Deletion of the KIT gene is associated with liver metastasis and poor prognosis in patients with gastrointestinal stromal tumor in the stomach

Abstract

The goal of this study was to investigate the association of mutations in the KIT gene and the plateletderived growth factor receptor • (PDGFRA) gene with clinicopathological features of patients with gastrointestinal stromal tumor (GIST) localized in the stomach. We evaluated 56 gastric GISTs for KIT and PDGFRA mutations. DNA was extracted from paraffin-embedded tumor specimens, and exons 9, 11, 13 and 17 of the KIT gene and exons 12 and 18 of the PDGFRA gene were amplified by polymerase chain reaction and sequenced. The genetic features were then compared with the clinicopathological features. Immunohistochemistry was performed for KIT, CD34, Ki-67 (as a marker of cell proliferation) and CD31 (as a marker of microvessel density), and apoptosis was assessed by in situ DNA nick-end labeling. Thirty-four (61%) of the 56 GISTs had a mutation in exon 11 of KIT, and 2 (4%) had a mutation in exon 13 of KIT. Deletions in exon 11 of KIT were the most common mutation encountered in the present study. No mutations were found in exon 9 or 17 of KIT. Six of the 20 GISTs lacking KIT mutations had a mutation in exon 18 of PDGFRA, and 1 had a mutation in exon 12 of PDGFRA. The KIT mutation-positive GISTs showed more frequent liver metastases and higher mortality than KIT mutation-negative GISTs. Our data indicate that KIT mutations, especially deletions in exon 11, are markers of poor prognosis for gastric GISTs.

Gastrointestinal stromal tumors: what do we know now?

“…The deletions are associated with a shorter progression-free and overall survival in comparison with the other exon 11 mutations. [12][13][14][15][16][17][18] In particular, deletions involving codons 557 and/or 558 are associated with malignant behavior. [19][20][21] Aside from exon 11 mutations, between 7 and 10% of GISTs have a mutation in an extracellular domain encoded by exon 9.…”

Clinicopathologic profile of gastrointestinal stromal tumors (GISTs) with primary KIT exon 13 or exon 17 mutations: a multicenter study on 54 cases

“…Constitutive KIT tyrosine phosphorylation by these mutations has not been documented. [21][22][23] Three of these mutations were identified in a relatively small cohort of 69 patients resulting in a surprisingly high frequency of unusual mutants. 22,23 The first two KIT exon 13 mutations reported in GISTs were homozygous by direct sequencing; however, results of fluorescence in situ hybridization (FISH) and loss of heterozygosity (LOH) studies suggested duplication of the mutant KIT allele in those cases.…”

“…10,14 However, these KIT domains are commonly affected by secondary mutations acquired during imatinib mesylate treatment and causing tumor resistance to this therapy. 15 Although several KIT exon 13 and exon 17 mutants have been reported, [8][9][10][11]14,[16][17][18][19][20][21][22][23][24][25] complete demographic and clinicopathologic data have been provided only in a few cases. Thus, the clinicopathologic profile of tumors with such mutations is not known.…”

KIT and PDGFRA mutations in gastrointestinal stromal tumors (GISTs)

“…Homozygous/ hemizygous mutations have been identified in 2 of 13 (15%) incidental GISTs smaller than 1 cm 64 ; identical frequency of these mutations has been reported in a study of 56 primary gastric GISTs. 65 However, little is known about their biological potential. Also, shift from KIT/PDGFRA heterozygosity to hemizygosity has been reported in progressive lesions during imatinib treatment.…”

“…However, in some cases, only mutant allele could be identified by direct sequencing of PCR products. 38,[64][65][66] This may represent true homozygous mutations, 38 or hemizygous mutations created by loss of a second allele. 66,67 Preferential amplification of the allele can mimic homo-or hemi-zygousity as well.…”