title: Post-transcriptional dysregulation by miRNAs is implicated in the pathogenesis of gastrointestinal stromal tumor [GIST].
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.
authors.affiliation: Histopathology Department, School of Medicine, Trinity College Dublin, Dublin, Ireland.
authors.forename: Lorna
authors.initials: L
authors.lastname: Kelly
authors.forename: Kenneth
authors.initials: K
authors.lastname: Bryan
authors.forename: Su Young
authors.initials: SY
authors.lastname: Kim
authors.forename: Katherine A
authors.initials: KA
authors.lastname: Janeway
authors.forename: J Keith
authors.initials: JK
authors.lastname: Killian
authors.forename: Hans-Ulrich
authors.initials: HU
authors.lastname: Schildhaus
authors.forename: Markku
authors.initials: M
authors.lastname: Miettinen
authors.forename: Lee
authors.initials: L
authors.lastname: Helman
authors.forename: Paul S
authors.initials: PS
authors.lastname: Meltzer
authors.forename: Matt
authors.initials: M
authors.lastname: van de Rijn
authors.forename: Maria
authors.initials: M
authors.lastname: Debiec-Rychter
authors.forename: Maureen
authors.initials: M
authors.lastname: O'Sullivan
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D045744:Cell Line, Tumor; D002648:Child; D002883:Chromosomes, Human, Pair 14; D016000:Cluster Analysis; D019295:Computational Biology; D019175:DNA Methylation; D005260:Female; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008297:Male; D035683:MicroRNAs / Q000235:genetics* / Q000378:metabolism; D008875:Middle Aged; D009154:Mutation; D012323:RNA Processing, Post-Transcriptional; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D015203:Reproducibility of Results; D013385:Succinate Dehydrogenase / Q000378:metabolism; D055815:Young Adult
chemical_list: D035683:MicroRNAs; D012333:RNA, Messenger; C108095:SDHB protein, human; D013385:Succinate Dehydrogenase