Decoding the Molecular and Mutational Ambiguities of Gastroenteropancreatic Neuroendocrine Neoplasm Pathobiology

Mark Kidd1, Irvin M. Modlin1, Lisa Bodei1, Ignat Drozdov1
1The Gnostic Consortium, Wren Laboratories, Branford, Connecticut

Tài liệu tham khảo

Modlin, 2008, Gastroenteropancreatic neuroendocrine tumours, Lancet Oncol, 9, 61, 10.1016/S1470-2045(07)70410-2 Strosberg, 2013, Evolving treatment strategies for management of carcinoid tumors, Curr Treat Options Oncol, 14, 374, 10.1007/s11864-013-0246-4 Baudin, 2012, Intervention in gastro-enteropancreatic neuroendocrine tumours, Best Pract Res Clin Gastroenterol, 26, 855, 10.1016/j.bpg.2013.01.008 Modlin, 2005, Current status of gastrointestinal carcinoids, Gastroenterology, 128, 1717, 10.1053/j.gastro.2005.03.038 Yao, 2008, One hundred years after “carcinoid”: epidemiology of and prognostic factors for neuroendocrine tumors in 35,825 cases in the United States, J Clin Oncol, 26, 3063, 10.1200/JCO.2007.15.4377 Ellis, 2010, Carcinoid tumors of the gastrointestinal tract: trends in incidence in England since 1971, Am J Gastroenterol, 105, 2563, 10.1038/ajg.2010.341 Maggard, 2004, Updated population-based review of carcinoid tumors, Ann Surg, 240, 117, 10.1097/01.sla.0000129342.67174.67 Lawrence, 2011, The epidemiology of gastroenteropancreatic neuroendocrine tumors, Endocrinol Metab Clin North Am, 40, 1, 10.1016/j.ecl.2010.12.005 Modlin, 2008, Priorities for improving the management of gastroenteropancreatic neuroendocrine tumors, J Natl Cancer Inst, 100, 1282, 10.1093/jnci/djn275 Powell, 2010, Multiple endocrine neoplasia type 1: clinical manifestations and management, Cancer Treat Res, 153, 287, 10.1007/978-1-4419-0857-5_16 de Mestier, 2014, Evaluating digestive neuroendocrine tumor progression and therapeutic responses in the era of targeted therapies: state of the art, Endocr Relat Cancer, 21, R105, 10.1530/ERC-13-0365 Bergsland, 2013, The evolving landscape of neuroendocrine tumors, Semin Oncol, 40, 4, 10.1053/j.seminoncol.2012.11.013 Wang, 2012, Heterogeneity in signaling pathways of gastroenteropancreatic neuroendocrine tumors: a critical look at notch signaling pathway, Mod Pathol, 24, 143 Sundin, 2012, Therapeutic monitoring of gastroenteropancreatic neuroendocrine tumors: the challenges ahead, Neuroendocrinology, 96, 261, 10.1159/000342270 Kidd, 2012, EGFR/TGFα and TGFβ/CTGF signaling in neuroendocrine neoplasia: theoretical therapeutic targets, Neuroendocrinology, 15, 15 Chan, 2011, New treatment options for patients with advanced neuroendocrine tumors, Curr Treat Options Oncol, 12, 136, 10.1007/s11864-011-0148-2 Oberg, 2010, Pancreatic endocrine tumors, Semin Oncol, 37, 594, 10.1053/j.seminoncol.2010.10.014 Garcia-Carbonero, 2010, Incidence, patterns of care and prognostic factors for outcome of gastroenteropancreatic neuroendocrine tumors (GEP-NETs): results from the National Cancer Registry of Spain (RGETNE), Ann Oncol, 21, 1794, 10.1093/annonc/mdq022 Strosberg, 2009, Survival and prognostic factor analysis of 146 metastatic neuroendocrine tumors of the mid-gut, Neuroendocrinology, 89, 471, 10.1159/000197899 Frilling, 2012, Neuroendocrine tumor disease: an evolving landscape, Endocr Relat Cancer, 19, R163, 10.1530/ERC-12-0024 Frilling, 2014, Recommendations for management of patients with neuroendocrine liver metastases, Lancet Oncol, 15, e8, 10.1016/S1470-2045(13)70362-0 Sippel, 2006, Carcinoid tumors, Surg Oncol Clin N Am, 15, 463, 10.1016/j.soc.2006.05.002 Ramage, 2012, Guidelines for the management of gastroenteropancreatic neuroendocrine (including carcinoid) tumours (NETs), Gut, 61, 6, 10.1136/gutjnl-2011-300831 Eisenhauer, 2009, New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1), Eur J Cancer, 45, 228, 10.1016/j.ejca.2008.10.026 Neperud, 2013, Can imaging patterns of neuroendocrine hepatic metastases predict response yttruim-90 radioembolotherapy?, World J Radiol, 5, 241, 10.4329/wjr.v5.i6.241 Denecke, 2013, Evaluation of radiological prognostic factors of hepatic metastases in patients with non-functional pancreatic neuroendocrine tumors, Eur J Radiol, 82, e550, 10.1016/j.ejrad.2013.06.017 Oberg, 2004, Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system, Ann Oncol, 15, 966, 10.1093/annonc/mdh216 Caplin, 2014, Lanreotide in metastatic enteropancreatic neuroendocrine tumors, N Engl J Med, 371, 224, 