Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA.
Eur J Cancer. 2012 Nov;48(17):3215-22. doi: 10.1016/j.ejca.2012.05.021. Epub 2012 Jul 4.
Data regarding the patterns and the mechanisms of deregulation of the insulin growth factor (IGF) pathway in adult and paediatric gastrointestinal stromal tumours (GISTs) are limited.
We investigated the expression profiling of the genes encoding the main components of the IGF signalling pathway in 131 GISTs (106 adults, 21 paediatric and four young adults) and 25 other soft-tissue sarcomas (STS) using an Affymetrix U133A platform. IGF2 was investigated for loss of imprinting (LOI) whereas IGF1R was analysed for copy number aberration and mutation.
IGF2 was the most highly overexpressed gene of the IGF pathway in GIST. IGF2 expression was also significantly higher than in other STS. IGF2 expression was correlated to the age onset and mutational status of GIST. Indeed, IGF2 expression was significantly higher in the 'adult' group than in the 'paediatric' and 'young adult' groups. Among adult GIST, IGF2 expression was higher in tumours lacking Homo sapiens v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog (KIT) or alpha-type platelet-derived growth factor receptor (PDGFRA) mutations in comparison with mutated cases. A trend for a higher expression of IGF2 in resistant GIST in comparison to responsive GIST was also found. Overexpression of IGF2 was not related to LOI. Conversely, the expression of the IGF1R gene was significantly higher in the paediatric group than in the adult group. No copy number gains or mutations of IGF1R were observed.
The IGF pathway is deregulated in GIST with distinct patterns according to age onset and mutational status. The IGF pathway may represent a therapeutic target in patients with primary or secondary resistance to imatinib.
有关成人和儿科胃肠道间质瘤（GIST）中胰岛素样生长因子（IGF）途径失调的模式和机制的数据有限。
我们使用 Affymetrix U133A 平台研究了 131 例 GIST（106 例成人、21 例儿科和 4 例年轻成人）和 25 例其他软组织肉瘤（STS）中编码 IGF 信号通路主要成分的基因的表达谱。我们研究了 IGF2 的印迹缺失（LOI），同时分析了 IGF1R 的拷贝数异常和突变。
IGF2 是 GIST 中 IGF 途径中过度表达最显著的基因。IGF2 的表达也明显高于其他 STS。IGF2 的表达与 GIST 的发病年龄和突变状态相关。事实上，IGF2 的表达在“成人”组中明显高于“儿科”和“年轻成人”组。在成年 GIST 中，与突变病例相比，缺乏 Homo sapiens v-kit Hardy-Zuckerman 4 猫肉瘤病毒致癌基因同源物（KIT）或 alpha 型血小板衍生生长因子受体（PDGFRA）突变的肿瘤中 IGF2 的表达更高。我们还发现，耐药 GIST 中 IGF2 的表达高于敏感 GIST。IGF2 的过表达与 LOI 无关。相反，IGF1R 基因的表达在儿科组中明显高于成年组。未观察到 IGF1R 的拷贝数增益或突变。
IGF 途径在 GIST 中失调，其模式根据发病年龄和突变状态而不同。IGF 途径可能成为对伊马替尼原发性或继发性耐药患者的治疗靶点。
