Differentiation of small bowel and pancreatic neuroendocrine tumors by gene-expression profiling

Carr, Jennifer C.; Boese, Erin A.; Spanheimer, Philip M.; Dahdaleh, Fadi S.; Martin, Molly E.; Calva, Daniel; Schafer, Blanca; Thole, David M.; Braun, Terry A.; O’Dorisio, Thomas M.; O’Dorisio, M. Sue; Howe, James R.

doi:10.1016/j.surg.2012.08.040

Cited by 15 publications

(21 citation statements)

References 22 publications

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“…Vesicular monoamine transporters (VMATs) facilitate the transport of monoamines from the cytoplasm into the secretory vesicles of neurons and neuroendocrine cells. Overexpression of VMAT-1 mRNA and protein level was described in primary as well as metastasized ileal carcinoids [17,26], and statistically significant upregulation of the VMAT-1 gene (22-fold) in SI-NETs was also observed in one study mentioned above [25]. Moreover, the mutually exclusive prevalence of VMAT-1 in serotonin-containing cells and of VMAT-2 in histamine-secreting cells could enable pathologists to distinguish SI-NETs among other types of NETs.…”

Section: Biochemical Markers In the Diagnosis And Prognosis Of Si-netsmentioning

confidence: 95%

“…DNA microarray analysis validated the significant difference in gene expression between these tumor types [24], allowing for a differential diagnosis depending on gene expression profile. Furthermore, another study using G protein-coupled receptor arrays identified two genes (oxytocin receptor and G protein-coupled receptor 113) that were upregulated by more than five-fold in all SI-NET samples, while no pancreatic neuroendocrine tumors shared this profile [25]. Vesicular monoamine transporters (VMATs) facilitate the transport of monoamines from the cytoplasm into the secretory vesicles of neurons and neuroendocrine cells.…”

Section: Biochemical Markers In the Diagnosis And Prognosis Of Si-netsmentioning

confidence: 99%

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Current Perspective on the Pathogenesis of Small Intestinal Neuroendocrine Tumors: Progress in Biomarkers and Molecular Events

Chen

Fang

2013

Gastrointest Tumors

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Background: Neuroendocrine tumors of the gastrointestinal tract differ in their histopathologic and clinical presentation. Small intestinal neuroendocrine tumors (SI-NETs), representing only a small portion within gastrointestinal malignancies, are often associated with a delayed diagnosis due to their non-specific symptoms. The increased incidence of SI-NETs during the last decades demands earlier diagnosis and more effective treatment, which both rely on a better understanding on the underlying molecular mechanisms. Summary: The purpose of this review is to discuss the biomolecular changes responsible for the pathogenesis of SI-NETs, and potential biomarkers in the diagnostic and prognostic evaluation. Key Message A greater understanding of the molecular mechanisms that underpin the pathogenesis of small intestinal neuroendocrine tumors (SI-NETs) facilitates the classification, diagnosis and treatment of these relatively rare gastrointestinal malignancies. Practical Implications Currently, SI-NETs are diagnosed using histological examination and staining for various neuroendocrine markers. Genetically, SI-NETs are characterized by an absence of alterations to K-ras, p53 and DNA mismatch repair genes. Loss of chromosome 18, deletion of Smad2 and Smad4, and amplification of SRC, EGFR and PDGFR have been reported. Abnormal DNA methylation status, reflected by overexpression of DNA methyltransferase, higher methylation of the RASSF1A promoter and overexpression of histone H1x are also associated with SI-NETs. These tumors are also associated with fibrosis, possibly due to the high levels of serotonin and other fibrotic factors produced. Genetic studies have pinpointed genes that can differentiate SI-NETs from other neuroendocrine tumors (oxytocin receptor, G protein-coupled receptor 113, VMAT-1, CDX-2), enabling more accurate diagnosis. Paraneoplastic antigen Ma2, neurokinin A and the CART peptide are under investigation as prognostic biomarkers. There is, however, still an unmet need for more sensitive biomarkers for earlier diagnosis and for a more specific classification system that encompasses tumor histology and reliable predictors of clinical response.

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Section: Biochemical Markers In the Diagnosis And Prognosis Of Si-netsmentioning

confidence: 95%

Section: Biochemical Markers In the Diagnosis And Prognosis Of Si-netsmentioning

confidence: 99%

Current Perspective on the Pathogenesis of Small Intestinal Neuroendocrine Tumors: Progress in Biomarkers and Molecular Events

Chen

Fang

2013

Gastrointest Tumors

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“…The target gene panel was selected from pilot experiments with GPCR and exon-expression microarrays, and evaluated in a large number of SBNETs and PNETs(15–17). Target genes, primers, and qPCR methods were as described(17).…”

Section: Methodsmentioning

confidence: 99%

“…To build on the success of somatostatin-based NET treatments, and respond to the dilemma of patients in whom they fail, our group used G protein-coupled receptor (GPCR) and exon-expression microarrays to find new therapeutic targets, determining expression of 384 genes in a small number of initial tumor samples(15), and validating expression of a panel of 13 genes in over 100 SBNETs and PNETs(15–17). In these studies, OPRK1 and OXTR in SBNETs and GIPR in both SBNETs and PNETs, emerged as potentially useful receptors.…”

