Sihto Harri, Sarlomo-Rikala Maarit, Tynninen Olli, Tanner Minna, Andersson Leif C, Franssila Kaarle, Nupponen Nina N, Joensuu Heikki
Department of Oncology, Helsinki University Central Hospital, Haartmaninkatu 4, PO Box 180, FIN-00029 Helsinki, Finland.
J Clin Oncol. 2005 Jan 1;23(1):49-57. doi: 10.1200/JCO.2005.02.093. Epub 2004 Nov 15.
Mutated KIT and platelet-derived growth factor receptor alpha (PDGFRalpha) tyrosine kinases are the principal targets for imatinib mesylate in the treatment of gastrointestinal stromal tumors (GISTs). The frequency of activating KIT and PDGFRA gene mutations in most other histologic types of human cancer is not known.
KIT exons 9, 11, 13, and 17 and PDGFRA exons 11 and 17 of 334 human cancers were screened for mutations using sensitive denaturing high-performance liquid chromatography (DHPLC). In addition, all KIT exons from 9 to 21 of 115 tumors were screened. Thirty-two histologic tumor types were examined. Samples with abnormal findings in DHLPC were sequenced. Immunostaining for the KIT protein (CD117) was performed in 322 (96.4%) of the 334 cases.
Of the 3,039 exons screened, only 17 had mutation. All 17 cases with either mutated KIT (n = 15) or PDGFRA (n = 2) were histologically GIST tumors, whereas none of the other histologic types of cancer (n = 316) harbored KIT or PDGFRA mutation. KIT immunostaining was rarely positive except in GISTs (18 of 18), small-cell lung cancer (10 of 30; 33%), and testicular teratocarcinoma (four of 17; 24%). Wild-type KIT gene amplification or chromosome 4 aneuploidy was common (seven of 12) in non-GIST tumors with strong KIT protein expression when studied with fluorescence in situ hybridization.
Despite frequent KIT protein expression in some tumor types, KIT and PDGFRA gene mutations are uncommon in most human cancers. Cancer KIT expression is frequently associated with multiple copies of the wild-type KIT gene.
突变的KIT和血小板衍生生长因子受体α（PDGFRα）酪氨酸激酶是甲磺酸伊马替尼治疗胃肠道间质瘤（GIST）的主要靶点。在大多数其他组织学类型的人类癌症中，KIT和PDGFRA基因激活突变的频率尚不清楚。
采用灵敏的变性高效液相色谱（DHPLC）对334例人类癌症的KIT第9、11、13和17外显子以及PDGFRA第11和17外显子进行突变筛查。此外，还对115例肿瘤的KIT第9至21外显子进行了筛查。检查了32种组织学肿瘤类型。对DHPLC结果异常的样本进行测序。对334例中的322例（96.4%）进行了KIT蛋白（CD117）免疫染色。
在筛查的3039个外显子中，只有17个发生了突变。17例发生KIT突变（n = 15）或PDGFRA突变（n = 2）的病例在组织学上均为GIST肿瘤，而其他组织学类型的癌症（n = 316）均未发生KIT或PDGFRA突变。除GIST（18/18）、小细胞肺癌（10/30；33%）和睾丸畸胎瘤（4/17；24%）外，KIT免疫染色很少呈阳性。在用荧光原位杂交研究时，野生型KIT基因扩增或4号染色体非整倍体在KIT蛋白表达强的非GIST肿瘤中很常见（7/12）。
尽管KIT蛋白在某些肿瘤类型中表达频繁，但KIT和PDGFRA基因突变在大多数人类癌症中并不常见。癌症中KIT表达常与野生型KIT基因的多个拷贝相关。
