Mutations in Exons 9 and 13 of KIT Gene Are Rare Events in Gastrointestinal Stromal Tumors

Abstract

Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, typically express the KIT protein. Activating mutations in the juxtamembrane domain (exon 11) of the c-kit gene have been shown in a subset of GISTs. These mutations lead into ligand-independent activation of the tyrosine kinase of c-kit, and have a transforming effect in vitro. Several groups have studied the clinical implication of the c-kit mutation status of exon 11 in GISTs and a possible relationship between c-kit mutations and malignant behavior has been established. Recently, a 1530ins6 mutation in exon 9 and missense mutations, 1945A>G in exon 13 of the c-kit gene were reported. The frequency and clinical importance of these findings are unknown. In this study we evaluated 200 GISTs for the presence of mutations in exons 9 and 13 of c-kit. Six cases revealed 1530ins6 mutation in exon 9 and two cases 1945A>G mutation in exon 13. All tumors with mutations in exon 9 and 13 lacked mutations in exon 11 of c-kit. None of the analyzed tumors had more than one type of c-kit mutation. All but one of the eight tumors with mutations in exon 9 or 13 of the c-kit gene were histologically and clinically malignant. All four of six cases with exon 9 mutation of which location of primary tumor was known, were small intestinal, suggesting that this type of mutation could preferentially occur in small intestinal tumors. Exon 9 and 13 mutations seem to be rare, and they cover only a small portion (8%) of the balance of GISTs that do not have mutations in exon 11 of c-kit. This finding indicates that other genetic alterations may activate c-kit in GISTs, or that KIT is not activated by mutations in all cases.

Differential expression of KIT/PDGFRA mutant isoforms in epithelioid and mixed variants of gastrointestinal stromal tumors depends predominantly on the tumor site

“…The other KIT mutations included exon 9 AY 502-503 duplication and exon 17 N822 K missense mutation, both being previously described in GISTs. 9,10,18 Activating mutations within the KIT gene were detected in 57-92% of GISTs in earlier reports. [9][10][11][12][13]16 The frequency of KIT mutations in our series was apparently lower in epithelioid than in mixed and spindle type GISTs.…”

Succinate dehydrogenase-deficient GISTs are characterized by IGF1R overexpression

“…15 Immunohistochemistry SDHB immunohistochemistry was performed on formalin-fixed paraffin-embedded tissue sections using a commercially available mouse monoclonal antibody (ABCAM ab14714, clone 21A11) using previously described methods. 3,14,16,17 Briefly, in order for immunohistochemistry for SDHB to be considered negative (a significant result) we required the entire tumor to demonstrate absent granular cytoplasmic staining (that is, absent mitochondrial staining) and for there to be readily identifiable internal positive controls in non-neoplastic cells (endothelial cells).…”

Prognostic significance of angiogenesis in gastrointestinal stromal tumor

“…The reported frequency of exon 11 mutations in GISTs varies from 52 to 71%. 3,4,6,39,40 A possible explanation for such variation may be related to the methodological difference in detecting mutations and to the difference in the types of tissue used for DNA extraction. 5 In addition, the prevalence of the spindle-cell type of GISTs might influence the low frequency of PDGFRA gene mutation in the current study, because, in general, PDGFRA mutation is more frequently present in epithelioid-cell type GISTs than in spindle-cell type GISTs (most of our cases were spindle-cell type).…”