Section: Introductionmentioning

confidence: 99%

GIPR expression in gastric and duodenal neuroendocrine tumors

Sherman

Maxwell

Carr

et al. 2014

Journal of Surgical Research

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Background Compounds targeting somatostatin-receptor-type-2 (SSTR2) are useful for small bowel (SBNET) and pancreatic neuroendocrine tumor (PNET) imaging and treatment. We recently characterized expression of 13 cell-surface receptor genes in SBNETs and PNETs, identifying three drug targets (GIPR, OXTR, and OPRK1). This study set out to characterize expression of this gene panel in the less-common neuroendocrine tumors of the stomach and duodenum (GDNETs). Methods Primary tumors and adjacent normal tissue were collected at surgery, RNA was extracted, and expression of 13 target genes was determined by quantitative-PCR. Expression was normalized to GAPDH and POLR2A internal control genes. Expression relative to normal tissue (ddCT) and absolute expression (dCT) were calculated. Wilcoxon tests compared median expression with false discovery rate correction for multiple comparisons. Results Gene expression was similar in 2 gastric and 7 duodenal tumors, and these were analyzed together. Like SBNETs (n=63) and PNETs (n=51), GDNETs showed significant overexpression compared to normal tissue of BRS3, GIPR, GRM1, GPR113, OPRK1, and SSTR2 (p<0.05 for all). Of these, SSTR2 had the highest absolute expression in GDNETs (median dCT 4.0). Absolute expression of BRS3, GRM1, GPR113, and OPRK1 was significantly lower than SSTR2 in GDNETs (p<0.05 for all), while expression of GIPR was similar to SSTR2 (median 4.3, p=0.4). Conclusions As in SBNETs and PNETs, GIPR shows absolute expression close to SSTR2, but has greater overexpression relative to normal tissue (21.1 vs. 3.5-fold overexpression). We conclude that GIPR could provide an improved signal-to-noise ratio for imaging versus SSTR2, and represents a promising novel therapeutic target in GDNETs.

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“…Initial studies of G protein-coupled receptor and exon expression arrays in a limited number of clinical specimens suggested that a formula based on expression of the oxytocin receptor ( OXTR ) and secretin receptor ( SCTR ) in metastases might discriminate between metastases of small bowel versus pancreatic origin. [28] However, validation of this formula in 45 SBNET and PNET liver metastases revealed an accuracy of only 71% for determining the primary site. [29]…”

Section: Introductionmentioning

confidence: 99%

Gene expression accurately distinguishes liver metastases of small bowel and pancreas neuroendocrine tumors

Sherman

Maxwell

Carr

et al. 2014

Clin Exp Metastasis

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Small bowel (SBNETs) and pancreatic neuroendocrine tumors (PNETs) often present with liver metastases. Although liver biopsy establishes a neuroendocrine diagnosis, the primary tumor site is frequently unknown without exploratory surgery. Gene expression differences in metastases may distinguish primary SBNETs and PNETs. This study sought to determine expression differences of four genes in neuroendocrine metastases and to create a gene expression algorithm to distinguish the primary site. Nodal and liver metastases from SBNETs and PNETs (n=136) were collected at surgery under an Institutional Review Board-approved protocol. Quantitative PCR measured expression of bombesin-like receptor-3, opioid receptor kappa-1, oxytocin receptor, and secretin receptor in metastases. Logistic regression models defined an algorithm predicting the primary tumor site. Models were developed on a training set of 21 nodal metastases and performance was validated on an independent set of nodal and liver metastases. Expression of all four genes was significantly different in SBNET compared to PNET metastases. The optimal model employed expression of bombesin-like receptor-3 and opioid receptor kappa-1. When these genes did not amplify, the algorithm used oxytocin receptor and secretin receptor expression, which allowed classification of all 136 metastases with 94.1% accuracy. In the independent liver metastasis validation set, 52/56 (92.9%) were correctly classified. Positive predictive values were 92.5% for SBNETs and 93.8% for PNETs. This validated algorithm accurately distinguishes SBNET and PNET metastases based on their expression of four genes. High accuracy in liver metastases demonstrates applicability to the clinical setting. Studies assessing this algorithm’s utility in prospective clinical decision-making are warranted.

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Differentiation of small bowel and pancreatic neuroendocrine tumors by gene-expression profiling

Cited by 15 publications

References 22 publications

Current Perspective on the Pathogenesis of Small Intestinal Neuroendocrine Tumors: Progress in Biomarkers and Molecular Events

Current Perspective on the Pathogenesis of Small Intestinal Neuroendocrine Tumors: Progress in Biomarkers and Molecular Events

GIPR expression in gastric and duodenal neuroendocrine tumors

Gene expression accurately distinguishes liver metastases of small bowel and pancreas neuroendocrine tumors

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