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Post-Transcriptional Dysregulation by miRNAs Is Implicated in the Pathogenesis of Gastrointestinal Stromal Tumor [GIST]
Kelly, Lorna Bryan, Kenneth Kim, Su Young Janeway, Katherine A. Killian, J. Keith Schildhaus, Hans-Ulrich Miettinen, Markku Helman, Lee Meltzer, Paul S. van de Rijn, Matt
Kelly, Lorna
Bryan, Kenneth
Kim, Su Young
Janeway, Katherine A.
Killian, J. Keith
Schildhaus, Hans-Ulrich
Miettinen, Markku
Helman, Lee
Meltzer, Paul S.
van de Rijn, Matt
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2013-05-24
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PLoSOne e64102.pdf
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Kelly 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.0064102
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 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.