Molecular Pathology of Pancreatic Endocrine Tumors

  • Gabriele Capurso
  • Stefano Festa
  • Matteo Piciucchi
  • Roberto Valente
  • Gianfranco Delle Fave
Reference work entry


The molecular biology of Pancreatic Endocrine Tumors (PETs) carcinogenesis is poorly understood and is generally different from that of exocrine pancreatic neoplasms. PETs represent a rare group of neoplasms with heterogenous clinico-pathological features. They are generally sporadic but can also arise within very rare hereditary syndromes, such as Multiple Endocrine Neoplasia type I (MEN-I), von Hippel-Lindau disease (VHL), Neurofibromatosis type 1 (NF1) and Tuberous Sclerosis Complex (TSC). In these syndromes although a specific genotype/phenotype association with PETs has been described, exact mechanisms leading to tumors development are still debated. Some clinical and biological features of PETs associated with hereditary syndromes are similar in sporadic cases. Allelic imbalances (i.e., gain or loss of DNA sequences) have been explored by means of different techniques in different subtypes of sporadic PETs. Overall, main genomic changes involve gain of 17q, 7q, 20q, 9p, 7p, 9q and loss of 11q, 6q, 11p, 3p, 1p, 10q, 1q, that identify the region of putative candidate Oncogenes or Tumor Suppressor Genes (TSGs) respectively. For some of them a possible relevant prognostic role has been described. “Classical” oncogenes involved in exocrine neoplasms (k-Ras, c-Jun, c-Fos) are of limited relevance in PETs; on the contrary overexpression of Src-like kinases and cyclin DI oncogene (CCNDI) have been described. As for TSGs, p53, DPC4/Smad and Rb are not implicated in PETs tumorigenesis, while for p16INK4a, TIMP-3, RASSF1A and hMLH1 more data are available, with data suggesting a role for methylation as silencing mechanism. Different molecular pathways, and the role of tyrosine kinase receptors have also been investigated in PETs (EGF, c-KIT) with interesting findings especially for VEGF and m-TOR, which encourage clinical development. Microarray analysis of expression profiles has recently been employed to investigate PETs, with a number of different strategies, even if these studies suffer from a number of limitations, mainly related with the poor repeatability and the poor concordance between different studies. However, apart from methodological limits, molecular biology studies are needed to better know this group of neoplasms, aiming at identifying novel markers and targets for therapy also highlighting relations with clinical outcome.


Tuberous Sclerosis Complex Allelic Loss Pancreatic Endocrine Tumor Gastric Carcinoid Putative Tumor Suppressor Gene 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


  1. 1.
    Metz DC, Jensen RT: Gastrointestinal neuroendocrine tumours: pancreatic endocrine tumours. Gastroenterology 2008;135(5):1469–1492.PubMedCrossRefGoogle Scholar
  2. 2.
    Duerr EM, Chung DC: Molecular genetics of neuroendocrine tumours. Best Pract Res Clin Endocrinol Metab 2007;21(1):1–14.PubMedCrossRefGoogle Scholar
  3. 3.
    Anlauf M, Garbrecht N, Bauersfeld J, Schmitt A, Henopp T, Komminoth P, Heitz PU, Perren A, Klöppel G: Hereditary neuroendocrine tumours of the gastroenteropancreatic system. Virchows Arch 2007;451(Suppl 1):S29–S38.PubMedCrossRefGoogle Scholar
  4. 4.
    Lemos MC, Thakker RV: Multiple Endocrine Neoplasia Type 1 (MEN1): Analysis of 1336 Mutations Reported in the First Decade Following Identification of the Gene. Hum Mut 2008;29(1):22–32.PubMedCrossRefGoogle Scholar
  5. 5.
    Milne TA, Hughes CM, Lloyd R, Yang Z, Rozenblatt-Rosen O, Dou Y, et al.: Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. Proc Natl Acad Sci USA 2005;102(3):749–754.PubMedCrossRefGoogle Scholar
  6. 6.
