Duerr Eva-Maria, Mizukami Yusuke, Ng Aylwin, Xavier Ramnik J, Kikuchi Hirotoshi, Deshpande Vikram, Warshaw Andrew L, Glickman Jonathan, Kulke Matthew H, Chung Daniel C
Gastrointestinal Unit, Department of Medicine, Cancer Center, Center for Computational and Integrative Biology, Massachusetts General Hospital, Boston, MA 02114, USA.
Endocr Relat Cancer. 2008 Mar;15(1):243-56. doi: 10.1677/ERC-07-0194.
Current classifications of human gastroenteropancreatic neuroendocrine tumors (NETs) are inconsistent and based upon histopathologic but not molecular features. We sought to compare a molecular classification with the World Health Organization (WHO) histologic classification, identify genes that may be important for tumor progression, and determine whether gastrointestinal NETs (GI-NETs) differ in their molecular profile from pancreatic NETs (PNETs). DNA microarray analysis was performed to identify differentially expressed genes in PNETs and GI-NETs. Confirmation of expression levels was obtained by quantitative real-time PCR. Immunoblotting and mutational analysis were performed for selected genes. Hierarchical clustering of 19 PNETs revealed a 'benign' and 'malignant' cluster that corresponded well with the WHO categories of well-differentiated endocrine tumor (WDET) and well-differentiated endocrine carcinoma (WDEC) respectively. FEV, adenylate cyclase 2 (ADCY2), nuclear receptor subfamily 4, group A, member 2 (NR4A2), and growth arrest and DNA-damage-inducible, beta (GADD45b) were the most highly up-regulated genes in the malignant group of PNETs. Platelet-derived growth factor receptor (PDGFR) was expressed in both WDETs and WDECs, and phosphorylation of PDGFR-beta was observed in 83% of all PNETs. Malignant ileal GI-NETs exhibited a distinctive gene expression profile, and extracellular matrix protein 1 (ECM), vesicular monoamine member 1 (VMAT1), galectin 4 (LGALS4), and RET Proto-oncogene (RET) were highly up-regulated genes. Gene expression profiles reflect the current WHO classification and can distinguish benign from malignant PNETs and also PNETs from GI-NETs. This suggests that molecular profiling may enhance tumor classification schemes. Potential gene targets have also been identified, and PDGFR and RET are candidates that may represent novel therapeutic targets.
目前人类胃肠胰神经内分泌肿瘤（NETs）的分类并不一致，且基于组织病理学而非分子特征。我们试图将分子分类与世界卫生组织（WHO）的组织学分类进行比较，确定可能对肿瘤进展重要的基因，并确定胃肠道NETs（GI-NETs）在分子特征上是否与胰腺NETs（PNETs）不同。进行DNA微阵列分析以鉴定PNETs和GI-NETs中差异表达的基因。通过定量实时PCR获得表达水平的确认。对选定基因进行免疫印迹和突变分析。对19个PNETs进行层次聚类，发现一个“良性”和“恶性”聚类，分别与WHO的高分化内分泌肿瘤（WDET）和高分化内分泌癌（WDEC）类别高度对应。FEV、腺苷酸环化酶2（ADCY2）、核受体亚家族4 A组成员2（NR4A2）以及生长停滞和DNA损伤诱导蛋白β（GADD45b）是PNETs恶性组中上调程度最高的基因。血小板衍生生长因子受体（PDGFR）在WDETs和WDECs中均有表达，并且在所有PNETs的83%中观察到PDGFR-β的磷酸化。恶性回肠GI-NETs表现出独特的基因表达谱，细胞外基质蛋白1（ECM）、囊泡单胺转运体1（VMAT1）、半乳糖凝集素4（LGALS4）和原癌基因RET均为上调程度高的基因。基因表达谱反映了当前的WHO分类，并且可以区分良性和恶性PNETs，以及PNETs和GI-NETs。这表明分子谱分析可能会改进肿瘤分类方案。还确定了潜在的基因靶点，PDGFR和RET是可能代表新治疗靶点的候选基因。
