Advertisement

The Molecular Biology of NET: Current Status and Evaluation of Biomarkers for Prediction and Prognosis

  • Mark Kidd
  • Diego Ferone
  • Manuela Albertelli
  • Elena Nazzari
  • Lisa Bodei
  • Irvin M. Modlin
Chapter

Abstract

Neuroendocrine neoplasms (NEN) represent a heterogeneous neoplasia that are ubiquitous in location, exhibit protean symptomatology, and have ill-defined pathobiology. Clinical challenges include but are not limited to the general inability to establish an early diagnosis as well as the lack of a predictably effective management strategy. While clinical guidelines are useful and serve as a template for consensus-based thought, there is a paucity of scientific and mechanistic data necessary to accurately guide optimal management.

The most relevant criteria for prognostic stratification include differentiation and proliferation-based grading, according to the 2010 WHO classification of the digestive system and 2015 WHO for thoracic tumors. Differentiation allows the identification of two distinct prognostic groups: well-differentiated (WD, also named neuroendocrine tumors, NETs) and poorly differentiated (PD, known as neuroendocrine carcinoma, NEC) neoplasms. The outcome (survival – either short-term progression or longer term demise) depends on the cell of origin, the organ of origin, histopathological grading, and the variety of treatment protocols including surgery that have been undertaken. These, for the most part, represent descriptive criteria since little is known of the molecular biology of the neoplasia.

The mechanisms of tumor development remain unidentified as are the potential drivers of the mutational phenotype. While factors that influence proliferation (e.g., TGFβ, EGF, and somatostatin) and angiogenesis (e.g., VEGF) have been identified, the mechanisms underlying metastasis and target organ tropism remain to be demarcated. Delineation of the somatostatin pathway has driven the development of diagnostics using somatostatin receptor-targeted imaging (either [111]Indium-Octreoscan or [68]Gallium-SSA-PET). Therapies have also evolved via targeting somatostatin receptors with drugs or isotopes (peptide receptor radiotherapy). Genomic and molecular biological analyses have, however, been less enlightening. Activating mutations are rarely identified and NEN disease is a tumor suppressor-driven disease. Epigenetic modifications frequently occur particularly in bronchopulmonary and pancreatic NETs. Most promising is the strategy of transcriptional profiling and network-based analyses to define the cellular toolkit and identify how a normal cell may transform, proliferate, and metastasize. Such techniques have also recently been leveraged for the development of multianalyte diagnostic tools which have facilitated more accurate molecular pathologic delineations of neuroendocrine disease.

Current knowledge of the molecular topography of neuroendocrine neoplasia is limited and represents a vast dark room illuminated by random lights – some of which are only reflections. Elucidation of the molecular machinery of NETs is inseparable from any possibility of rational or meaningful progress in the management of this disease.

Keywords

Neuroendocrine neoplasms Molecular genetic analyses Epigenetics Molecular transcriptomics Metastatic dissemination 

Bibliography

  1. 1.
    de Mestier L, Dromain C, d’Assignies G et al (2014) Evaluating digestive neuroendocrine tumor progression and therapeutic responses in the era of targeted therapies: state of the art. Endocr Relat Cancer 21:R105–R120. doi: 10.1530/ERC-1513-0365. Print 2014PubMedCrossRefGoogle Scholar
  2. 2.
    Bergsland EK (2013) The evolving landscape of neuroendocrine tumors. Semin Oncol 40:4–22. doi: 10.1053/j.seminoncol.2012.1011.1013 PubMedCrossRefGoogle Scholar
  3. 3.
    Wang H, Chen Y, Fernandez-Del Castillo C, Yilmaz O, Deshpande V (2012) Heterogeneity in signaling pathways of gastroenteropancreatic neuroendocrine tumors: a critical look at notch signaling pathway. Mod Pathol 24:143Google Scholar
  4. 4.
    Sundin A, Rockall A (2012) Therapeutic monitoring of gastroenteropancreatic neuroendocrine tumors: the challenges ahead. Neuroendocrinology 96:261–271. doi: 10.1159/000342270. Epub 000342012 Oct 000342212PubMedCrossRefGoogle Scholar
  5. 5.
    Kidd M, Schimmack S, Lawrence B, Alaimo D, Modlin IM (2012) EGFR/TGFalpha and TGFbeta/CTGF signaling in neuroendocrine neoplasia: theoretical therapeutic targets. Neuroendocrinology 15:15Google Scholar
  6. 6.
    Chan JA, Kulke MH (2011) New treatment options for patients with advanced neuroendocrine tumors. Curr Treat Options in Oncol 12:136–148CrossRefGoogle Scholar
  7. 7.
    Oberg K (2010) Pancreatic endocrine tumors. Semin Oncol 37:594–618PubMedCrossRefGoogle Scholar
  8. 8.
    Garcia-Carbonero R, Capdevila J, Crespo-Herrero G et al (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 21:1794–1803. doi: 10.1093/annonc/mdq1022. Epub 2010 Feb 1795PubMedCrossRefGoogle Scholar
  9. 9.
