Profiling of GEPNETs

Table 2

Summary of expression profiling studies on pancreatic neuroendocrine tumors (PNETs).

Study	Tumor type (number)	Profiling platform	Main findings	Therapeutic implications
Maitra et al. [45] Clin Cancer Res	PNET (𝑛=8) (all NF-PNET, well-differentiated 6 benign, 2 malignant)	Expression array (Affymetrix U133)	Overexpression of 66 transcripts (≥3-fold versus normal islets) Underexpression of 119 transcripts(≤3-fold versus normal islets) Verified proteines include IGFBP3, Fibronectin, p21, and CD99	Candidate pathways for targeted therapy include IGF signaling
Hansel et al. [46] Clin Cancer Res	PNET (𝑛=12) (all well-differentiated, F-PNET, and NF-PNET–5 benign, 7 malignant)	Expression array (Affymetrix U133)	Overexpression of 65 genes (≥3-fold malignant versus benign) Underexpression of 57 genes (≤3-fold malignant versus benign) Verified proteins include MET and IGFBP3, which are overexpressed in metastatic tumors	Candidates for targeted therapy include IGF signaling and MET tyrosine kinase
Bloomston et al. [47] Annals Surg Oncol	PNET (𝑛=9) (pooled samples)	Expression array (Affymetrix U133)	1340 differentially expressed genes in PNETs versus normal pancreas Overexpressed genes verified by PCR include ANG2, NPDC1, ELOVLA4, and CALCR	Candidates for targeted therapy include ANG2
Dilley et al. [48] Mol Cancer	PNET (𝑛=8) (all MEN1 tumors; 4 F-PNET, 4 NF-PNET; 4 benign, 4 malignant	Expression array (Affymetrix U95Av2)	Overexpression of 45 genes (PNET versus normal pancreas), underexpression of 148 genes (PNET versus normal pancreas) Apoptosis-related genes frequently downregulated. Verified genes include FGF9, IER3, PHLDA2, IAPP, SST	Candidates for targeted therapy include HGF
Couvelard et al. [52] Gastroenterology	PNET (𝑛=24) (all well-differentiated; 18 sporadic, 5 VHL, 1 MEN1; 20 NF-PNET, 4 F-PNET 12 benign, 12 malignant)	Expression array (Sanger Center)	Overexpression of 72 genes and underexpression of 51 genes (malignant versus benign tumors). Verified proteins include CD34 E-selectin, MKK4, and MDR1	Candidates for targeted therapy include IGF1, MAP2K4 (MKK4), and DDR1
Capurso et al. [49] Endocr Relat Cancer	PNET (𝑛=13) (all NF-PNET; 10 WDEC, 3PDEC)	Expression array (Affymetrix 133)	Overexpression of 667 genes and underexpression of 323 genes (PNETs versus pancreatic islets) Verified genes include BIN1, SERPINA10, LCK, BST2 Highly similar expression profile of primaries and metastases.	Candidates for targeted therapy include LCK (Src family of PTKs) and BST2
Roldo et al. [63] J Clin Oncol	PNET (𝑛=40) (all sporadic, well-differentiated; 28 NF-PNET,12 F-PNET; 22 benign, 18 malignant)	miRNA array (Ohio State University)	Distinct pattern of miRNA distinguish PNETs from normal pancreas. 87 miRNA upregulated and 8 miRNA downregulated in PNET versus normal pancreas Expression of miR-103 and miR-107, and lack of miR-155 distinguish PNET from normal pancreas. miR-204 is primarily expressed in insulinoma. miR-21 is associated with high proliferation and liver metastases.	—
Lowe et al. [50] PLoS ONE	PNET (𝑛=6) (4 NF-PNET, 2 insulinoma)	Expression array (Stanford University)	Overexpression of 311 genes in PNET (PNET versus normal pancreas) including neuroendocrine markers, CHGA, CHGB, SYP, PAM, DDC, and SSTR1. High Expression of AXL, MAFB and AXIN2	Candidates for targeted therapy include AXIN2 and Wnt signaling
de Sá et al. [51] Clin Cancer Res	PNET (𝑛=10) (6 benign insulinomas 4 malignant insulinomas)	Expression array (CodeLink)	Overexpression of 110 genes and underexpression of 120 genes (malignant versus benign tumors). Validated genes include PRSS2,CTRB1, SERPINA1, AGT, and CFB. SERPINA1 (alpha-1-antitryspin) is a marker of malignancy in insulinoma	—
Duerr et al. [60] Endocr Relat Cancer	PNET (𝑛=24) (5 benign, 11 low-grade malignant, 8 malignant; 5 NF-PNET, 12 insulinoma, 3 gastrinoma, 2 other)	Expression array (Affymetrix U133)	PNET forms “benign” and “malignant”clusters differing in “transcription regulation” and “binding”. Validated genes upregulated in malignant cluster include FEV, ADCY2, NR4A2, and GADD45β. Expression pattern of PNET is different from GI-NETs. PDGFR- β is frequently activated (phosphorylated) in PNET.	Candidates for targeted therapy include PDGFR- β
Missiaglia et al. [61] J Clin Oncol	PNET (𝑛=72) (39 WDET, 30 WDEC, 3 PDEC; 16 F-PNET, 56 NF-PNET)	Expression array (Ohio State University)	Unsupervised hierarchical clustering separates NF-PNET from insulinoma. TSC2 and PTEN are downregulated in PNET and associated with short survival. SSTR2 is upregulated in NF-PNET. FGF13 expression in PNET correlates with metastatic potential.	Candidates for targeted therapy include AKT-mTOR pathway and SSTR2

For genes and proteins in bold, therapeutic agents are available for preclinical or clinical testing. F-PNET: functioning PNET; GI-NET: gastrointestinal neuroendocrine tumor; MEN1: multiple endocrine neoplasia type 1; NF-PNET: non-functioning PNET; PDEC: poorly differentiated endocrine carcinoma; PNET: pancreatic neuroendocrine tumor; WDET: well-differentiated endocrine tumor; WDEC: well differentiated endocrine carcinoma.