10.1056/NEJMoa1316158 Rinke, 2009, Placebo-controlled, double-blind, prospective, randomized study on the effect of octreotide LAR in the control of tumor growth in patients with metastatic neuroendocrine midgut tumors: a report from the PROMID Study Group, J Clin Oncol, 27, 4656, 10.1200/JCO.2009.22.8510 Yao, 2008, Targeting vascular endothelial growth factor in advanced carcinoid tumor: a random assignment phase II study of depot octreotide with bevacizumab and pegylated interferon alpha-2b, J Clin Oncol, 26, 1316, 10.1200/JCO.2007.13.6374 Yao, 2011, Everolimus for advanced pancreatic neuroendocrine tumors, N Engl J Med, 364, 514, 10.1056/NEJMoa1009290 Raymond, 2011, Sunitinib malate for the treatment of pancreatic neuroendocrine tumors, N Engl J Med, 364, 501, 10.1056/NEJMoa1003825 Lawrence, 2010, New pharmacologic therapies for gastroenteropancreatic neuroendocrine tumors, Gastroenterol Clin North Am, 39, 615, 10.1016/j.gtc.2010.08.013 Qi, 2013, Incidence and risk of treatment-related mortality with mTOR inhibitors everolimus and temsirolimus in cancer patients: a meta-analysis, PLoS ONE, 8, e65166, 10.1371/journal.pone.0065166 Yao, 2013, Targeted therapies in neuroendocrine tumors (NET): clinical trial challenges and lessons learned, Oncologist, 18, 525, 10.1634/theoncologist.2012-0434 Champaneria, 2006, Friedrich Feyrter: a precise intellect in a diffuse system, Neuroendocrinology, 83, 394, 10.1159/000096050 Peto, 1975, Cancer and ageing in mice and men, Br J Cancer, 32, 411, 10.1038/bjc.1975.242 Frank, 2007 Berge, 1976, Carcinoid tumours. Frequency in a defined population during a 12-year period, Acta Pathol Microbiol Scand A, 84, 322 Gustafsson, 2008, Neuroendocrine tumors of the diffuse neuroendocrine system, Curr Opin Oncol, 20, 1, 10.1097/CCO.0b013e3282f1c595 McGinnis, 2013, The unexpected applicability of paraconsistent logic: a Chomskyan route to dialetheism, Found Sci, 18, 625, 10.1007/s10699-012-9294-7 Kloppel, 2004, The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification, Ann NY Acad Sci, 1014, 13, 10.1196/annals.1294.002 Kidd, 2009, Delineation of the chemomechanosensory regulation of gastrin secretion using pure rodent G cells, Gastroenterology, 137, 231, 10.1053/j.gastro.2009.01.005 Gustafsson, 2006, A new method for visualization of gut mucosal cells, describing the enterochromaffin cell in the rat gastrointestinal tract, Scand J Gastroenterol, 41, 390, 10.1080/00365520500331281 Bohorquez, 2011, Axon-like basal processes in enteroendocrine cells: characteristics and potential targets, Clin Transl Sci, 4, 387, 10.1111/j.1752-8062.2011.00299.x Kidd, 2009, IL1β- and LPS-induced serotonin secretion is increased in EC cells derived from Crohn’s disease, Neurogastroenterol Motil, 21, 439, 10.1111/j.1365-2982.2008.01210.x Hauso, 2007, Long slender cytoplasmic extensions: a common feature of neuroendocrine cells?, J Neuroendocrinol, 19, 739, 10.1111/j.1365-2826.2007.01578.x Schimmack, 2012, The clinical implications and biologic relevance of neurofilament expression in gastroenteropancreatic neuroendocrine neoplasms, Cancer, 118, 2763, 10.1002/cncr.26592 Ardill, 2003, The importance of the measurement of circulating markers in patients with neuroendocrine tumours of the pancreas and gut, Endocr Relat Cancer, 10, 459, 10.1677/erc.0.0100459 Kidd, 2008, Luminal regulation of normal and neoplastic human EC cell serotonin release is mediated by bile salts, amines, tastants, and olfactants, Am J Physiol Gastrointest Liver Physiol, 295, G260, 10.1152/ajpgi.00056.2008 Wiedenmann, 1998, Molecular and cell biological aspects of neuroendocrine tumors of the gastroenteropancreatic system, J Mol Med, 76, 637, 10.1007/s001090050261 Bloom, 1978, Gut hormones, Proc Nutr Soc, 37, 259, 10.1079/PNS19780037 Bloom, 1978 Modlin, 2010, Chromogranin A—biological function and clinical utility in neuro endocrine tumor disease, Ann Surg Oncol, 17, 2427, 10.1245/s10434-010-1006-3 Chieregatti, 2002, SNAP-25 and synaptotagmin 1 function in Ca2+-dependent reversible docking of granules to the plasma membrane, Traffic, 3, 496, 10.1034/j.1600-0854.2002.30706.x Portela-Gomes, 2001, Selective processing of chromogranin A in the different islet cells in human pancreas, J Histochem Cytochem, 49, 483, 10.1177/002215540104900408 Marotta, 2012, Limitations of chromogranin A in clinical practice, Biomarkers, 