    Strosberg J, Gardner N, Kvols L (2009) Survival and prognostic factor analysis of 146 metastatic neuroendocrine tumors of the mid-gut. Neuroendocrinology 89:471–476. Epub 2009 Jan 2028PubMedCrossRefGoogle Scholar
  10. 10.
    Modlin IM, Oberg K, Chung DC et al (2008) Gastroenteropancreatic neuroendocrine tumours. Lancet Oncol 9:61–72PubMedCrossRefGoogle Scholar
  11. 11.
    Frilling A, Modlin I, Kidd M et al (2014) Recommendations for management of patients with neuroendocrine liver metastases. Lancet Oncol 15:e8–21PubMedCrossRefGoogle Scholar
  12. 12.
    Pusceddu S, Femia D, Lo Russo G et al (2016) Update on medical treatment of small intestinal neuroendocrine tumors. Expert Rev Anticancer Ther 16:969–976. doi: 10.1080/14737140.14732016.11207534. Epub 14732016 Jul 14737113PubMedCrossRefGoogle Scholar
  13. 13.
    Yao JC, Lagunes DR, Kulke MH (2013) Targeted therapies in neuroendocrine tumors (NET): clinical trial challenges and lessons learned. Oncologist 18:525–532. doi: 10.1634/theoncologist. 2012-0434. Epub 2013 Apr 1624PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Caplin ME, Pavel M, Cwikla JB et al (2014) Lanreotide in metastatic enteropancreatic neuroendocrine tumors. N Engl J Med 371:224–233. doi: 10.1056/NEJMoa1316158 PubMedCrossRefGoogle Scholar
  15. 15.
    Rinke A, Muller HH, Schade-Brittinger C et al (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 27:4656–4663. Epub 2009 Aug 4624PubMedCrossRefGoogle Scholar
  16. 16.
    Rankin EB, Giaccia AJ (2016) Hypoxic control of metastasis. Science 352:175–180. doi: 10.1126/science.aaf4405. Epub 2016 Apr 1127PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Yang Y (2015) Cancer immunotherapy: harnessing the immune system to battle cancer. J Clin Invest 125:3335–3337. doi: 10.1172/JCI83871. Epub 82015 Sep 83871PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Riihimaki M, Hemminki A, Sundquist K, Sundquist J, Hemminki K (2016) The epidemiology of metastases in neuroendocrine tumors. Int J Cancer 139:2679–2686. doi: 10.1002/ijc.30400. Epub 32016 Sep 30409PubMedCrossRefGoogle Scholar
  19. 19.
    Kidd M, Modlin I, Bodei L, Drozdov I (2015) Decoding the molecular and mutational ambiguities of gastroenteropancreatic neuroendocrine neoplasm pathobiology. Cellular and Molecular Gastroenterology and Hepatology 1:131–153PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Leotlela PD, Jauch A, Holtgreve-Grez H, Thakker RV (2003) Genetics of neuroendocrine and carcinoid tumours. Endocr Relat Cancer 10:437–450PubMedCrossRefGoogle Scholar
  21. 21.
    Elsasser SJ, Allis CD, Lewis PW (2011) Cancer. New epigenetic drivers of cancers. Science 331:1145–1146. doi: 10.1126/science.1203280 PubMedCrossRefGoogle Scholar
  22. 22.
    Franklin DS, Godfrey VL, Lee H et al (1998) CDK inhibitors p18(INK4c) and p27(Kip1) mediate two separate pathways to collaboratively suppress pituitary tumorigenesis. Genes Dev 12:2899–2911PubMedPubMedCentralCrossRefGoogle Scholar
  23. 23.
    Metz DC, Jensen RT (2008) Gastrointestinal neuroendocrine tumors: pancreatic endocrine tumors. Gastroenterology 135:1469–1492PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Modlin IM, Kidd M, Latich I, Zikusoka MN, Shapiro MD (2005) Current status of gastrointestinal carcinoids. Gastroenterology 128:1717–1751PubMedCrossRefGoogle Scholar
  25. 25.
    Tomita H, Takaishi S, Menheniott TR et al (2011) Inhibition of gastric carcinogenesis by the hormone gastrin is mediated by suppression of TFF1 epigenetic silencing. Gastroenterology 140:879–891. doi: 10.1053/j.gastro.2010.1011.1037. Epub 2010 Nov 1025PubMedCrossRefGoogle Scholar
  26. 26.
    Selvik LK, Rao S, Steigedal TS et al (2014) Salt-inducible kinase 1 (SIK1) is induced by gastrin and inhibits migration of gastric adenocarcinoma cells. PLoS One 9:e112485. doi: 10.111371/journal.pone.0112485. eCollection 0112014PubMedPubMedCentralCrossRefGoogle Scholar
  27. 27.
    Porta C, Paglino C, Mosca A (2014) Targeting PI3K/Akt/mTOR signaling in cancer. Front Oncol 4:64PubMedPubMedCentralCrossRefGoogle Scholar
  28. 28.
    Svejda B, Kidd M, Kazberouk A, Lawrence B, Pfragner R, Modlin IM (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 117:4141–4154PubMedCrossRefGoogle Scholar
  29. 29.
