Correlation of KIT and platelet-derived growth factor receptor α mutations with gene activation and expression profiles in gastrointestinal stromal tumors

Abstract

Activating mutations of KIT and platelet-derived growth factor receptor a (PDGFRA) are known to be alternative and mutually exclusive genetic events in the development of gastrointestinal stromal tumors (GISTs). We examined the effect of the mutations of these two genes on the gene expression profile of 22 GISTs using the oligonucleotide microarray. Mutations of KIT and PDGFRA were found in 17 cases and three cases, respectively. The remaining two cases had no detectable mutations in either gene. The mutation status of KIT and PDGFRA was directly related to the expression levels of activated KIT and PDGFRA, and was also related to the different expression levels of activated proteins that play key roles in the downstream of the receptor tyrosine kinase III family. To evaluate the impact of mutation status and the importance of the type of mutation in gene expression and clinical features, microarray-derived data from 22 GISTs were interpreted using a principal component analysis (PCA). Three relevant principal component representing mutation of KIT, PDGFRA and chromosome 14q deletion were identified from the interpretation of the oligonucleotide microarray data with PCA. After supervised analysis, there was at least a two fold difference in expression between GISTs with KIT and PDGFRA mutation in 70 genes. Our findings demonstrate that mutations of KIT and PDGFRA affect differential activation and expression of some genes, and can be used for the molecular classification of GISTs.

Clinical and molecular genetics of patients with the Carney–Stratakis syndrome and germline mutations of the genes coding for the succinate dehydrogenase subunits SDHB, SDHC, and SDHD

“…1,10 -12 GISTs in these families are characterized by development at multiple primary sites and presentation at a median age of 46 years; polyclonal diffuse hyperplasia of ICCs within the myenteric plexus is considered the primary effect of KIT constitutive activation. 10,22,23 Other abnormalities may be present in patients with familial GISTs: for example, patients with germline KIT exon 11 mutations often show cutaneous hyperpigmentation in the perineum, face, neck, digits, axillae, groin and knees and less frequently urticaria pigmentosa or diffuse cutaneous mastocytosis in infancy. 10,23 Patients with germline PDGFRA mutations present with multiple gastric GISTs or the condition known as intestinal neurofibromatosis.…”

Gastrointestinal stromal tumors: what do we know now?

“…When expressed in transfected cell lines, mutant forms of PDGFRA have constitutive kinase activity in the absence of their ligand, PDGF-A, 37,38 the activated downstream pathways are identical to those in KIT-mutant GISTs, 37,39 and PDGFRA is also stabilized by HSP90. 40 In addition, both types of tumors are immunopositive Figure 3 (a) KIT and PDGFRA cell signaling pathways.…”

KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs)

“…Although KIT exon 11 mutations have been reported in GISTs from different locations from esophagus to anus, [105][106][107][108][109][110][111][112] duplications showed strong predilection to gastric location; 59 of 67 (88%) reported GISTs with KIT exon 11 duplications originated from stomach. 61,74,76,77,83,84,97,101,113 …”

“…74,81,101 Technical problems limiting detection of duplications in FFPE tissues may contribute to this discrepancy, since other studies from Korea and China have been reported KIT exon 11 duplications in GISTs. 83,84,99,100 …”