17, 186, 10.3109/1354750X.2012.654511 Kanakis, 2012, Biochemical markers for gastroenteropancreatic neuroendocrine tumours (GEP-NETs), Best Pract Res Clin Gastroenterol, 26, 791, 10.1016/j.bpg.2012.12.006 Lawrence, 2011, The clinical relevance of chromogranin A as a biomarker for gastroenteropancreatic neuroendocrine tumors, Endocrinol Metab Clin North Am, 40, 111, 10.1016/j.ecl.2010.12.001 Giovinazzo, 2013, Chromogranin A and its fragments as regulators of small intestinal neuroendocrine neoplasm proliferation, PLoS ONE, 8, e81111, 10.1371/journal.pone.0081111 Wank, 1998, G protein-coupled receptors in gastrointestinal physiology. I. CCK receptors: an exemplary family, Am J Physiol, 274, G607 Alvarez, 2012, Calcium dynamics in the secretory granules of neuroendocrine cells, Cell Calcium, 51, 331, 10.1016/j.ceca.2011.12.002 Drews, 2010, Electrophysiology of islet cells, Adv Exp Med Biol, 654, 115, 10.1007/978-90-481-3271-3_7 Cases, 2014, Expression of glucagon-like peptide 1 receptor and its effects on biologic behavior in pancreatic neuroendocrine tumors, Pancreas, 43, 1, 10.1097/MPA.0b013e3182a71537 Hook, 2008, Differential activation of enkephalin, galanin, somatostatin, NPY, and VIP neuropeptide production by stimulators of protein kinases A and C in neuroendocrine chromaffin cells, Neuropeptides, 42, 503, 10.1016/j.npep.2008.05.001 Garcia-Osta, 2004, Increased CRE-binding activity and tryptophan hydroxylase mRNA expression induced by 3,4-methylenedioxymethamphetamine (MDMA, “ecstasy”) in the rat frontal cortex but not in the hippocampus, Brain Res Mol Brain Res, 126, 181, 10.1016/j.molbrainres.2004.04.006 Chin, 2012, The role of mechanical forces and adenosine in the regulation of intestinal enterochromaffin cell serotonin secretion, Am J Physiol Gastrointest Liver Physiol, 302, G397, 10.1152/ajpgi.00087.2011 Papadopulos, 2013, Secretagogue stimulation of neurosecretory cells elicits filopodial extensions uncovering new functional release sites, J Neurosci, 33, 19143, 10.1523/JNEUROSCI.2634-13.2013 Reubi, 2013, Illuminating somatostatin analog action at neuroendocrine tumor receptors, Trends Pharmacol Sci, 34, 676, 10.1016/j.tips.2013.10.001 Tentler, 1997, Somatostatin acts by inhibiting the cyclic 3’,5’-adenosine monophosphate (cAMP)/protein kinase A pathway, cAMP response element-binding protein (CREB) phosphorylation, and CREB transcription potency, Mol Endocrinol, 11, 859 Peri, 2001, Regulation of L-type calcium channels in pituitary GH4C1 cells by depolarization, J Biol Chem, 276, 31667, 10.1074/jbc.M102613200 Rozengurt, 2001, Gastrin, CCK, signaling, and cancer, Ann Rev Physiol, 63, 49, 10.1146/annurev.physiol.63.1.49 Chalmers, 2007, The duration of ERK1/2 activity determines the activation of c-Fos and Fra-1 and the composition and quantitative transcriptional output of AP-1, Cell Signal, 19, 695, 10.1016/j.cellsig.2006.09.001 Treinies, 1999, Activated MEK stimulates expression of AP-1 components independently of phosphatidylinositol 3-kinase (PI3-kinase) but requires a PI3-kinase signal To stimulate DNA synthesis, Mol Cell Biol, 19, 321, 10.1128/MCB.19.1.321 Kinoshita, 1998, Comparison of the signal transduction pathways activated by gastrin in enterochromaffin-like and parietal cells, Gastroenterology, 115, 93, 10.1016/S0016-5085(98)70369-5 Abraham, 2012, Proton pump inhibitors: potential adverse effects, Curr Opin Gastroenterol, 28, 615, 10.1097/MOG.0b013e328358d5b9 Lawrence, 2011, A clinical perspective on gastric neuroendocrine neoplasia, Curr Gastroenterol Rep, 13, 101, 10.1007/s11894-010-0158-4 Berna, 2008, A prospective study of gastric carcinoids and enterochromaffin-like cell changes in multiple endocrine neoplasia type 1 and Zollinger-Ellison syndrome: identification of risk factors, J Clin Endocrinol Metab, 93, 1582, 10.1210/jc.2007-2279 Furukawa, 2005, Increased expression of insulin-like growth factor I and/or its receptor in gastrinomas is associated with low curability, increased growth, and development of metastases, Clin Cancer Res, 11, 3233, 10.1158/1078-0432.CCR-04-1915 Kidd, 2007, Small bowel carcinoid (enterochromaffin cell) neoplasia exhibits transforming growth factor-β1-mediated regulatory abnormalities including up-regulation of C-Myc and MTA1, Cancer, 109, 2420, 10.1002/cncr.22725 Papouchado, 2005, Epidermal growth factor receptor and activated