    Li HJ, Kapoor A, Giel-Moloney M, Rindi G, Leiter AB (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 371:156–169PubMedPubMedCentralCrossRefGoogle Scholar
  30. 30.
    Rozengurt E, Walsh JH (2001) Gastrin, CCK, signaling, and cancer. Annu Rev Physiol 63:49–76PubMedCrossRefGoogle Scholar
  31. 31.
    Treinies I, Paterson HF, Hooper S, Wilson R, Marshall CJ (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 19:321–329PubMedPubMedCentralCrossRefGoogle Scholar
  32. 32.
    Kinoshita Y, Nakata H, Kishi K, Kawanami C, Sawada M, Chiba T (1998) Comparison of the signal transduction pathways activated by gastrin in enterochromaffin-like and parietal cells. Gastroenterology 115:93–100PubMedCrossRefGoogle Scholar
  33. 33.
    Abraham NS (2012) Proton pump inhibitors: potential adverse effects. Curr Opin Gastroenterol 28:615–620PubMedCrossRefGoogle Scholar
  34. 34.
    Kidd M, Modlin IM, Pfragner R et al (2007) Small bowel carcinoid (enterochromaffin cell) neoplasia exhibits transforming growth factor-beta1-mediated regulatory abnormalities including up-regulation of C-Myc and MTA1. Cancer 109:2420–2431PubMedCrossRefGoogle Scholar
  35. 35.
    Papouchado B, Erickson LA, Rohlinger AL et al (2005) Epidermal growth factor receptor and activated epidermal growth factor receptor expression in gastrointestinal carcinoids and pancreatic endocrine carcinomas. Mod Pathol 18:1329–1335PubMedCrossRefGoogle Scholar
  36. 36.
    Gilbert JA, Adhikari LJ, Lloyd RV et al (2010) Molecular markers for novel therapies in neuroendocrine (carcinoid) tumors. Endocr Relat Cancer 17:623–636PubMedCrossRefGoogle Scholar
  37. 37.
    Susini C, Buscail L (2006) Rationale for the use of somatostatin analogs as antitumor agents. Ann Oncol 17:1733–1742PubMedCrossRefGoogle Scholar
  38. 38.
    Wolin EM (2012) The expanding role of somatostatin analogs in the management of neuroendocrine tumors. Gastrointestinal Cancer Res 5:161–168Google Scholar
  39. 39.
    Oberg K, Kvols L, Caplin M et al (2004) Consensus report on the use of somatostatin analogs for the management of neuroendocrine tumors of the gastroenteropancreatic system. Ann Oncol 15:966–973PubMedCrossRefGoogle Scholar
  40. 40.
    Zhang J, Jia Z, Li Q et al (2007) Elevated expression of vascular endothelial growth factor correlates with increased angiogenesis and decreased progression-free survival among patients with low-grade neuroendocrine tumors. Cancer 109:1478–1486PubMedCrossRefGoogle Scholar
  41. 41.
    Besig S, Voland P, Baur DM, Perren A, Prinz C (2009) Vascular endothelial growth factors, angiogenesis, and survival in human ileal enterochromaffin cell carcinoids. Neuroendocrinology 90:402–415. doi: 10.1159/000245900. Epub 000242009 Oct 000245908PubMedCrossRefGoogle Scholar
  42. 42.
    Olsson AK, Dimberg A, Kreuger J, Claesson-Welsh L (2006) VEGF receptor signalling - in control of vascular function. Nat Rev Mol Cell Biol 7:359–371PubMedCrossRefGoogle Scholar
  43. 43.
    Bowen KA, Silva SR, Johnson JN et al (2009) An analysis of trends and growth factor receptor expression of GI carcinoid tumors. J Gastrointest Surg 13:1773–1780PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Kidd M, Modlin IM, Shapiro MD et al (2007) CTGF, intestinal stellate cells and carcinoid fibrogenesis. World J Gastroenterol 13:5208–5216PubMedPubMedCentralCrossRefGoogle Scholar
  45. 45.
    Yao JC, Phan A, Hoff PM et al (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 26:1316–1323PubMedCrossRefGoogle Scholar
  46. 46.
    Phan AT, Halperin DM, Chan JA et al (2015) Pazopanib and depot octreotide in advanced, well-differentiated neuroendocrine tumours: a multicentre, single-group, phase 2 study. Lancet Oncol 16:695–703PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Raymond E, Dahan L, Raoul JL et al (2011) Sunitinib malate for the treatment of pancreatic neuroendocrine tumors. N Engl J Med 364:501–513PubMedCrossRefGoogle Scholar
  48. 48.
    Walenkamp A, Crespo G, Fierro Maya F et al (2014) Hallmarks of gastrointestinal neuroendocrine tumours: implications for treatment. Endocr Relat Cancer 21:R445–R460. doi: 10.1530/ERC-1514-0106 PubMedCrossRefGoogle Scholar
  49. 49.
    Jiang WG, Sanders AJ, Katoh M et al (2015) Tissue invasion and metastasis: Molecular, biological and clinical perspectives. Semin Cancer Biol 35:S244–S275. doi: 10.1016/j.semcancer.2015.1003.1008. Epub 2015 Apr 1010PubMedCrossRefGoogle Scholar
  50. 50.
