Lasota J, Wozniak A, Sarlomo-Rikala M, Rys J, Kordek R, Nassar A, Sobin L H, Miettinen M
Department of Soft Tissue Pathology, Armed Forces Institute of Pathology, Washington, DC, USA.
Am J Pathol. 2000 Oct;157(4):1091-5. doi: 10.1016/S0002-9440(10)64623-8.
Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, typically express the KIT protein. Activating mutations in the juxtamembrane domain (exon 11) of the c-kit gene have been shown in a subset of GISTs. These mutations lead into ligand-independent activation of the tyrosine kinase of c-kit, and have a transforming effect in vitro. Several groups have studied the clinical implication of the c-kit mutation status of exon 11 in GISTs and a possible relationship between c-kit mutations and malignant behavior has been established. Recently, a 1530ins6 mutation in exon 9 and missense mutations, 1945A>G in exon 13 of the c-kit gene were reported. The frequency and clinical importance of these findings are unknown. In this study we evaluated 200 GISTs for the presence of mutations in exons 9 and 13 of c-kit. Six cases revealed 1530ins6 mutation in exon 9 and two cases 1945A>G mutation in exon 13. All tumors with mutations in exon 9 and 13 lacked mutations in exon 11 of c-kit. None of the analyzed tumors had more than one type of c-kit mutation. All but one of the eight tumors with mutations in exon 9 or 13 of the c-kit gene were histologically and clinically malignant. All four of six cases with exon 9 mutation of which location of primary tumor was known, were small intestinal, suggesting that this type of mutation could preferentially occur in small intestinal tumors. Exon 9 and 13 mutations seem to be rare, and they cover only a small portion (8%) of the balance of GISTs that do not have mutations in exon 11 of c-kit. This finding indicates that other genetic alterations may activate c-kit in GISTs, or that KIT is not activated by mutations in all cases.
胃肠道间质瘤(GISTs)是胃肠道最常见的间叶组织肿瘤,通常表达KIT蛋白。已在一部分GISTs中发现c-kit基因近膜结构域(外显子11)存在激活突变。这些突变导致c-kit酪氨酸激酶的配体非依赖性激活,并在体外具有转化作用。多个研究小组研究了外显子11的c-kit突变状态在GISTs中的临床意义,并已确定c-kit突变与恶性行为之间可能存在关联。最近,有报道称c-kit基因外显子9存在1530ins6突变以及外显子13存在错义突变(1945A>G)。这些发现的频率和临床重要性尚不清楚。在本研究中,我们评估了200例GISTs中c-kit基因外显子9和13的突变情况。6例显示外显子9存在1530ins6突变,2例显示外显子13存在1945A>G突变。所有外显子9和13发生突变的肿瘤在c-kit基因外显子11均无突变。所有分析的肿瘤均未出现一种以上类型的c-kit突变。c-kit基因外显子9或13发生突变的8例肿瘤中,除1例之外,其余在组织学和临床上均为恶性。已知原发肿瘤位置的6例外显子9突变病例中,有4例位于小肠,提示这种类型的突变可能优先发生于小肠肿瘤。外显子9和13突变似乎较为罕见,它们仅占c-kit基因外显子11无突变的GISTs其余部分的一小部分(8%)。这一发现表明,其他基因改变可能在GISTs中激活c-kit,或者并非在所有情况下KIT均由突变激活。