Yasuoka Rie, Sakakura Chohei, Shimomura Katsumi, Fujita Yoshifumi, Nakanishi Masayoshi, Aragane Hideki, Hagiwara Akeo, Bamba Masamichi, Abe Tatsuo, Yamagishi Hisakazu
Department of Digestive Surgery, Kyoto Prefectural University of Medicine, Kyoto, Japan.
Dig Surg. 2003;20(3):183-91. doi: 10.1159/000070384.
BACKGROUND/AIMS: Gain-of-function mutations in exons 9, 11 and 13 of the c-kit gene in gastrointestinal stromal tumors (GISTs) have been identified, and it has been reported that the prognosis is worse for patients with mutation-positive GISTs than for those with mutation-negative GISTs. We studied c-kit mutations in gastrointestinal mesenchymal tumors. By chance, the c-kit mutation in exon 11 was found in myogenic and neurogenic tumors as well as in GISTs. Furthermore, we studied the clinical prognostic utility of these mutations.
Ten gastrointestinal mesenchymal tumors were stained with HE and immunohistochemically analyzed with alpha-smooth muscle actin, S-100 protein, CD34 and c-kit. In these tumors, as well as in 11 cases of leiomyomas, PCR-amplified DNA from the juxtamembrane (JM) domain of exon 11, the extracellular domain of exon 9 and the tyrosine kinase domain 1 of exon 13 showed a high frequency of c-kit mutation and was sequenced.
Although c-kit mutations have previously been reported only in GISTs, we found c-kit mutations in the JM domain of exon 11 in one myogenic and one neurogenic tumor as well as in two GISTs. No c-kit mutation was seen in the 11 cases of leiomyomas. In addition, all four cases with c-kit mutation in exon 11 suffered a relapse sooner than the other cases without c-kit mutations.
Clinically, the prognosis was worse for the patients with mutation-positive gastrointestinal mesenchymal tumors than for those with mutation-negative tumors. We therefore conclude that the gain-of-function mutation in exon 11 of the c-kit gene is an important prognostic factor for gastrointestinal mesenchymal tumors, including myogenic and neurogenic tumors as well as GISTs.
背景/目的：已在胃肠道间质瘤（GIST）中鉴定出c-kit基因第9、11和13外显子的功能获得性突变，并且有报道称，c-kit突变阳性的GIST患者的预后比突变阴性的患者更差。我们研究了胃肠道间叶肿瘤中的c-kit突变。偶然发现，在肌源性和神经源性肿瘤以及GIST中均存在第11外显子的c-kit突变。此外，我们研究了这些突变的临床预后价值。
对10例胃肠道间叶肿瘤进行苏木精-伊红（HE）染色，并采用α-平滑肌肌动蛋白、S-100蛋白、CD34和c-kit进行免疫组化分析。在这些肿瘤以及11例平滑肌瘤中，对第11外显子的近膜（JM）结构域、第9外显子的细胞外结构域和第13外显子的酪氨酸激酶结构域1进行PCR扩增的DNA显示出高频率的c-kit突变，并进行测序。
尽管此前仅在GIST中报道过c-kit突变，但我们在1例肌源性肿瘤、1例神经源性肿瘤以及2例GIST中发现了第11外显子JM结构域中的c-kit突变。11例平滑肌瘤中未发现c-kit突变。此外，第11外显子c-kit突变的所有4例患者比其他无c-kit突变的患者更早复发。
临床上，c-kit突变阳性的胃肠道间叶肿瘤患者的预后比突变阴性的患者更差。因此，我们得出结论，c-kit基因第11外显子的功能获得性突变是胃肠道间叶肿瘤（包括肌源性和神经源性肿瘤以及GIST）的重要预后因素。