    Boo YJ, Park SS, Kim JH, Mok YJ, Kim SJ, Kim CS (2007) Gastric neuroendocrine carcinoma: clinicopathologic review and immunohistochemical study of E-cadherin and Ki-67 as prognostic markers. J Surg Oncol 95:110–117PubMedCrossRefGoogle Scholar
  51. 51.
    Fujimori M, Ikeda S, Shimizu Y, Okajima M, Asahara T (2001) Accumulation of beta-catenin protein and mutations in exon 3 of beta-catenin gene in gastrointestinal carcinoid tumor. Cancer Res 61:6656–6659PubMedGoogle Scholar
  52. 52.
    Galvan JA, Astudillo A, Vallina A et al (2013) Epithelial-mesenchymal transition markers in the differential diagnosis of gastroenteropancreatic neuroendocrine tumors. Am J Clin Pathol 140:61–72. doi: 10.1309/AJCPIV1340ISTBXRAX PubMedCrossRefGoogle Scholar
  53. 53.
    Jeffery N, McLean MH, El-Omar EM, Murray GI (2009) The matrix metalloproteinase/tissue inhibitor of matrix metalloproteinase profile in colorectal polyp cancers. Histopathology 54:820–828. doi: 10.1111/j.1365-2559.2009.03301.x PubMedCrossRefGoogle Scholar
  54. 54.
    Zhang Q, Yang M, Shen J, Gerhold LM, Hoffman RM, Xing HR (2010) The role of the intravascular microenvironment in spontaneous metastasis development. Int J Cancer 126:2534–2541. doi: 10.1002/ijc.24979 PubMedCrossRefGoogle Scholar
  55. 55.
    Gurevich LE (2003) Role of matrix metalloproteinases 2 and 9 in determination of invasive potential of pancreatic tumors. Bull Exp Biol Med 136:494–498PubMedCrossRefGoogle Scholar
  56. 56.
    Capurso G, Lattimore S, Crnogorac-Jurcevic T et al (2006) Gene expression profiles of progressive pancreatic endocrine tumours and their liver metastases reveal potential novel markers and therapeutic targets. Endocr Relat Cancer 13:541–558PubMedCrossRefGoogle Scholar
  57. 57.
    Di Florio A, Adesso L, Pedrotti S et al (2011) Src kinase activity coordinates cell adhesion and spreading with activation of mammalian target of rapamycin in pancreatic endocrine tumour cells. Endocr Relat Cancer 18:541–554. doi: 10.1530/ERC-1510-0153. Print 2011 OctPubMedCrossRefGoogle Scholar
  58. 58.
    Gaur P, Sceusi EL, Samuel S et al (2011) Identification of cancer stem cells in human gastrointestinal carcinoid and neuroendocrine tumors. Gastroenterology 141:1728–1737. doi: 10.1053/j.gastro.2011.1707.1037. Epub 2011 Jul 1730PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Scoazec JY (2013) Angiogenesis in neuroendocrine tumors: therapeutic applications. Neuroendocrinology 97:45–56. doi: 10.1159/000338371. Epub 000332012 Jun 000338377PubMedCrossRefGoogle Scholar
  60. 60.
    Sei Y, Zhao X, Forbes J et al (2015) A hereditary form of small intestinal carcinoid associated with a germline mutation in inositol polyphosphate multikinase. Gastroenterology 149:67–78. doi: 10.1053/j.gastro.2015.1004.1008. Epub 2015 Apr 1059PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Fernandez-Cuesta L, Peifer M, Lu X et al (2014) Frequent mutations in chromatin-remodelling genes in pulmonary carcinoids. Nat Commun 5:3518. doi: 10.1038/ncomms4518 PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Simbolo M, Mafficini A, Sikora KO et al (2016) Lung neuroendocrine tumours: deep sequencing of the four World Health Organization histotypes reveals chromatin-remodelling genes as major players and a prognostic role for TERT, RB1, MEN1 and KMT2D. J Pathol 22Google Scholar
  63. 63.
    Zhang J, Francois R, Iyer R, Seshadri M, Zajac-Kaye M, Hochwald SN (2013) Current understanding of the molecular biology of pancreatic neuroendocrine tumors. J Natl Cancer Inst 105:1005–1017. doi: 10.1093/jnci/djt1135. Epub 2013 Jul 1009PubMedCrossRefGoogle Scholar
  64. 64.
    Agarwal SK, Jothi R (2012) Genome-wide characterization of menin-dependent H3K4me3 reveals a specific role for menin in the regulation of genes implicated in MEN1-like tumors. PLoS One 7:e37952. doi: 10.31371/journal.pone.0037952. Epub 0032012 May 0037930PubMedPubMedCentralCrossRefGoogle Scholar
  65. 65.
    Marinoni I, Kurrer AS, Vassella E et al (2014) Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors. Gastroenterology 146:453–460.e455. doi: 10.1053/j.gastro.2013.1010.1020. Epub 2013 Oct 1019PubMedCrossRefGoogle Scholar
  66. 66.