epidermal growth factor receptor expression in gastrointestinal carcinoids and pancreatic endocrine carcinomas, Mod Pathol, 18, 1329, 10.1038/modpathol.3800427 Wulbrand, 1998, Growth factor receptor expression in human gastroenteropancreatic neuroendocrine tumours, Eur J Clin Invest, 28, 1038, 10.1046/j.1365-2362.1998.00397.x Nilsson, 1995, Expression of transforming growth factor alpha and its receptor in human neuroendocrine tumours, Int J Cancer, 60, 645, 10.1002/ijc.2910600514 Gilbert, 2010, Molecular markers for novel therapies in neuroendocrine (carcinoid) tumors, Endocr Relat Cancer, 17, 623, 10.1677/ERC-09-0318 Krishnamurthy, 1997, Immunohistochemical expression of transforming growth factor alpha and epidermal growth factor receptor in gastrointestinal carcinoids, Am J Surg Pathol, 21, 327, 10.1097/00000478-199703000-00009 Susini, 2006, Rationale for the use of somatostatin analogs as antitumor agents, Ann Oncol, 17, 1733, 10.1093/annonc/mdl105 Theodoropoulou, 2013, Somatostatin receptors: from signaling to clinical practice, Front Neuroendocrinol, 34, 228, 10.1016/j.yfrne.2013.07.005 Wolin, 2012, The expanding role of somatostatin analogs in the management of neuroendocrine tumors, Gastrointest Cancer Res, 5, 161 Li, 2012, Notch signaling differentially regulates the cell fate of early endocrine precursor cells and their maturing descendants in the mouse pancreas and intestine, Dev Biol, 371, 156, 10.1016/j.ydbio.2012.08.023 Nakakura, 2005, Regulation of neuroendocrine differentiation in gastrointestinal carcinoid tumor cells by notch signaling, J Clin Endocrinol Metab, 90, 4350, 10.1210/jc.2005-0540 Fendrich, 2007, Snail and Sonic Hedgehog activation in neuroendocrine tumors of the ileum, Endocr Relat Cancer, 14, 865, 10.1677/ERC-07-0108 Shida, 2006, Sonic Hedgehog-Gli1 signaling pathway might become an effective therapeutic target in gastrointestinal neuroendocrine carcinomas, Cancer Biol Ther, 5, 1530, 10.4161/cbt.5.11.3458 Di Florio, 2011, Src kinase activity coordinates cell adhesion and spreading with activation of mammalian target of rapamycin in pancreatic endocrine tumour cells, Endocr Relat Cancer, 18, 541, 10.1530/ERC-10-0153 Porta, 2014, Targeting PI3K/Akt/mTOR Signaling in Cancer, Front Oncol, 4, 64, 10.3389/fonc.2014.00064 Silva, 2014, BRAFV600E cooperates with PI3K signaling, independent of Akt, to regulate melanoma cell proliferation, Mol Cancer Res, 12, 447, 10.1158/1541-7786.MCR-13-0224-T Svejda, 2011, Limitations in small intestinal neuroendocrine tumor therapy by mTOR kinase inhibition reflect growth factor-mediated PI3K feedback loop activation via ERK1/2 and Akt, Cancer, 117, 4141, 10.1002/cncr.26011 Rozengurt, 2014, Suppression of feedback loops mediated by PI3K/mTOR induces multiple overactivation of compensatory pathways: an unintended consequence leading to drug resistance, Mol Cancer Ther, 13, 2477, 10.1158/1535-7163.MCT-14-0330 Tannapfel, 2005, BRAF gene mutations are rare events in gastroenteropancreatic neuroendocrine tumors, Am J Clin Pathol, 123, 256, 10.1309/YQBR9C05RU4DD3RN Perren, 2004, BRAF and endocrine tumors: mutations are frequent in papillary thyroid carcinomas, rare in endocrine tumors of the gastrointestinal tract and not detected in other endocrine tumors, Endocr Relat Cancer, 11, 855, 10.1677/erc.1.00841 Karhoff, 2007, Rap1/B-Raf signaling is activated in neuroendocrine tumors of the digestive tract and Raf kinase inhibition constitutes a putative therapeutic target, Neuroendocrinology, 85, 45, 10.1159/000100508 Wang, 2002, Differential expression of the PTEN tumor suppressor protein in fetal and adult neuroendocrine tissues and tumors: progressive loss of PTEN expression in poorly differentiated neuroendocrine neoplasms, Appl Immunohistochem Mol Morphol, 10, 139, 10.1097/00129039-200206000-00008 Shah, 2006, Epidermal growth factor receptor expression and activation in neuroendocrine tumours, J Neuroendocrinol, 18, 355, 10.1111/j.1365-2826.2006.01425.x Wong, 1999, Cell proliferation in gastrointestinal mucosa, J Clin Pathol, 52, 321, 10.1136/jcp.52.5.321 Bouwens, 1996, Islet cell neogenesis in the pancreas, Virchows Arch, 427, 553, 10.1007/BF00202885 Knudson, 1971, Mutation and cancer: statistical study of retinoblastoma, Proc Natl Acad Sci U S A, 68, 820, 10.1073/pnas.68.4.820 Vogelstein, 2004, Cancer genes and the pathways they