Ito Takashi, Yamamura Masahiro, Hirai Toshihiro, Ishikawa Takashi, Kanda Tatsuo, Nakai Takuya, Ohkouchi Mizuka, Hashikura Yuka, Isozaki Koji, Hirota Seiichi
Department of Surgical Pathology, Hyogo College of Medicine Hyogo, Japan ; Department of Pathology, Sanda Municipal Hospital Hyogo, Japan.
Department of Clinical Oncology, Kawasaki Medical School Okayama, Japan.
Int J Clin Exp Pathol. 2014 Oct 15;7(11):8024-31. eCollection 2014.
Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the human gut. Most sporadic GISTs have somatic gain-of-function mutations of the c-kit gene. The mutations are frequently found at exon 11, sometimes at exon 9 and rarely at exon 13 or 17. Recently, exon 8 c-kit gene mutations were reported in very minor proportion of sporadic GISTs. We also found 3 GISTs with exon 8 c-kit gene mutations in approximately 1,000 sporadic GISTs examined. In the present report, we showed the clinicopathological data of those GISTs. One case had a deletion of codon 419 of aspartate, and 2 cases had a substitution of 3 amino acids of codon 417 to codon 419 to tyrosine. The former was the same mutation recently reported in 2 GIST cases, but the latter has not been reported in any GISTs. All three cases occurred at extragastric sites and two of three showed distant metastasis. Since the remaining case was regarded as high risk for recurrence, imatinib adjuvant treatment has been done without evidence of metastasis. Our results confirmed the idea that exon 8 mutations are minor but actually existing abnormalities in sporadic GISTs, and suggested that such GISTs have a feature of extragastric development and a metastasis-prone nature. Since the exon 8 mutations appeared to be really sensitive to imatinib as shown in the present case study, accurate genotyping including exon 8 of the c-kit gene is necessary in GISTs to predict response to imatinib in both the unresectable/metastatic and adjuvant settings.
胃肠道间质瘤（GISTs）是人类肠道最常见的间叶性肿瘤。大多数散发性GISTs存在c-kit基因的体细胞功能获得性突变。这些突变常见于第11外显子，有时见于第9外显子，很少见于第13或17外显子。最近，有报道称在极少数散发性GISTs中存在第8外显子c-kit基因突变。在我们检测的约1000例散发性GISTs中，也发现了3例具有第8外显子c-kit基因突变的病例。在本报告中，我们展示了这些GISTs的临床病理数据。1例存在天冬氨酸密码子419缺失，2例存在密码子417至419的3个氨基酸被酪氨酸替代。前者是最近在2例GIST病例中报道的相同突变，但后者在任何GISTs中均未被报道。所有3例均发生于胃外部位，3例中有2例出现远处转移。由于其余1例被视为复发高危，已在无转移证据的情况下进行了伊马替尼辅助治疗。我们的结果证实了第8外显子突变在散发性GISTs中虽少见但确实存在异常的观点，并提示此类GISTs具有胃外生长和易转移的特点。鉴于本病例研究显示第8外显子突变似乎对伊马替尼真的敏感，在GISTs中进行包括c-kit基因第8外显子在内的准确基因分型对于预测不可切除/转移性及辅助治疗情况下对伊马替尼的反应是必要的。
