Clinical and molecular characteristics of gastrointestinal stromal tumors in the pediatric and young adult population

Abstract

Gastrointestinal stromal tumors (GISTs) typically occur late in life; however, there are also reports of these tumors in pediatric patients and young adults. This rare, but fascinating subset of GISTs, have distinct clinical-pathological and molecular deviations from their adult counterparts. The majority of pediatric GIST patients are female and often present with multi-focal tumors that are completely or partly epithelioid in nature. These young patients often have metastatic disease, but still follow a slow course of disease progression. Molecularly, most pediatric GISTs lack the gain-of-function mutations in the KIT and PDGFRA genes, which are commonly found in adult cases. Recent expression profiling and genomic studies of pediatric GISTs show distinct molecular signatures, suggesting a unique origin as compared to adult GISTs. We and others have shown that the insulin-like growth factor 1 receptor (IGF1R) may have a prominent role in driving those adult and pediatric GISTs that lack KIT and PDGFRA activating mutations and clinical trials are currently being designed to exploit these types of discoveries.

Combination of Imatinib Mesylate and AKT Inhibitor Provides Synergistic Effects in Preclinical Study of Gastrointestinal Stromal Tumor

“…NPTX1 , one of several human pentraxins expressed primarily in nervous tissue, has been linked to the induction of neural lineage (45). The identification of two neural genes is particularly intriguing as it has been well established that GIST have both smooth muscle and neural elements (46). The WTS results for both BEX1 and NPTX1 were confirmed by qRT-PCR in the xenografts from the study, and the induction of BEX1 by the drug combination was also confirmed in IM-sensitive GIST-T1 and IM-resistant GIST430 cell lines, providing cellular models for exploring this finding.…”

Oncogenic KIT-containing exosomes increase gastrointestinal stromal tumor cell invasion

“…others in vitro and in vivo (15,19) and express the most common type of mutation found in GISTs (i.e., KIT exon 11), which is involved in the pathogenesis of this disease (19). We investigated whether these GIST cells release exosomes enriched in oncogenic KIT.…”

“…This similarity between GISTs and ICCs is further borne out by the expression of the KIT protein (also called CD117) in nonneoplastic ICC and most GISTs (11). The identification of a fundamental hallmark of the biology of GISTs (i.e., gain-of-function KIT mutations) resulted in the rapid transformation of the treatment paradigm for this tumor type (15,16). Small molecule tyrosine kinase inhibitors, most notably imatinib mesylate (also known as Gleevec), have been developed and were found to be effective in the treatment of GISTs (16)(17)(18).…”

The Utility of Discovered on Gastrointestinal Stromal Tumor 1 (DOG1) Antibody in Surgical Pathology—the GIST of It

“…22,25,28 There is currently strong evidence to suggest that the majority of pediatric GIST is biologically distinct from the typical adult-type GIST, as they do not usually harbor receptor tyrosine kinase mutations. [43][44][45] Nonetheless, some pediatric GIST do show at least initial response to newer generation receptor tyrosine kinase inhibitor. 46 Furthermore, a subset of the KIT/PDGFRA wild-type pediatric GIST contain genetic aberrations in genes coding for the succinate dehydrogenase subunits-SDHB, SDHC, and SDHD, 47 and there may be targeted therapy available in the future.…”