      Ontology (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 acetylcholinesterase ACHE gene. Corresponding 
      changes in spliceosome composition were indicated by co-decreases in the splicing 
      factors ASF/SF(2) and SC35. Parallel tumor-associated changes occurred in colon 
      cancer as well, but the majority of the apparent hyper-splicing events were 
      particular to MG-thymoma and could be validated by Fluorescent 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.
FAU - Soreq, Lilach
AU  - Soreq L
AD  - Department of Physiology, The Hebrew University, Hadassah Medical School, 
      Jerusalem, Israel. soreq@cc.huji.ac.il
FAU - Gilboa-Geffen, Adi
AU  - Gilboa-Geffen A
FAU - Berrih-Aknin, Sonia
AU  - Berrih-Aknin S
FAU - Lacoste, Paul
AU  - Lacoste P
FAU - Darvasi, Ariel
AU  - Darvasi A
FAU - Soreq, Eyal
AU  - Soreq E
FAU - Bergman, Hagai
AU  - Bergman H
FAU - Soreq, Hermona
AU  - Soreq H
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PT  - Research Support, U.S. Gov't, Non-P.H.S.
DEP - 20080611
PL  - United States
TA  - PLoS One
JT  - PloS one
JID - 101285081
RN  - 0 (RNA, Messenger)
SB  - IM
MH  - *Alternative Splicing
MH  - Colonic Neoplasms/genetics
MH  - *Exons
MH  - Humans
MH  - In Situ Hybridization, Fluorescence
MH  - Proteomics
MH  - RNA, Messenger/genetics
MH  - Reverse Transcriptase Polymerase Chain Reaction
MH  - Thymus Neoplasms/*genetics
PMC - PMC2409220
COIS- Competing Interests: The authors have declared that no competing interests exist.
EDAT- 2008/06/12 09:00
MHDA- 2008/08/21 09:00
PMCR- 2008/06/11
CRDT- 2008/06/12 09:00
PHST- 2008/02/22 00:00 [received]
PHST- 2008/03/27 00:00 [accepted]
PHST- 2008/06/12 09:00 [pubmed]
PHST- 2008/08/21 09:00 [medline]
PHST- 2008/06/12 09:00 [entrez]
PHST- 2008/06/11 00:00 [pmc-release]
AID - 08-PONE-RA-03725R1 [pii]
AID - 10.1371/journal.pone.0002392 [doi]
PST - epublish
SO  - PLoS One. 2008 Jun 11;3(6):e2392. doi: 10.1371/journal.pone.0002392.