    Karnik SK, Hughes CM, Gu X, Rozenblatt-Rosen O, McLean GW, Xiong Y, Meyerson M, Kim SK: Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c Proc Natl Acad Sci USA 2005;102(41):14659–14664.PubMedCrossRefGoogle Scholar
  7. 7.
    Bai F, Pei XH, Nishikawa T, Smith MD, Xiong Y: p18Ink4c, but not p27Kip1, collaborates with Men1 to suppress neuroendocrine organ tumours. Mol Cell Biol 2007;27(4):1495–1504.PubMedCrossRefGoogle Scholar
  8. 8.
    Hughes CM, Rozenblatt-Rosen O, Milne TA, Copeland TD, Levine SS, Lee JC, et al.: Menin associates with a trithorax family histone methyltransferase complex and with the hoxc8 locus. Mol Cell 2004;13(4):587–597.PubMedCrossRefGoogle Scholar
  9. 9.
    Bazzi W, Renon M, Vercherat C, Hamze Z, Lacheretz-Bernigaud A, Wang H, Blanc M, Roche C, Calender A, Chayvialle JA, Scoazec JY, Cordier-Bussat M: MEN1 Missense Mutations Impair Sensitization to Apoptosis Induced by Wild-Type Menin in Endocrine Pancreatic Tumour Cells. Gastroenterology 2008;135(5):1698–1709.PubMedCrossRefGoogle Scholar
  10. 10.
    Anlauf M, Perren A, Henopp T, Rudolph T, Garbrecht N, Schmitt A, Raffel A, Gimm O, Weihe E, Knoefel WT, Dralle H, Heitz PU, Komminoth P, Klöppel G: Allelic deletion of the MEN1 gene in duodenal gastrin and somatostatin cell neoplasms and their precursor lesions. Gut 2007;56:637–644.PubMedCrossRefGoogle Scholar
  11. 11.
    Machens A, Schaaf L, Karges W, Frank-Raue K, Bartsch DK, Rothmund M, Schneyer U, Goretzki P, Raue F, Dralle H: Age-related penetrance of endocrine tumours in multiple endocrine neoplasia type 1 (MEN1): a multicentre study of 258 gene carriers. Clin Endocrinol (Oxf) 2007;67(4):613–622.Google Scholar
  12. 12.
    Ballian N, Hu M, Liu SH, Brunicardi FC: Proliferation, hyperplasia, neogenesis, and neoplasia in the islets of Langerhans. Pancreas 2007;35(3):199–206.PubMedCrossRefGoogle Scholar
  13. 13.
    Anlauf M, Perren A, Klöppel G: Endocrine precursor lesions and microadenomas of the duodenum and pancreas with and without MEN1: criteria, molecular concepts and clinical significance. Clin Endocrinol 2007;67:613–622.Google Scholar
  14. 14.
    Pereira T, Zheng X, Ruas JL, Tanimoto K, Poellinger L: Identification of residues critical for regulation of protein stability and the transactivation function of the hypoxia-inducible factor-1alpha by the von Hippel-Lindau tumour suppressor gene product. J Biol Chem 2003;278(9):6816–6823.PubMedGoogle Scholar
  15. 15.
    Woodward ER, Maher ER: Von Hippel-Lindau disease and endocrine tumour susceptibility. Endocr Relat Cancer 2006;13:415–425.PubMedCrossRefGoogle Scholar
  16. 16.
    Berna MJ, Annibale B, Marignani M, Luong TV, Corleto V, Pace A, Ito T, Liewehr D, Venzon DJ, Delle Fave G, Bordi C, Jensen RT: 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 2008;93(5):1582–1591.PubMedCrossRefGoogle Scholar
  17. 17.
    Anlauf M, Garbrecht N, Henopp T, Schmitt A, Schlenger R, Raffel A, Krausch M, Gimm O, Eisenberger CF, Knoefel WT, Dralle H, Komminoth P, Heitz PU, Perren A, Klöppel G: Sporadic versus hereditary gastrinomas of the duodenum and pancreas: distinct clinico-pathological and epidemiological feature. World J Gastroenterol 2006;12(34):5440–5446.PubMedGoogle Scholar
  18. 18.