    Scarpa A, Chang DK, Nones K et al (2017) Whole-genome landscape of pancreatic neuroendocrine tumours. Nature 543:65–71. doi: 10.1038/nature21063. Epub 22017 Feb 21015 PubMedCrossRefGoogle Scholar
  67. 67.
    Cao Y, Gao Z, Li L et al (2013) Whole exome sequencing of insulinoma reveals recurrent T372R mutations in YY1. Nat Commun 4:2810. doi: 10.1038/ncomms3810 PubMedGoogle Scholar
  68. 68.
    He Y, Sandoval J, Casaccia-Bonnefil P (2007) Events at the transition between cell cycle exit and oligodendrocyte progenitor differentiation: the role of HDAC and YY1. Neuron Glia Biol 3:221–231. doi: 10.1017/S1740925X08000057 PubMedPubMedCentralCrossRefGoogle Scholar
  69. 69.
    Zhuang Z, Vortmeyer AO, Pack S et al (1997) Somatic mutations of the MEN1 tumor suppressor gene in sporadic gastrinomas and insulinomas. Cancer Res 57:4682–4686PubMedGoogle Scholar
  70. 70.
    Zhou C, Dhall D, Nissen NN, Chen CR, Yu R (2009) Homozygous P86S mutation of the human glucagon receptor is associated with hyperglucagonemia, alpha cell hyperplasia, and islet cell tumor. Pancreas 38:941–946PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Jiao Y, Shi C, Edil BH et al (2011) DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors. Science 331:1199–1203PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Cromer MK, Choi M, Nelson-Williams C et al (2015) Neomorphic effects of recurrent somatic mutations in Yin Yang 1 in insulin-producing adenomas. Proc Natl Acad Sci U S A 112:4062–4067. doi: 10.1073/pnas.1503696112. Epub 1503692015 Mar 1503696118PubMedPubMedCentralCrossRefGoogle Scholar
  73. 73.
    Francis JM, Kiezun A, Ramos AH et al (2013) Somatic mutation of CDKN1B in small intestine neuroendocrine tumors. Nat Genet 45:1483–1486. doi: 10.1038/ng.2821. Epub 2013 Nov 1483PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Lee M, Pellegata NS (2013) Multiple endocrine neoplasia syndromes associated with mutation of p27. J Endocrinol Investig 36:781–787. doi: 10.3275/9021. Epub 2013 Jun 3226Google Scholar
  75. 75.
    Karnik SK, Hughes CM, Gu X et al (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 102:14659–14664. Epub 12005 Sep 14629PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Banck MS, Kanwar R, Kulkarni AA et al (2013) The genomic landscape of small intestine neuroendocrine tumors. J Clin Invest 15Google Scholar
  77. 77.
    Ghimenti C, Lonobile A, Campani D, Bevilacqua G, Caligo MA (1999) Microsatellite instability and allelic losses in neuroendocrine tumors of the gastro-entero-pancreatic system. Int J Oncol 15:361–366PubMedGoogle Scholar
  78. 78.
    Arnold CN, Sosnowski A, Blum HE (2004) Analysis of molecular pathways in neuroendocrine cancers of the gastroenteropancreatic system. Ann N Y Acad Sci 1014:218–219PubMedCrossRefGoogle Scholar
  79. 79.
    Banck MS, Kanwar R, Kulkarni AA et al (2013) The genomic landscape of small intestine neuroendocrine tumors. J Clin Investig 123:2502–2508PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Kidd M, Eick G, Shapiro MD, Camp RL, Mane SM, Modlin IM (2005) Microsatellite instability and gene mutations in transforming growth factor-beta type II receptor are absent in small bowel carcinoid tumors. Cancer 103:229–236PubMedCrossRefGoogle Scholar
  81. 81.
    House MG, Herman JG, Guo MZ et al (2003) Prognostic value of hMLH1 methylation and microsatellite instability in pancreatic endocrine neoplasms. Surgery 134:902–908. discussion 909PubMedCrossRefGoogle Scholar
  82. 82.
    el-Naggar AK, Ballance W, Karim FW et al (1991) Typical and atypical bronchopulmonary carcinoids. A clinicopathologic and flow cytometric study. Am J Clin Pathol 95:828–834PubMedCrossRefGoogle Scholar
  83. 83.
    Debelenko LV, Swalwell JI, Kelley MJ et al (2000) MEN1 gene mutation analysis of high-grade neuroendocrine lung carcinoma. Genes Chromosom Cancer 28:58–65PubMedCrossRefGoogle Scholar
  84. 84.
    Swarts DR, Ramaekers FC, Speel EJ (2012) Molecular and cellular biology of neuroendocrine lung tumors: evidence for separate biological entities. Biochim Biophys Acta 1826:255–271. doi: 10.1016/j.bbcan.2012.1005.1001. Epub 2012 May 1010PubMedGoogle Scholar
  85. 85.
    Padberg BC, Woenckhaus J, Hilger G et al (1996) DNA cytophotometry and prognosis in typical and atypical bronchopulmonary carcinoids. A clinicomorphologic study of 100 neuroendocrine lung tumors. Am J Surg Pathol 20:815–822PubMedCrossRefGoogle Scholar
  86. 86.
