Genetic and pathologic characteristics of gastrointestinal stromal tumors in extragastric lesions

Abstract

Abstract. The goal of this study was to investigate differences in the clinicopathologic and genetic characteristics of gastric and extragastric gastrointestinal stromal tumors (GISTs). We evaluated 13 extragastric GISTs and compared them with 56 gastric GISTs, which were described previously. 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 platelet-derived growth factor receptor · (PDGFRA) gene were amplified by polymerase chain reaction and sequenced. 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. Of the 13 extragastric GISTs 7 (54%) had a mutation in exon 11 of KIT, and 2 (15%) had a mutation in exon 13 of KIT. Deletions in exon 11 of KIT were the most common mutation encountered in the extragastric GISTs. The extragastric GISTs, especially small intestinal GISTs, showed larger deletions, leading to deletions of amino acid residues in the KIT protein, and higher vascularity than did the gastric GISTs. These data suggest that extragastric GISTs differ from gastric GISTs with respect to associated mutations and angiogenic activity.

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.…”

Molecular features and genetic markers of gastrointestinal stromal tumors

“…Описаны случаи ГИСО с двойной мутацией K642E и V643I и случай множест-венной ГИСО с этой мутацией [62]. У пациентов из Азии выявлены уникальные мутации в 13-м экзоне KIT: E635K, L641P, V643A, L647P, M651V и N655K [63,64]. Мутации K642E и N655K приводят к конститутив-ному фосфорилированию ТК KIT и отвечают за чувст-вительность к иматинибу [65].…”

“…Описаны наследственные мутации в ТК-доменах KIT (K642E и N820Y) [65,72] и PDGFRА (Y555C и V561D) [68]. Опухоли с мутацией K642E чувствительны к иматинибу [63]. Делеция D419 в 8-м экзоне KIT впервые была описана как герми-нальная мутация, однако недавно выявлена в спора-дических опухолях -в 1,4 % случаях ГИСО, которые относили к дикому типу [69].…”

“…Чаще всего встречаются мутации KIT V654A (13-й экзон), T670I (14-й экзон), D816A / G / H / V, N822H / K, Y823D (17-й экзон), причем мутация V654A менее устойчива к иматинибу, чем T670I [63,65]. Вторичные мутации очень редко возникают у пациентов с мута-циями PDGFRA и не появляются у больных ГИСО с диким типом KIT и PDGFRA.…”