    Corcos O, Couvelard A, Giraud S, Vullierme MP, Dermot O’Toole, Rebours V, Stievenart JL, Penfornis A, Niccoli-Sire P, Baudin E, Sauvanet A, Levy P, Ruszniewski P, Richard S, Hammel P: Endocrine pancreatic tumours in von Hippel-Lindau disease: clinical, histological, and genetic features. Pancreas 2008;37(1):85–93.PubMedCrossRefGoogle Scholar
  19. 19.
    Lott ST, Chandler DS, Curley SA, Foster CJ, El-Naggar A, Frazier M, Strong LC, Lovel M, Killary AM: High frequency loss of Heterozygosity in von Hippel-Lindau (VHL)-associated and sporadic pancreatic islet cell tumours: evidence for a stepwise mechanism for malignant conversion in VHL tumourigenesis. Cancer Res 2002;62:1952–1955.PubMedGoogle Scholar
  20. 20.
    Mukhopadhyay B, Sahdev A, Monson JP, Besser GM, Reznek RH, Chew SL: Pancreatic lesions in von Hippel–Lindau disease. Clin Endocrinol 2002;57:603–608.CrossRefGoogle Scholar
  21. 21.
    Chetty R, Kennedy M, Ezzat S, Asa SL: Pancreatic endocrine pathology in von Hippel-Lindau disease: an expanding spectrum of lesions. Endocr Pathol 2004;15:141–148.PubMedCrossRefGoogle Scholar
  22. 22.
    Perren A, Wiesli P, Schmid S, Montani M, Schmitt A, Schmid C, Moch H, Komminoth P: Pancreatic endocrine tumours are a rare manifestation of the neurofibromatosis type 1 phenotype: molecular analysis of a malignant insulinoma in a NF-1 patient. Am J Surg Pathol 2006;30(8):1047–1051.PubMedCrossRefGoogle Scholar
  23. 23.
    McClatchey AI: Neurofibromatosis. Annu Rev Pathol 2007;2:191–216.PubMedCrossRefGoogle Scholar
  24. 24.
    Rosner M, Hanneder M, Siegel N, Valli A, Fuchs C, Hengstschläger M: The mTOR pathway and its role in human genetic diseases. Mutat Res 2008;659(3):284–292.PubMedCrossRefGoogle Scholar
  25. 25.
    Garbrecht N, Anlauf M, Schmitt A, Henopp T, Sipos B, Raffel A, Eisenberger CF, Knoefel WT, Pavel M, Fottner C, Musholt TJ, Rinke A, Arnold R, Berndt U, Plöckinger U, Wiedenmann B, Moch H, Heitz PU, Komminoth P, Perren A, Klöppel G: Somatostatin-producing neuroendocrine tumours of the duodenum and pancreas: incidence, types, biological behavior, association with inherited syndromes, and functional activity. Endocr Relat Cancer 2008;15(1):229–241.PubMedCrossRefGoogle Scholar
  26. 26.
    Nesi G, Marcucci T, Rubio CA, Brandi ML, Tonelli F: Somatostatinoma: clinico-pathological features of three cases and literature reviewed. Gastroenterol Hepatol 2008;23(4):521–526.CrossRefGoogle Scholar
  27. 27.
    Fujisawa T, Osuga T, Maeda M, Sakamoto N, Maeda T, Sakaguchi K, Onishi Y, Toyoda M, Maeda H, Miyamoto K, Kawaraya N, Kusumoto C, Nishigami T: Malignant endocrine tumour of the pancreas associated with von Recklinghausen’s disease. J Gastroenterol 2002;37(1):59–67.PubMedCrossRefGoogle Scholar
  28. 28.
    Curatolo P, Bombardieri R, Jozwiak S: Tuberous sclerosis. Lancet 2008;372(9639):657–668.PubMedCrossRefGoogle Scholar
  29. 29.
    Rosner M, Hanneder M, Siegel N, Valli A, Hengstschläger M: The tuberous sclerosis gene products hamartin and tuberin are multifunctional proteins with a wide spectrum of interacting partners. Mutat Res 2008;658(3):234–246.PubMedCrossRefGoogle Scholar
  30. 30.