    Speel EJ, Richter J, Moch H et al (1999) Genetic differences in endocrine pancreatic tumor subtypes detected by comparative genomic hybridization. Am J Pathol 155:1787–1794PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Speel EJ, Scheidweiler AF, Zhao J et al (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 61:5186–5192PubMedGoogle Scholar
  88. 88.
    Simon B, Lubomierski N (2004) Implication of the INK4a/ARF locus in gastroenteropancreatic neuroendocrine tumorigenesis. Ann N Y Acad Sci 1014:284–299PubMedCrossRefGoogle Scholar
  89. 89.
    Zikusoka MN, Kidd M, Eick G, Latich I, Modlin IM (2005) The molecular genetics of gastroenteropancreatic neuroendocrine tumors. Cancer 104:2292–2309PubMedCrossRefGoogle Scholar
  90. 90.
    Perren A, Komminoth P, Saremaslani P et al (2000) Mutation and expression analyses reveal differential subcellular compartmentalization of PTEN in endocrine pancreatic tumors compared to normal islet cells. Am J Pathol 157:1097–1103PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Missiaglia E, Dalai I, Barbi S et al (2010) Pancreatic endocrine tumors: expression profiling evidences a role for AKT-mTOR pathway. J Clin Oncol 28:245–255PubMedCrossRefGoogle Scholar
  92. 92.
    Jonkers YM, Claessen SM, Perren A et al (2005) Chromosomal instability predicts metastatic disease in patients with insulinomas. Endocr Relat Cancer 12:435–447PubMedCrossRefGoogle Scholar
  93. 93.
    Kytola S, Hoog A, Nord B et al (2001) Comparative genomic hybridization identifies loss of 18q22-qter as an early and specific event in tumorigenesis of midgut carcinoids. Am J Pathol 158:1803–1808PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Lollgen RM, Hessman O, Szabo E, Westin G, Akerstrom G (2001) Chromosome 18 deletions are common events in classical midgut carcinoid tumors. Int J Cancer 92:812–815PubMedCrossRefGoogle Scholar
  95. 95.
    Kytola S, Nord B, Elder EE et al (2002) Alterations of the SDHD gene locus in midgut carcinoids, Merkel cell carcinomas, pheochromocytomas, and abdominal paragangliomas. Genes Chromosom Cancer 34:325–332PubMedCrossRefGoogle Scholar
  96. 96.
    Andersson E, Sward C, Stenman G, Ahlman H, Nilsson O (2009) High-resolution genomic profiling reveals gain of chromosome 14 as a predictor of poor outcome in ileal carcinoids. Endocr Relat Cancer 16:953–966PubMedCrossRefGoogle Scholar
  97. 97.
    Chan AO, Kim SG, Bedeir A, Issa JP, Hamilton SR, Rashid A (2003) CpG island methylation in carcinoid and pancreatic endocrine tumors. Oncogene 22:924–934PubMedCrossRefGoogle Scholar
  98. 98.
    Kulke MH, Hornick JL, Frauenhoffer C et al (2009) O6-methylguanine DNA methyltransferase deficiency and response to temozolomide-based therapy in patients with neuroendocrine tumors. Clin Cancer Res 15:338–345PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Walter T, van Brakel B, Vercherat C et al (2015) O6-Methylguanine-DNA methyltransferase status in neuroendocrine tumours: prognostic relevance and association with response to alkylating agents. Br J Cancer 112:523–531PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Schmitt AM, Schmid S, Rudolph T et al (2009) VHL inactivation is an important pathway for the development of malignant sporadic pancreatic endocrine tumors. Endocr Relat Cancer 16:1219–1227PubMedCrossRefGoogle Scholar
  101. 101.
    Dejeux E, Olaso R, Dousset B et al (2009) Hypermethylation of the IGF2 differentially methylated region 2 is a specific event in insulinomas leading to loss-of-imprinting and overexpression. Endocr Relat Cancer 16:939–952PubMedCrossRefGoogle Scholar
  102. 102.
    Fotouhi O, Adel Fahmideh M, Kjellman M et al (2014) Global hypomethylation and promoter methylation in small intestinal neuroendocrine tumors: an in vivo and in vitro study. Epigenetics 9:987–997PubMedPubMedCentralCrossRefGoogle Scholar
  103. 103.
    Arnold CN, Sosnowski A, Schmitt-Graff A, Arnold R, Blum HE (2007) Analysis of molecular pathways in sporadic neuroendocrine tumors of the gastro-entero-pancreatic system. Int J Cancer 120:2157–2164PubMedCrossRefGoogle Scholar
  104. 104.
    Kidd M, Modlin I, Oberg K (2016) Towards a new classification of gastroenteropancreatic neuroendocrine neoplasms. Nat Rev Clin Oncol 13:691–705. doi: 10.1038/nrclinonc.2016.1085. Epub 2016 Jun 1037PubMedCrossRefGoogle Scholar
  105. 105.