control, Nat Med, 10, 789, 10.1038/nm1087 Berger, 2011, A continuum model for tumour suppression, Nature, 476, 163, 10.1038/nature10275 Roche, 2013, Peto’s paradox revisited: theoretical evolutionary dynamics of cancer in wild populations, Evol Appl, 6, 109, 10.1111/eva.12025 Metz, 2008, Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors, Gastroenterology, 135, 1469, 10.1053/j.gastro.2008.05.047 Vortmeyer, 2004, Non-islet origin of pancreatic islet cell tumors, J Clin Endocrinol Metab, 89, 1934, 10.1210/jc.2003-031575 Oberg, 2005, Endocrine tumours of the pancreas, Best Pract Res Clin Gastroenterol, 19, 753, 10.1016/j.bpg.2005.06.002 Rindi, 1999, Molecular aspects of the endocrine tumours of the pancreas and the gastrointestinal tract, Ital J Gastroenterol Hepatol, 31, S135 Yoshimoto, 1992, ras mutations in endocrine tumors: mutation detection by polymerase chain reaction-single strand conformation polymorphism, Jpn J Cancer Res, 83, 1057, 10.1111/j.1349-7006.1992.tb02722.x Chamberlain, 2014, Menin determines K-RAS proliferative outputs in endocrine cells, J Clin Invest, 124, 4093, 10.1172/JCI69004 Leotlela, 2003, Genetics of neuroendocrine and carcinoid tumours, Endocr Relat Cancer, 10, 437, 10.1677/erc.0.0100437 Zhang, 2013, Current understanding of the molecular biology of pancreatic neuroendocrine tumors, J Natl Cancer Inst, 105, 1005, 10.1093/jnci/djt135 Marinoni, 2014, Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors, Gastroenterology, 146, 453, 10.1053/j.gastro.2013.10.020 Cao, 2013, Whole exome sequencing of insulinoma reveals recurrent T372R mutations in YY1, Nat Commun, 4, 2810, 10.1038/ncomms3810 He, 2007, Events at the transition between cell cycle exit and oligodendrocyte progenitor differentiation: the role of HDAC and YY1, Neuron Glia Biol, 3, 221, 10.1017/S1740925X08000057 Speel, 1999, Genetic differences in endocrine pancreatic tumor subtypes detected by comparative genomic hybridization, Am J Pathol, 155, 1787, 10.1016/S0002-9440(10)65495-8 Speel, 2001, Genetic evidence for early divergence of small functioning and nonfunctioning endocrine pancreatic tumors: gain of 9Q34 is an early event in insulinomas, Cancer Res, 61, 5186 Rigaud, 2001, High resolution allelotype of nonfunctional pancreatic endocrine tumors: identification of two molecular subgroups with clinical implications, Cancer Res, 61, 285 Zhao, 2001, Genomic imbalances in the progression of endocrine pancreatic tumors, Genes Chromosomes Cancer, 32, 364, 10.1002/gcc.1201 Chung, 2000, Overexpression of cyclin D1 occurs frequently in human pancreatic endocrine tumors, J Clin Endocrinol Metab, 85, 4373 Chung, 1998, Localization of putative tumor suppressor loci by genome-wide allelotyping in human pancreatic endocrine tumors, Cancer Res, 58, 3706 Perren, 2000, Mutation and expression analyses reveal differential subcellular compartmentalization of PTEN in endocrine pancreatic tumors compared to normal islet cells, Am J Pathol, 157, 1097, 10.1016/S0002-9440(10)64624-X Missiaglia, 2010, Pancreatic endocrine tumors: expression profiling evidences a role for Akt-mTOR pathway, J Clin Oncol, 28, 245, 10.1200/JCO.2008.21.5988 Hu, 2010, Gene amplifications in well-differentiated pancreatic neuroendocrine tumors inactivate the p53 pathway, Genes Cancer, 1, 360, 10.1177/1947601910371979 D’Adda, 2005, Malignancy-associated X chromosome allelic losses in foregut endocrine neoplasms: further evidence from lung tumors, Mod Pathol, 18, 795, 10.1038/modpathol.3800353 Ghimenti, 1999, Microsatellite instability and allelic losses in neuroendocrine tumors of the gastro-entero-pancreatic system, Int J Oncol, 15, 361 Arnold, 2004, Analysis of molecular pathways in neuroendocrine cancers of the gastroenteropancreatic system, Ann NY Acad Sci, 1014, 218, 10.1196/annals.1294.023 Banck, 2013, The genomic landscape of small intestine neuroendocrine tumors, J Clin Invest, 15 Francis, 2013, Somatic mutation of CDKN1B in small intestine neuroendocrine tumors, Nat Genet, 45, 1483, 10.1038/ng.2821 Warth, 2011, Genetics and epigenetics of small bowel adenocarcinoma: the interactions of CIN, MSI, and CIMP, Mod Pathol, 24, 564, 10.1038/modpathol.2010.223 Kidd, 2005, Microsatellite instability and gene mutations in transforming growth factor-beta type II receptor are absent in small bowel carcinoid tumors, Cancer, 103, 229, 10.1002/cncr.20750 