    Francalanci P, Diomedi-Camassei F, Purificato C, Santorelli FM, Giannotti A, Dominici C, Inserra A, Boldrini R: Malignant pancreatic endocrine tumour in a child with tuberous sclerosis. Am J Surg Pathol 2003;27(10):1386–1389.PubMedCrossRefGoogle Scholar
  31. 31.
    Terris B, Meddeb M, Marchio A, Danglot G, Fléjou JF, Belghiti J, Ruszniewski P, Bernheim A: Comparative genomic hybridization analysis of sporadic neuroendocrine tumours of the digestive system. Genes Chromosomes Cancer 1998;22(1):50–56.PubMedCrossRefGoogle Scholar
  32. 32.
    Speel EJ, Richter J, Moch H, Egenter C, Saremaslani P, Rütimann K, Zhao J, Barghorn A, Roth J, Heitz PU, Komminoth P: Genetic differences in endocrine pancreatic tumour subtypes detected by comparative genomic hybridization. Am J Pathol 1999;155(6):1787–1794.PubMedGoogle Scholar
  33. 33.
    Stumpf E, Aalto Y, Höög A, Kjellman M, Otonkoski T, Knuutila S, Andersson LC: Chromosomal alterations in human pancreatic endocrine tumours. Genes Chromosomes Cancer 2000;29(1):83–87.PubMedCrossRefGoogle Scholar
  34. 34.
    Yu F, Jensen RT, Lubensky IA, Mahlamaki EH, Zheng YL, Herr AM, Ferrin LJ: Survey of genetic alterations in gastrinomas. Cancer Res 2000;60(19):5536–5542.PubMedGoogle Scholar
  35. 35.
    Speel EJ, Scheidweiler AF, Zhao J, Matter C, Saremaslani P, Roth J, Heitz PU, Komminoth P: Genetic evidence for early divergence of small functioning and nonfunctioning endocrine pancreatic tumours: gain of 9Q34 is an early event in insulinomas. Cancer Res 2001;61(13):5186–5192.PubMedGoogle Scholar
  36. 36.
    Zhao J, Moch H, Scheidweiler AF, Baer A, Schäffer AA, Speel EJ, Roth J, Heitz PU, Komminoth P: Genomic imbalances in the progression of endocrine pancreatic tumours. Genes Chromosomes Cancer 2001;32(4):364–372.PubMedCrossRefGoogle Scholar
  37. 37.
    Tönnies H, Toliat MR, Ramel C, Pape UF, Neitzel H, Berger W, Wiedenmann B: Analysis of sporadic neuroendocrine tumours of the enteropancreatic system by comparative genomic hybridisation. Gut 2001;48(4):536–541.PubMedCrossRefGoogle Scholar
  38. 38.
    Floridia G, Grilli G, Salvatore M, Pescucci C, Moore PS, Scarpa A, Taruscio D: Chromosomal alterations detected by comparative genomic hybridization in nonfunctioning endocrine pancreatic tumours. Cancer Genet Cytogenet 2005;156(1):23–30.PubMedCrossRefGoogle Scholar
  39. 39.
    Jonkers YM, Claessen SM, Perren A, Schmid S, Komminoth P, Verhofstad AA, Hofland LJ, de Krijger RR, Slootweg PJ, Ramaekers FC, Speel EJ: Chromosomal instability predicts metastatic disease in patients with insulinomas. Endocr Relat Cancer 2005;12(2):435–447.PubMedCrossRefGoogle Scholar
  40. 40.
    Chung DC, Brown SB, Graeme-Cook F, Tillotson LG, Warshaw AL, Jensen RT, Arnold A: Localization of putative tumour suppressor loci by genome-wide allelotyping in human pancreatic endocrine tumours. Cancer Res 1998;58(16):3706–3711.PubMedGoogle Scholar
  41. 41.
    Rigaud G, Missiaglia E, Moore PS, Zamboni G, Falconi M, Talamini G, Pesci A, Baron A, Lissandrini D, Rindi G, Grigolato P, Pederzoli P, Scarpa A: High resolution allelotype of nonfunctional pancreatic endocrine tumours: identification of two molecular subgroups with clinical implications. Cancer Res 2001;61(1):285–292.PubMedGoogle Scholar
  42. 42.
