Association of KIT exon 9 mutations with nongastric primary site and aggressive behavior: KIT mutation analysis and clinical correlates of 120 gastrointestinal stromal tumors.
Association of KIT exon 9 mutations with nongastric primary site and aggressive behavior: KIT mutation analysis and clinical correlates of 120 gastrointestinal stromal tumors.
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发表时间：
2003-08
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通讯作者：
C. Antonescu;G. Sommer;Lisa Sarran;Sylvia J. Tschernyavsky;E. Riedel;J. Woodruff;M. Robson;R. Maki-R.-Ma
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作者：
C. Antonescu;G. Sommer;Lisa Sarran;Sylvia J. Tschernyavsky;E. Riedel;J. Woodruff;M. Robson;R. Maki-R.-Ma
目的 KIT 近膜区域的激活突变是胃肠道间质瘤 (GIST) 中最常见的遗传事件，并被认为是独立的预后因素。 KIT 突变对其他区域（例如细胞外或激酶结构域）的影响尚不明确，迄今为止已发表的案例还不到 30 个。实验设计 对经 KIT 免疫反应性证实的 120 个 GIST 进行了 KIT 外显子 9、11、13 和 17 突变的存在评估。使用Fisher精确检验和对数秩检验分析KIT突变的存在/类型与临床病理因素之间的关系。结果 44%的肿瘤位于胃，47%位于小肠，6%位于直肠，3%位于腹膜后。总体而言，78% 的患者检测到 KIT 突变，具体情况如下：67% 位于外显子 11，11% 位于外显子 9，外显子 13 或 17 中无突变。KIT 外显子 11 突变的类型是异质的，并聚集在外显子 11 5' 端的经典“热点”。7% 的病例在外显子 11 3' 端显示内部串联重复 (ITD)，其中我们指定该区域为 KIT 突变的第二个热点区域。有趣的是，这些病例与以下因素相关：女性占主导地位、胃的位置、老年患者的发生以及良好的结果。外显子 9 突变与肿瘤大小 (P < 0.001) 和胃外位置 (P = 0.02) 之间存在显着相关性。这13名患者中，随访1年以上的患者中有10名出现了复发性疾病。结论 大多数表达 KIT 的 GIST 显示 KIT 突变优先位于外显子 11 的经典热点内。此外，我们发现外显子 11 3' 端的第二个热点（以 ITD 为特征）与老年女性临床惰性胃 GIST 亚组之间存在关联。 KIT 外显子 9 突变似乎定义了 GIST 的一个独特子集，主要位于小肠，并与不利的临床病程相关。
PURPOSE Activating mutations of the KIT juxtamembrane region are the most common genetic events in gastrointestinal stromal tumors (GISTs) and have been noted as independent prognostic factors. The impact of KIT mutation in other regions, such as the extracellular or kinase domains, is not well-defined and fewer than 30 cases have been published to date. EXPERIMENTAL DESIGN One hundred twenty GISTs, confirmed by KIT immunoreactivity, were evaluated for the presence of KIT exon 9, 11, 13, and 17 mutations. The relation between the presence/type of KIT mutation and clinicopathological factors was analyzed using Fisher's exact test and log-rank test. RESULTS Forty-four % of the tumors were located in the stomach, 47% in the small bowel, 6% in the rectum, and 3% in the retroperitoneum. Overall, KIT mutations were detected in 78% of patients as follows: 67% in exon 11, 11% in exon 9, and none in exon 13 or 17. The types of KIT exon 11 mutations were heterogeneous and clustered in the classic "hot spot" at the 5' end of exon 11. Seven % of cases showed internal tandem duplications (ITD) at the 3' end of exon 11, in a region that we designate as a second hot spot for KIT mutations. Interestingly, these cases were associated with: female predominance, stomach location, occurrence in older patients, and favorable outcome. There were significant associations between exon 9 mutations and large tumor size (P < 0.001) and extragastric location (P = 0.02). Ten of these 13 patients with more than 1-year follow-up have developed recurrent disease. CONCLUSIONS Most KIT-expressing GISTs show KIT mutations that are preferentially located within the classic hot spot of exon 11. In addition, we found an association between a second hot spot at the 3'end of exon 11, characterized by ITDs, and a subgroup of clinically indolent gastric GISTs in older females. KIT exon 9 mutations seem to define a distinct subset of GISTs, located predominantly in the small bowel and associated with an unfavorable clinical course.