Lee, 2013, Multiple endocrine neoplasia syndromes associated with mutation of p27, J Endocrinol Invest, 36, 781 Karnik, 2005, Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c, Proc Natl Acad Sci U S A, 102, 14659, 10.1073/pnas.0503484102 Vijayvergia N, Boland P, Gustafson K, et al. Molecular profiling of advanced stage neuroendocrine tumors (NETs): the Fox Chase Cancer Center (FCCC) experience. Poster presented at the 2015 Gastrointestinal Cancers Symposium, San Francisco, Jan 15-17, 2015; abstract 245; NANETs Abstract Handbook 2014, abstract BT13. Available at: http://meetinglibrary.asco.org/content/139139-158. Tonnies, 2001, Analysis of sporadic neuroendocrine tumours of the enteropancreatic system by comparative genomic hybridisation, Gut, 48, 536, 10.1136/gut.48.4.536 Kytola, 2001, Comparative genomic hybridization identifies loss of 18q22-qter as an early and specific event in tumorigenesis of midgut carcinoids, Am J Pathol, 158, 1803, 10.1016/S0002-9440(10)64136-3 Kytola, 2002, Alterations of the SDHD gene locus in midgut carcinoids, Merkel cell carcinomas, pheochromocytomas, and abdominal paragangliomas, Genes Chromosomes Cancer, 34, 325, 10.1002/gcc.10081 Lollgen, 2001, Chromosome 18 deletions are common events in classical midgut carcinoid tumors, Int J Cancer, 92, 812, 10.1002/ijc.1276 Andersson, 2009, High-resolution genomic profiling reveals gain of chromosome 14 as a predictor of poor outcome in ileal carcinoids, Endocr Relat Cancer, 16, 953, 10.1677/ERC-09-0052 Kulke, 2008, High-resolution analysis of genetic alterations in small bowel carcinoid tumors reveals areas of recurrent amplification and loss, Genes Chromosomes Cancer, 47, 591, 10.1002/gcc.20561 Fearon, 1995, The deleted in colorectal cancer (DCC) gene: a candidate tumour suppressor gene encoding a cell surface protein with similarity to neural cell adhesion molecules, Cancer Surv, 24, 3 Petzmann, 2004, Analysis of chromosome-11 aberrations in pulmonary and gastrointestinal carcinoids: an array comparative genomic hybridization-based study, Virchows Arch, 445, 151, 10.1007/s00428-004-1052-y Walsh, 2011, A pilot genome-wide association study shows genomic variants enriched in the non-tumor cells of patients with well-differentiated neuroendocrine tumors of the ileum, Endocr Relat Cancer, 18, 171, 10.1677/ERC-10-0248 Muneyuki, 2000, Combination analysis of genetic alterations and cell proliferation in small intestinal carcinomas, Dig Dis Sci, 45, 2022, 10.1023/A:1005560428937 Planck, 2003, Microsatellite instability and expression of MLH1 and MSH2 in carcinomas of the small intestine, Cancer, 97, 1551, 10.1002/cncr.11197 Bloomston, 2004, Identification of molecular markers specific for pancreatic neuroendocrine tumors by genetic profiling of core biopsies, Ann Surg Oncol, 11, 413, 10.1245/ASO.2004.03.077 Duerr, 2008, Defining molecular classifications and targets in gastroenteropancreatic neuroendocrine tumors through DNA microarray analysis, Endocr Relat Cancer, 15, 243, 10.1677/ERC-07-0194 Kidd, 2006, The role of genetic markers—NAP1L1, MAGE-D2, and MTA1—in defining small-intestinal carcinoid neoplasia, Ann Surg Oncol, 13, 253, 10.1245/ASO.2006.12.011 Hofer, 2006, Comprehensive analysis of the expression of the metastasis-associated gene 1 in human neoplastic tissue, Arch Pathol Lab Med, 130, 989, 10.5858/2006-130-989-CAOTEO Drozdov, 2009, Predicting neuroendocrine tumor (carcinoid) neoplasia using gene expression profiling and supervised machine learning, Cancer, 115, 1638, 10.1002/cncr.24180 Leja, 2009, Novel markers for enterochromaffin cells and gastrointestinal neuroendocrine carcinomas, Mod Pathol, 22, 261, 10.1038/modpathol.2008.174 Cui, 2010, Paraneoplastic antigen Ma2 autoantibodies as specific blood biomarkers for detection of early recurrence of small intestine neuroendocrine tumors, PLoS ONE, 5, e16010, 10.1371/journal.pone.0016010 Edfeldt, 2011, Different gene expression profiles in metastasizing midgut carcinoid tumors, Endocr Relat Cancer, 18, 479, 10.1530/ERC-10-0256 Kidd, 2014, Gene network-based analysis identifies two potential subtypes of small intestinal neuroendocrine tumors, BMC Genomics, 15, 595, 10.1186/1471-2164-15-595 Drozdov, 2011, Gene network inference and biochemical assessment delineates GPCR pathways and CREB targets in small intestinal neuroendocrine neoplasia, PloS ONE, 6, e22457, 