    Nagano Y, Kim do H, Zhang L, White JA, Yao JC, Hamilton SR, Rashid A: Allelic alterations in pancreatic endocrine tumours identified by genome-wide single nucleotide polymorphism analysis. Endocr Relat Cancer 2007;14(2):483–492.PubMedCrossRefGoogle Scholar
  43. 43.
    Barghorn A, Speel EJ, Farspour B, Saremaslani P, Schmid S, Perren A, Roth J, Heitz PU, Komminoth P: Putative tumour suppressor loci at 6q22 and 6q23-q24 are involved in the malignant progression of sporadic endocrine pancreatic tumours. Am J Pathol 2001;158(6):1903–1911.PubMedGoogle Scholar
  44. 44.
    Barghorn A, Komminoth P, Bachmann D, Rütimann K, Saremaslani P, Muletta-Feurer S, Perren A, Roth J, Heitz PU, Speel EJ: Deletion at 3p25.3-p23 is frequently encountered in endocrine pancreatic tumours and is associated with metastatic progression. J Pathol 2001;194(4):451–458.PubMedCrossRefGoogle Scholar
  45. 45.
    Ebrahimi SA, Wang EH, Wu A, Schreck RR, Passaro E Jr., Sawicki MP: Deletion of chromosome 1 predicts prognosis in pancreatic endocrine tumours. Cancer Res 1999;59(2):311–315.PubMedGoogle Scholar
  46. 46.
    Vogelstein B, Kinzler KW: Cancer genes and the pathways they control. Nat Med 2004;10(8):789–799.PubMedCrossRefGoogle Scholar
  47. 47.
    Guo SS, Wu AY, Sawicki MP: Deletion of chromosome 1, but not mutation of MEN-1, predicts prognosis in sporadic pancreatic endocrine tumours. World J Surg 2002;26(7):843–847.PubMedCrossRefGoogle Scholar
  48. 48.
    Chen YJ, Vortmeyer A, Zhuang Z, Huang S, Jensen RT: Loss of heterozygosity of chromosome 1q in gastrinomas: occurrence and prognostic significance. Cancer Res 2003;63(4):817–823.PubMedGoogle Scholar
  49. 49.
    Yang YM, Liu TH, Chen YJ, Jiang WJ, Qian JM, Lu X, Gao J, Wu SF, Sang XT, Chen J: Chromosome 1q loss of heterozygosity frequently occurs in sporadic insulinomas and is associated with tumour malignancy. Int J Cancer 2005;117(2):234–240.PubMedCrossRefGoogle Scholar
  50. 50.
    Pavelic K, Hrascan R, Kapitanovic S, Vranes Z, Cabrijan T, Spaventi S, Korsic M, Krizanac S, Li YQ, Stambrook P, Gluckman JL, Pavelic ZP: Molecular genetics of malignant insulinoma. Anticancer Res 1996;16(4A):1707–1717.PubMedGoogle Scholar
  51. 51.
    Chung DC, Smith AP, Louis DN, Graeme-Cook F, Warshaw AL, Arnold A: A novel pancreatic endocrine tumour suppressor gene locus on chromosome 3p with clinical prognostic implications. J Clin Invest 1997;100(2):404–410.PubMedCrossRefGoogle Scholar
  52. 52.
    Nikiforova MN, Nikiforov YE, Biddinger P, Gnepp DR, Grosembacher LA, Wajchenberg BL, Fagin JA, Cohen RM: Frequent loss of heterozygosity at chromosome 3p14.2-3p21 in human pancreatic islet cell tumours. Clin Endocrinol (Oxf) 1999;51(1):27–33.CrossRefGoogle Scholar
  53. 53.
    Guo SS, Arora C, Shimoide AT, Sawicki MP: Frequent deletion of chromosome 3 in malignant sporadic pancreatic endocrine tumours. Mol Cell Endocrinol 2002;190(1–2):109–114.PubMedCrossRefGoogle Scholar
  54. 54.
