Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate
Polyclonal evolution of multiple secondary KIT mutations in gastrointestinal stromal tumors under treatment with imatinib mesylate
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DOI：
10.1158/1078-0432.ccr-05-1211
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发表时间：
2006-03-15
影响因子：
11.5
通讯作者：
Hohenberger, P
中科院分区：
文献类型：
--
作者：
Wardelmann, E;Merkelbach-Bruse, S;Hohenberger, P
胃肠道间质瘤（GIST）的特点是强烈的KIT受体激活，最常见的是由KIT突变。在没有KIT突变的较小肿瘤亚组中，在血小板衍生生长因子受体α（PDGFR α）基因中发现了类似的激活突变。PDGFR α和KIT受体都是酪氨酸激酶抑制剂伊马替尼（Glivec）的靶点，伊马替尼显著改善了晚期GISTS的治疗。然而，一个亚组的肿瘤显示继发性进展与伊马替尼治疗后的初步反应。继发性耐药的一个可能机制是新获得的KIT突变的发展。在本研究中，我们评估了一系列GIST患者中继发性KIT突变的频率，这些患者在治疗期间切除了肿瘤组织。我们检查了32例患者（共104个样本）的1至7个不同的肿瘤区域，并在14例患者（43.8%）中发现了多达4个新获得的KIT突变。这些总是位于编码第一或第二酪氨酸激酶结构域的外显子（外显子13、14或17）。仅在每个病例分析的样本子集中发现突变，而其他样本在同一区域保留野生型序列。在同一个样本中从来没有超过一个新的突变。与二次克隆进化一致，在来自每个肿瘤的所有样品中总是可检测到原发突变。根据我们的研究结果，除了原发性突变之外，新获得的KIT突变的鉴定取决于分析的组织样本的数量，并且对进一步的治疗策略具有很高的意义。
Gastrointestinal stromal tumors (GIST) are characterized by a strong KIT receptor activation most often resulting from KIT mutations. In a smaller subgroup of tumors without KIT mutations, analogous activating mutations are found in the platelet-derived growth factor receptor alpha (PDGFR alpha) gene. Both PDGFR alpha and KIT receptors are targets of the tyrosine kinase inhibitor imatinib (Glivec) which has improved the treatment of advanced GISTS significantly. However, a subgroup of tumors show a secondary progress under therapy with imatinib after initial response. One possible mechanism of secondary resistance is the development of newly acquired KIT mutations. In the present study, we evaluated the frequency of such secondary KIT mutations in a series of GIST patients in which tumor tissue was resected under treatment. We examined one to seven different tumor areas in 32 cases (total of 104 samples) and found up to four newly acquired KIT mutations in 14 patients (43.8%). These were always located in exons encoding the first or second tyrosine kinase domain (exon 13, 14, or 17). Mutations were found only in a subset of samples analyzed from each case whereas others retained the wild-type sequence in the same region. There was never more than one new mutation in the same sample. Consistent with a secondary clonal evolution, the primary mutation was always detectable in all samples from each tumor. According to our results, the identification of newly acquired KIT mutations in addition to the primary mutation is dependent on the number of tissue samples analyzed and has high implications for further therapeutic strategies.