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dc.contributor.authorKelly, Lorna*
dc.contributor.authorBryan, Kenneth*
dc.contributor.authorKim, Su Young*
dc.contributor.authorJaneway, Katherine A.*
dc.contributor.authorKillian, J. Keith*
dc.contributor.authorSchildhaus, Hans-Ulrich*
dc.contributor.authorMiettinen, Markku*
dc.contributor.authorHelman, Lee*
dc.contributor.authorMeltzer, Paul S.*
dc.contributor.authorvan de Rijn, Matt*
dc.contributor.authorDebiec-Rychter, Maria*
dc.contributor.authorO'Sullivan, Maureen*
dc.date.accessioned2014-08-20T14:19:23Z
dc.date.available2014-08-20T14:19:23Z
dc.date.issued2013-05-24
dc.identifier.citationKelly L, Bryan K, Kim SY, Janeway KA, Killian JK, et al. (2013) Post-Transcriptional Dysregulation by miRNAs Is Implicated in the Pathogenesis of Gastrointestinal Stromal Tumor [GIST]. PLoS ONE 8(5): e64102. doi:10.1371/journal.pone.0064102en_GB
dc.identifier.urihttp://hdl.handle.net/11019/705
dc.descriptionpeer-revieweden_GB
dc.description.abstractIn contrast to adult mutant gastrointestinal stromal tumors [GISTs], pediatric/wild-type GISTs remain poorly understood overall, given their lack of oncogenic activating tyrosine kinase mutations. These GISTs, with a predilection for gastric origin in female patients, show limited response to therapy with tyrosine kinase inhibitors and generally pursue a more indolent course, but still may prove fatal. Defective cellular respiration appears to underpin tumor development in these wild-type cases, which as a group lack expression of succinate dehydrogenase [SDH] B, a surrogate marker for respiratory chain metabolism. Yet, only a small subset of the wild-type tumors show mutations in the genes coding for the SDH subunits [SDHx]. To explore additional pathogenetic mechanisms in these wild-type GISTs, we elected to investigate posttranscriptional regulation of these tumors by conducting microRNA (miRNA) profiling of a mixed cohort of 73 cases including 18 gastric pediatric wild-type, 25 (20 gastric, 4 small bowel and 1 retroperitoneal) adult wild-type GISTs and 30 gastric adult mutant GISTs. By this approach we have identified distinct signatures for GIST subtypes which correlate tightly with clinico-pathological parameters. A cluster of miRNAs on 14q32 show strikingly different expression patterns amongst GISTs, a finding which appears to be explained at least in part by differential allelic methylation of this imprinted region. Small bowel and retroperitoneal wild-type GISTs segregate with adult mutant GISTs and express SDHB, while adult wildtype gastric GISTs are dispersed amongst adult mutant and pediatric wild-type cases, clustering in this situation on the basis of SDHB expression. Interestingly, global methylation analysis has recently similarly demonstrated that these wild-type, SDHB-immunonegative tumors show a distinct pattern compared with KIT and PDGFRA mutant tumors, which as a rule do express SDHB. All cases with Carney triad within our cohort cluster together tightly.en_GB
dc.description.sponsorshipFunding was obtained from the Medical Research Charities Group (http://www.mrcg.ie/) and Health Research Board of Ireland (http://www.hrb.ie) (MO’S), The Children’s Medical and Research Foundation (http://www.cmrf.org) (MO’S), the GIST Cancer Awareness Foundation [GCAF] (http://www. gistawareness.org/)(MO’S), and research grants from the Life Raft Group (http://www.liferaftgroup.org/)(MD-R) and from the Fonds voor Wetenschappelijk Onderzoek Vlaanderen (http://www.fwo.be/)(grant # G.0286.05 MD-R).en_GB
dc.language.isoenen_GB
dc.publisherPLOSen_GB
dc.relation.ispartofseriesPLOS ONE;vol 8
dc.subjectgastrointestinal stromal tumorsen_GB
dc.titlePost-Transcriptional Dysregulation by miRNAs Is Implicated in the Pathogenesis of Gastrointestinal Stromal Tumor [GIST]en_GB
dc.typeArticleen_GB
dc.identifier.doihttp://dx.doi.org/10.1371/journal.pone.0064102
dc.contributor.sponsorMedical Research Charities Group
dc.contributor.sponsorHealth Research Board
dc.contributor.sponsorChildren’s Medical and Research Foundation
dc.contributor.sponsorGIST Cancer Awareness Foundation
dc.contributor.sponsorLife Raft Group
dc.contributor.sponsorFonds voor Wetenschappelijk Onderzoek Vlaanderen
dc.contributor.sponsorGrantNumberG.0286.05 MD-R
refterms.dateFOA2018-01-12T08:03:30Z


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