10.1371/journal.pone.0022457 Roldo, 2006, MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior, J Clin Oncol, 24, 4677, 10.1200/JCO.2005.05.5194 Thorns, 2014, Global MicroRNA profiling of pancreatic neuroendocrine neoplasias, Anticancer Res, 34, 2249 Li, 2013, MicroRNA array analysis finds elevated serum miR-1290 accurately distinguishes patients with low-stage pancreatic cancer from healthy and disease controls, Clin Cancer Res, 19, 3600, 10.1158/1078-0432.CCR-12-3092 Li, 2013, Global microRNA profiling of well-differentiated small intestinal neuroendocrine tumors, Mod Pathol, 26, 685, 10.1038/modpathol.2012.216 Ruebel, 2010, MicroRNA expression in ileal carcinoid tumors: downregulation of microRNA-133a with tumor progression, Mod Pathol, 23, 367, 10.1038/modpathol.2009.161 Jarhult, 2010, First report on metastasizing small bowel carcinoids in first-degree relatives in three generations, Neuroendocrinology, 91, 318, 10.1159/000299790 Larsson, 1988, Multiple endocrine neoplasia type 1 gene maps to chromosome 11 and is lost in insulinoma, Nature, 332, 85, 10.1038/332085a0 Boissan, 2010, Implication of metastasis suppressor NM23-H1 in maintaining adherens junctions and limiting the invasive potential of human cancer cells, Cancer Res, 70, 7710, 10.1158/0008-5472.CAN-10-1887 Hendy, 2005, Menin and TGF-beta superfamily member signaling via the Smad pathway in pituitary, parathyroid and osteoblast, Horm Metab Res, 37, 375, 10.1055/s-2005-870152 Gurung, 2013, Menin directly represses Gli1 expression independent of canonical Hedgehog signaling, Mol Cancer Res, 11, 1215, 10.1158/1541-7786.MCR-13-0170 Yang, 2013, Menin mediates epigenetic regulation via histone H3 lysine 9 methylation, Cell Death Dis, 4, e583, 10.1038/cddis.2013.98 Hughes, 2004, Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus, Mol Cell, 13, 587, 10.1016/S1097-2765(04)00081-4 Matkar, 2013, Menin: a scaffold protein that controls gene expression and cell signaling, Trends Biochem Sci, 38, 394, 10.1016/j.tibs.2013.05.005 Richard, 1998, Maladie de von Hippel-Lindau: progrès génétiques récents et prise en charge des patients. [Von Hippel-Lindau disease: recent genetic progress and patient management.] Francophone Study Group of von Hippel-Lindau Disease (GEFVH), Ann Endocrinol (Paris), 59, 452 Kibel, 1995, Binding of the von Hippel-Lindau tumor suppressor protein to Elongin B and C, Science, 269, 1444, 10.1126/science.7660130 Bluyssen, 2004, Fibronectin is a hypoxia-independent target of the tumor suppressor VHL, FEBS Lett, 556, 137, 10.1016/S0014-5793(03)01392-9 Ruggieri, 1999, The neurofibromatoses. An overview, Ital J Neurol Sci, 20, 89, 10.1007/s100720050017 Au, 2004, Molecular genetic basis of tuberous sclerosis complex: from bench to bedside, J Child Neurol, 19, 699, 10.1177/08830738040190091101 Zikusoka, 2005, The molecular genetics of gastroenteropancreatic neuroendocrine tumors, Cancer, 104, 2292, 10.1002/cncr.21451 Calender, 2000, Molecular genetics of neuroendocrine tumors, Digestion, 62, 3, 10.1159/000051850 Hiripi, 2009, Familial gastrointestinal carcinoid tumours and associated cancers, Ann Oncol, 20, 950, 10.1093/annonc/mdn706 Hemminki, 2001, Familial carcinoid tumors and subsequent cancers: a nation-wide epidemiologic study from Sweden, Int J Cancer, 94, 444, 10.1002/ijc.1473 Hassan, 2008, Family history of cancer and associated risk of developing neuroendocrine tumors: a case-control study, Cancer Epidemiol Biomarkers Prev, 17, 959, 10.1158/1055-9965.EPI-07-0750 Sun, 2012, Activation of the ATM-Snail pathway promotes breast cancer metastasis, J Mol Cell Biol, 4, 304, 10.1093/jmcb/mjs048 Lee, 2012, Metastasis of neuroendocrine tumors are characterized by increased cell proliferation and reduced expression of the ATM gene, PLoS ONE, 7, e34456, 10.1371/journal.pone.0034456 Shin, 2012, Prognostic significance of ATM and cyclin B1 in pancreatic neuroendocrine tumor, Tumour Biol, 33, 1645, 10.1007/s13277-012-0420-5 Li, 2012, Metastasis-associated protein 1/nucleosome remodeling and histone deacetylase complex in cancer, Cancer Res, 72, 387, 10.1158/0008-5472.CAN-11-2345 Azzoni, 2011, Involvement of HER-2/neu and metastasis-related proteins in the development of ileal neuroendocrine tumors, Virchows Arch, 458, 525, 10.1007/s00428-011-1069-y Sundin, 2012, Radiological and nuclear medicine imaging of