Post-Transcriptional Dysregulation by miRNAs Is Implicated in the Pathogenesis of Gastrointestinal Stromal Tumor [GIST

Lorna Kelly,Paul S Meltzer,Maria Debiec-Rychter,Hans-Ulrich Schildhaus,Su Young Kim,Matt Van De Rijn,Maureen O’Sullivan,J Keith Killian,Katherine A Janeway,Markku Miettinen,Kenneth Bryan,Lee Helman,Regine Schneider-Stock

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 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.

Highlights

Gastrointestinal stromal tumor (GIST) is the commonest sarcoma of the gastrointestinal tract, typically presenting clinically in patients aged 55–65 years [1]
MicroRNA Profiling Unsupervised hierarchical clustering based on all miRNAs showed a separation into clusters A and B (Figure 1), with cluster B subdivided into B1 and B2
Adult mutant cases are located in Clusters A and B1 and pediatric GISTs in Cluster B2, with adult WT GISTs dispersed amongst both adult mutant and pediatric

Summary

Introduction

Gastrointestinal stromal tumor (GIST) is the commonest sarcoma of the gastrointestinal tract, typically presenting clinically in patients aged 55–65 years [1]. GISTs are characterised by activating mutations in the genes encoding the type III tyrosine kinase receptors, KIT [2] occurring in ,80–85%, or Platelet-Derived Growth Factor Receptor, alpha PDGFRA [3], in 5–8% of GISTs [1]. These mutually exclusive mutations cause ligandindependent auto-phosphorylation of the receptor, activating crucial growth and survival signalling cascades. The majority of pediatric GISTs are WT, typically presenting as slow-growing gastric tumors in prepubescent girls

Methods

Results

Conclusion