    Bhattacharjee A, Richards WG, Staunton J et al (2001) Classification of human lung carcinomas by mRNA expression profiling reveals distinct adenocarcinoma subclasses. Proc Natl Acad Sci U S A 98:13790–13795. Epub 12001 Nov 13713PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Guo Y, Eichler GS, Feng Y, Ingber DE, Huang S (2006) Towards a holistic, yet gene-centered analysis of gene expression profiles: a case study of human lung cancers. J Biomed Biotechnol 2006:69141PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Swarts DR, Van Neste L, Henfling ME et al (2013) An exploration of pathways involved in lung carcinoid progression using gene expression profiling. Carcinogenesis 34:2726–2737. doi: 10.1093/carcin/bgt2271. Epub 2013 Aug 2728PubMedCrossRefGoogle Scholar
  108. 108.
    Toffalorio F, Belloni E, Barberis M et al (2014) Gene expression profiling reveals GC and CEACAM1 as new tools in the diagnosis of lung carcinoids. Br J Cancer 110:1244–1249. doi: 10.1038/bjc.2014.1241. Epub 2014 Feb 1211PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Lee HW, Lee EH, Ha SY et al (2012) Altered expression of microRNA miR-21, miR-155, and let-7a and their roles in pulmonary neuroendocrine tumors. Pathol Int 62:583–591. doi: 10.1111/j.1440-1827.2012.02845.x PubMedCrossRefGoogle Scholar
  110. 110.
    Mairinger FD, Ting S, Werner R et al (2014) Different micro-RNA expression profiles distinguish subtypes of neuroendocrine tumors of the lung: results of a profiling study. Mod Pathol 27:1632–1640. doi: 10.1038/modpathol.2014.1674. Epub 2014 May 1630PubMedCrossRefGoogle Scholar
  111. 111.
    Rapa I, Votta A, Felice B et al (2015) Identification of MicroRNAs differentially expressed in lung carcinoid subtypes and progression. Neuroendocrinology 101:246–255. doi: 10.1159/000381454. Epub 000382015 Mar 000381416PubMedCrossRefGoogle Scholar
  112. 112.
    Kidd M, Modlin IM, Mane SM et al (2006) Utility of molecular genetic signatures in the delineation of gastric neoplasia. Cancer 106:1480–1488PubMedCrossRefGoogle Scholar
  113. 113.
    Duerr EM, Mizukami Y, Ng A et al (2008) Defining molecular classifications and targets in gastroenteropancreatic neuroendocrine tumors through DNA microarray analysis. Endocr Relat Cancer 15:243–256PubMedCrossRefGoogle Scholar
  114. 114.
    Dilley WG, Kalyanaraman S, Verma S, Cobb JP, Laramie JM, Lairmore TC (2005) Global gene expression in neuroendocrine tumors from patients with the MEN1 syndrome. Mol Cancer 4:9PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Sadanandam A, Wullschleger S, Lyssiotis CA et al (2015) A cross-species analysis in pancreatic neuroendocrine tumors reveals molecular subtypes with distinctive clinical, metastatic, developmental, and metabolic characteristics. Cancer Discov 5:1296–1313PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Roldo C, Missiaglia E, Hagan JP et al (2006) MicroRNA expression abnormalities in pancreatic endocrine and acinar tumors are associated with distinctive pathologic features and clinical behavior. J Clin Oncol 24:4677–4684. Epub 2006 Sep 4611PubMedCrossRefGoogle Scholar
  117. 117.
    Thorns C, Schurmann C, Gebauer N et al (2014) Global MicroRNA profiling of pancreatic neuroendocrine neoplasias. Anticancer Res 34:2249–2254PubMedGoogle Scholar
  118. 118.
    Li A, Yu J, Kim H et al (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 19:3600–3610. doi: 10.1158/1078-0432.CCR-3612-3092. Epub 2013 May 3622PubMedPubMedCentralCrossRefGoogle Scholar
  119. 119.
    Kidd M, Modlin IM, Drozdov I (2014) Gene network-based analysis identifies two potential subtypes of small intestinal neuroendocrine tumors. BMC Genomics 15:595PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Kidd M, Modlin IM, Mane SM, Camp RL, Eick G, Latich I (2006) The role of genetic markers--NAP1L1, MAGE-D2, and MTA1--in defining small-intestinal carcinoid neoplasia. Ann Surg Oncol 13:253–262PubMedCrossRefGoogle Scholar
  121. 121.
    Leja J, Essaghir A, Essand M et al (2009) Novel markers for enterochromaffin cells and gastrointestinal neuroendocrine carcinomas. Mod Pathol 22:261–272PubMedCrossRefGoogle Scholar
  122. 122.
    Cui T, Hurtig M, Elgue G et al (2010) Paraneoplastic antigen Ma2 autoantibodies as specific blood biomarkers for detection of early recurrence of small intestine neuroendocrine tumors. PLoS One 5:e16010PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Li SC, Essaghir A, Martijn C et al (2013) Global microRNA profiling of well-differentiated small intestinal neuroendocrine tumors. Mod Pathol 26:685–696. doi: 10.1038/modpathol.2012.1216. Epub 2013 Jan 1018PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    Ruebel K, Leontovich AA, Stilling GA et al (2010) MicroRNA expression in ileal carcinoid tumors: downregulation of microRNA-133a with tumor progression. Mod Pathol 23:367–375PubMedCrossRefGoogle Scholar
  125. 125.
