dc.contributor.author | O'SULLIVAN, MAUREEN | en |
dc.date.accessioned | 2014-12-11T10:47:06Z | |
dc.date.available | 2014-12-11T10:47:06Z | |
dc.date.issued | 2013 | en |
dc.date.submitted | 2013 | en |
dc.identifier.citation | Kelly,Lorna L., Bryan,Kenneth K., Kim,Suyoung S., Janeway,Katherine A. K.A., Killian,Jonathan Keith J.K., Schildhaus,Hans Ulrich H.U., Miettinen,Markku M A M.M.A., Helman,Lee J R F L.J.R.F., Meltzer,Paul S. P.S., Van De Rijn,Matt M., DÈ©biec-Rychter,Maria M., O'Sullivan,Maureen J. M.J., Post-Transcriptional Dysregulation by miRNAs Is Implicated in the Pathogenesis of Gastrointestinal Stromal Tumor [GIST], PLoS ONE, 8, 5, 2013 | en |
dc.identifier.other | Y | en |
dc.identifier.uri | http://hdl.handle.net/2262/72431 | |
dc.description | PUBLISHED | en |
dc.description.abstract | In 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 post-transcriptional 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 wild-type 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 |
dc.description.sponsorship | Funding 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). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. | en |
dc.language.iso | en | en |
dc.relation.ispartofseries | PLoS ONE | en |
dc.relation.ispartofseries | 8 | en |
dc.relation.ispartofseries | 5 | en |
dc.rights | Y | en |
dc.subject | adult mutant gastrointestinal stromal tumors | en |
dc.title | Post-Transcriptional Dysregulation by miRNAs Is Implicated in the Pathogenesis of Gastrointestinal Stromal Tumor [GIST] | en |
dc.type | Journal Article | en |
dc.type.supercollection | scholarly_publications | en |
dc.type.supercollection | refereed_publications | en |
dc.identifier.peoplefinderurl | http://people.tcd.ie/osullm10 | en |
dc.identifier.rssinternalid | 98307 | en |
dc.identifier.doi | http://dx.doi.org/10.1371/journal.pone.0064102 | en |
dc.rights.ecaccessrights | openAccess | |