    Beghelli S, Pelosi G, Zamboni G, Falconi M, Iacono C, Bordi C, Scarpa A: Pancreatic endocrine tumours: evidence for a tumour suppressor pathogenesis and for a tumour suppressor gene on chromosome 17p. J Pathol 1998;186(1):41–50.PubMedCrossRefGoogle Scholar
  55. 55.
    Evers BM, Rady PL, Sandoval K, Arany I, Tyring SK, Sanchez RL, Nealon WH, Townsend CM Jr., Thompson JC: Gastrinomas demonstrate amplification of the HER-2/neu proto-oncogene. Ann Surg 1994;219(6):596–601; discussion 602–604.PubMedCrossRefGoogle Scholar
  56. 56.
    Goebel SU, Iwamoto M, Raffeld M, Gibril F, Hou W, Serrano J, Jensen RT: Her-2/neu expression and gene amplification in gastrinomas: correlations with tumour biology, growth, and aggressiveness. Cancer Res 2002;62(13):3702–3710.PubMedGoogle Scholar
  57. 57.
    Wild A, Langer P, Ramaswamy A, Chaloupka B, Bartsch DK: A novel insulinoma tumour suppressor gene locus on chromosome 22q with potential prognostic implications. J Clin Endocrinol Metab 2001;86:5782–5787.PubMedCrossRefGoogle Scholar
  58. 58.
    Wild A, Langer P, Celik I, Chaloupka B, Bartsch DK: Chromosome 22q in pancreatic endocrine tumours: identification of a homozygous deletion and potential prognostic associations of allelic deletions. Eur J Endocrinol 2002;147(4):507–513.PubMedCrossRefGoogle Scholar
  59. 59.
    Pizzi S, D’Adda T, Azzoni C, Rindi G, Grigolato P, Pasquali C, Corleto VD, Delle Fave G, Bordi C: Malignancy-associated allelic losses on the X-chromosome in foregut but not in midgut endocrine tumours. J Pathol 2002;196(4):401–407.PubMedCrossRefGoogle Scholar
  60. 60.
    D’Adda T, Candidus S, Denk H, Bordi C, Höfler H: Gastric neuroendocrine neoplasms: tumour clonality and malignancy-associate large X-chromosomal deletions. J Pathol 1999;189:394–401.PubMedCrossRefGoogle Scholar
  61. 61.
    Chen YJ, Vortmeyer A, Zhuang Z, Gibril F, Jensen RT: X-chromosome loss of heterozygosity frequently occurs in gastrinomas and is correlated with aggressive tumour growth. Cancer 2004;100(7):1379–1387.PubMedCrossRefGoogle Scholar
  62. 62.
    Missiaglia E, Moore PS, Williamson J, Lemoine NR, Falconi M, Zamboni G, Scarpa A: Sex chromosome anomalies in pancreatic endocrine tumours. Int J Cancer 2002;98(4):532–538.PubMedCrossRefGoogle Scholar
  63. 63.
    Azzoni C, Bottarelli L, Pizzi S, D’Adda T, Rindi G, Bordi C: Xq25 and Xq26 identify the common minimal deletion region in malignant gastroenteropancreatic endocrine carcinomas. Virchows Arch 2006;448:119–126.PubMedCrossRefGoogle Scholar
  64. 64.
    Brandau O, Schuster V, Weiss M, Hellebrand H, Fink FM, Kreczy A, Friedrich W, Strahm B, Niemeyer C, Belohradsky BH, Meindl A: Epstein–Barr virus-negative boys with non-Hodgkin lymphoma are mutated in the SH2D1A gene, as are patients with X-linked lymphoproliferative disease (XLP). Hum Mol Genet 1999;8:2407–2413.PubMedCrossRefGoogle Scholar
  65. 65.
    Seki Y, Suico MA, Uto A, Hisatsune A, Shuto T, Isohama Y, Kai H: The ETS transcription factor MEF is a candidate tumour suppressor gene on the X chromosome. Cancer Res 2002 62:6579–6586.PubMedGoogle Scholar
  66. 66.