gastroenteropancreatic neuroendocrine tumours, Best Pract Res Clin Gastroenterol, 26, 803, 10.1016/j.bpg.2012.12.004 Reubi, 1987, Somatostatin receptors in human endocrine tumors, Cancer Res, 47, 551 Nilsson, 1998, Comparative studies on the expression of somatostatin receptor subtypes, outcome of octreotide scintigraphy and response to octreotide treatment in patients with carcinoid tumours, Br J Cancer, 77, 632, 10.1038/bjc.1998.101 Bodei, 2014, The status of neuroendocrine tumor imaging: from darkness to light?, Neuroendocrinology, 10.1159/000367850 Pearse, 1966, 5-hydroxytryptophan uptake by dog thyroid ‘C’ cells, and its possible significance in polypeptide hormone production, Nature, 211, 598, 10.1038/211598a0 Neels, 2008, Manipulation of [11C]-5-hydroxytryptophan and 6-[18F]fluoro-3,4-dihydroxy-l-phenylalanine accumulation in neuroendocrine tumor cells, Cancer Res, 68, 7183, 10.1158/0008-5472.CAN-08-0095 Blackmore, 2001, Measurement of secretory vesicle pH reveals intravesicular alkalinization by vesicular monoamine transporter type 2 resulting in inhibition of prohormone cleavage, J Physiol, 531, 605, 10.1111/j.1469-7793.2001.0605h.x Kolby, 2003, Uptake of meta-iodobenzylguanidine in neuroendocrine tumours is mediated by vesicular monoamine transporters, Br J Cancer, 89, 1383, 10.1038/sj.bjc.6601276 Baum, 2012, Peptides and receptors in image-guided therapy: theranostics for neuroendocrine neoplasms, Semin Nucl Med, 42, 190, 10.1053/j.semnuclmed.2012.01.002 Koopmans, 2006, Staging of carcinoid tumours with 18F-DOPA PET: a prospective, diagnostic accuracy study, Lancet Oncol, 7, 728, 10.1016/S1470-2045(06)70801-4 Orlefors, 2005, Whole-body 11C-5-hydroxytryptophan positron emission tomography as a universal imaging technique for neuroendocrine tumors: comparison with somatostatin receptor scintigraphy and computed tomography, J Clin Endocrinol Metab, 90, 3392, 10.1210/jc.2004-1938 Binderup, 2010, 18F-fluorodeoxyglucose positron emission tomography predicts survival of patients with neuroendocrine tumors, Clin Cancer Res, 16, 978, 10.1158/1078-0432.CCR-09-1759 Grozinsky-Glasberg, 2012, Inhibition of mTOR in carcinoid tumors, Target Oncol, 7, 189, 10.1007/s11523-012-0225-x Cierpicki, 2014, Challenges and opportunities in targeting the menin-MLL interaction, Future Med Chem, 6, 447, 10.4155/fmc.13.214 Shi, 2012, Structural insights into inhibition of the bivalent menin-MLL interaction by small molecules in leukemia, Blood, 120, 4461, 10.1182/blood-2012-05-429274 Mohammad, 2011, TGF-beta-RI kinase inhibitor SD-208 reduces the development and progression of melanoma bone metastases, Cancer Res, 71, 175, 10.1158/0008-5472.CAN-10-2651 Della Gatta, 2012, Reverse engineering of TLX oncogenic transcriptional networks identifies RUNX1 as tumor suppressor in T-ALL, Nat Med, 18, 436, 10.1038/nm.2610 Piccaluga, 2011, Gene expression analysis uncovers similarity and differences among Burkitt lymphoma subtypes, Blood, 117, 3596, 10.1182/blood-2010-08-301556 Modlin, 2009, Principal component analysis, hierarchical clustering, and decision tree assessment of plasma mRNA and hormone levels as an early detection strategy for small intestinal neuroendocrine (carcinoid) tumors, Ann Surg Oncol, 16, 487, 10.1245/s10434-008-0251-1 Modlin, 2013, A multitranscript blood neuroendocrine tumor molecular signature to identify treatment efficacy and disease progress, J Clin Oncol, 31, A4137, 10.1200/jco.2013.31.15_suppl.4137 Modlin, 2014, Blood transcript analysis and metastatic recurrent small bowel carcinoid management, BMC Cancer, 14, 564, 10.1186/1471-2407-14-564 Modlin, 2014, A multianalyte PCR blood test outperforms single analyte ELISAs for neuroendocrine tumor detection, Endocr Relat Cancer, 21, 615, 10.1530/ERC-14-0190 Modlin, 2013, The identification of gut neuroendocrine tumor disease by multiple synchronous transcript analysis in blood, PloS ONE, e63364, 10.1371/journal.pone.0063364 Modlin, 2014, Gut neuroendocrine tumor blood qPCR fingerprint assay: characteristics and reproducibility, Clin Chem, 52, 419 Modlin, 2014, A PCR blood test outperforms chromogranin A in carcinoid detection and is unaffected by PPIs, Endocr Connect, 3, 215, 10.1530/EC-14-0100 Franceschini, 2013, STRING v9.1: protein-protein interaction networks, with increased coverage and integration, Nucleic Acids Res, 41, D808, 10.1093/nar/gks1094