    Li SC, Khan M, Caplin M, Meyer T, Oberg K, Giandomenico V (2015) Somatostatin analogs treated small intestinal neuroendocrine tumor patients circulating MicroRNAs. PLoS One 10:e0125553. doi: 10.0121371/journal.pone.0125553. eCollection 0122015PubMedPubMedCentralCrossRefGoogle Scholar
  126. 126.
    Kerr SE, Schnabel CA, Sullivan PS et al (2014) A 92-gene cancer classifier predicts the site of origin for neuroendocrine tumors. Mod Pathol 27:44–54. doi: 10.1038/modpathol.2013.1105. Epub 2013 Jul 1012PubMedCrossRefGoogle Scholar
  127. 127.
    Gilad S, Lithwick-Yanai G, Barshack I et al (2012) Classification of the four main types of lung cancer using a microRNA-based diagnostic assay. J Mol Diagn 14:510–517. doi: 10.1016/j.jmoldx.2012.1003.1004. Epub 2012 Jun 1027PubMedCrossRefGoogle Scholar
  128. 128.
    Modlin I, Drozdov I, Alaimo D et al (2014) A multianalyte PCR blood test outperforms single analyte ELISAs for neuroendocrine tumor detection. Endocr Relat Cancer 21:615–628PubMedCrossRefGoogle Scholar
  129. 129.
    Modlin IM, Kidd M, Bodei L, Drozdov I, Aslanian H (2015) The clinical utility of a novel blood-based multi-transcriptome assay for the diagnosis of neuroendocrine tumors of the gastrointestinal tract. Am J Gastroenterol 110:1223–1232. doi: 10.1038/ajg.2015.1160. Epub 2015 Jun 1222PubMedCrossRefGoogle Scholar
  130. 130.
    Kidd M, Drozdov I, Modlin I (2015) Blood and tissue neuroendocrine tumor gene cluster analysis correlate, define hallmarks and predict disease status. Endocr Relat Cancer 22:561–575. doi: 10.1530/ERC-1515-0092. Epub 2015 Jun 1532PubMedCrossRefGoogle Scholar
  131. 131.
    Modlin IM, Frilling A, Salem RR et al (2016) Blood measurement of neuroendocrine gene transcripts defines the effectiveness of operative resection and ablation strategies. Surgery 159:336–347. doi: 10.1016/j.surg.2015.1006.1056. Epub 2015 Oct 1019PubMedCrossRefGoogle Scholar
  132. 132.
    Cwikla JB, Bodei L, Kolasinska-Cwikla A, Sankowski A, Modlin IM, Kidd M (2015) Circulating transcript analysis (NETest) in GEP-NETs treated with Somatostatin Analogs defines Therapy. J Clin Endocrinol Metab 100:E1437–E1445PubMedCrossRefGoogle Scholar
  133. 133.
    Bodei L, Kidd M, Modlin IM et al (2016) Measurement of circulating transcripts and gene cluster analysis predicts and defines therapeutic efficacy of peptide receptor radionuclide therapy (PRRT) in neuroendocrine tumors. Eur J Nucl Med Mol Imaging 43:839–851. doi: 10.1007/s00259-00015-03250-z. Epub 02015 Nov 00223PubMedCrossRefGoogle Scholar
  134. 134.
    Kidd M, Modlin IM (2017) Therapy: The role of liquid biopsies to manage and predict PRRT for NETs. Nat Rev Gastroenterol Hepatol 15:26Google Scholar
  135. 135.
    Schimmack S, Svejda B, Lawrence B, Kidd M, Modlin IM (2011) The diversity and commonalities of gastroenteropancreatic neuroendocrine tumors. Langenbeck’s Arch Surg 396:273–298CrossRefGoogle Scholar
  136. 136.
    Spans L, Clinckemalie L, Helsen C et al (2013) The genomic landscape of prostate cancer. Int J Mol Sci 14:10822–10851. doi: 10.13390/ijms140610822 PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  • Mark Kidd
    • 1
  • Diego Ferone
    • 2
    • 3
  • Manuela Albertelli
    • 4
  • Elena Nazzari
    • 4
  • Lisa Bodei
    • 5
  • Irvin M. Modlin
    • 6
  1. 1.Wren LaboratoriesBranfordUSA
  2. 2.Endocrinology Unit, Department of Internal Medicine and Medical Specialties (DiMI)University of GenovaGenoaItaly
  3. 3.Center of Excellence for Biomedical Research (CEBR); IRCCS AOU San Martino-IST, University of GenovaGenoaItaly
  4. 4.Endocrinology UnitDepartment of Internal Medicine and Medical Specialties (DiMI), University of GenovaGenoaItaly
  5. 5.Memorial Sloan Kettering Cancer CenterNew YorkUSA
  6. 6.Yale University School of MedicineNew HavenUSA

Personalised recommendations