    Kim H, Xu GL, Borczuk AC, Busch S, Filmus J, Capurro M, Brody JS, Lange J, D’Armiento JM, Rothman PB, Powell CA: The heparan sulfate proteoglycan GPC3 is a potential lung tumour suppressor. Am J Respir Cell Mol Biol 2003;29:694–701.PubMedCrossRefGoogle Scholar
  67. 67.
    Jonkers YM, Claessen SM, Feuth T, van Kessel AG, Ramaekers FC, Veltman JA, Speel EJ: Novel candidate tumour suppressor gene loci on chromosomes 11q23–24 and 22q13 involved in human insulinoma tumourigenesis. J Pathol 2006;210(4):450–458.PubMedCrossRefGoogle Scholar
  68. 68.
    Moore PS, Orlandini S, Zamboni G, et al.: Pancreatic tumours: molecular pathways implicated in ductal cancer are involved in ampullary but in exocrine nonductal or endocrine tumourigenesis. Br J Cancer 2001;84:253–262.PubMedCrossRefGoogle Scholar
  69. 69.
    Pellegata NS, Sessa F, Renault B, et al.: K-ras and p53 gene mutations in pancreatic cancer: ductal and nonductal tumours progress through different genetic lesions. Cancer Res 1994;54:1556–1560.PubMedGoogle Scholar
  70. 70.
    Yashiro T, Flton N, Hara H, et al.: Comparison of mutations of ras oncogene in human pancreatic exocrine and endoxrine tumours. Surgery 1993;114:758–764.PubMedGoogle Scholar
  71. 71.
    Hoffer H, Ruhri C, Putz B, et al.: Oncogene expression in endocrine pancreatic tumours. Virchows Arch B Cell Pathol Incl Mol Pathol 1998;55:355–361.Google Scholar
  72. 72.
    Sato T, Konishi K, Kimura H, et al.: Evaluation of PCNA, p53, K-ras and LOH in endocrine pancreas tumours. Hepatogastroenterology 2000;47:875–879.PubMedGoogle Scholar
  73. 73.
    Tannapfel A, Vomschloss S, Karhoff D, Markwarth A, Hengge UR, Wittekind C, Arnold R, Hörsch D: BRAF gene mutations are rare events in gastroenteropancreatic neuroendocrine tumours. Am J Clin Pathol 2005;123(2):256–260.PubMedCrossRefGoogle Scholar
  74. 74.
    Capurso G, Lattimore S, Crnogorac-Jurcevic T, Panzuto F, Milione M, Bhakta V, Campanini N, Swift SM, Bordi C, Delle Fave G, Lemoine NR: Gene expression profiles of progressive pancreatic endocrine tumours and their liver metastases reveal potential novel markers and therapeutic targets. Endocr Relat Cancer 2006;13:541–558.PubMedCrossRefGoogle Scholar
  75. 75.
    Wang DG, Johnston CF, Buchanan KD: Oncogene expression in gastroenteropancreatic neuroendocrine tumours: implications for pathogenesis. Cancer 1997;80:668–675.PubMedCrossRefGoogle Scholar
  76. 76.
    Roncalli M, Springall DR, Varndell IM, et al.: Oncoprotein immunoreactivity in human endocrine tumours. J Pathol 1991;163:117–127.PubMedCrossRefGoogle Scholar
  77. 77.
    Di Florio A, Capurso G, Milione M, Panzuto F, Geremia R, Delle Fave G, Sette C: Src family kinase activity regulates adhesion, spreading and migration of pancreatic endocrine tumour cells. Endocr Relat Cancer 2007;14(1):111–124.PubMedCrossRefGoogle Scholar
  78. 78.
    Rane SG, Cosenza SC, Mettus RV, Reddy EP: Germ line transmission of the Cdk4(R24C) mutation facilitates tumourigenesis and escare from cellular senescence. Mol Cell Biol 2002;22:644–656.PubMedCrossRefGoogle Scholar
  79. 79.
    Vax VV, Bibi R, Diaz-Cano S, et al.: Activating point mutations in cyclin-dependent kinase 4 are not seen in sporadic pituitary adenomas, insulinomas or Leydig cell tumours. J Endocrinol 2003;178:301–310.PubMedCrossRefGoogle Scholar
  80. 80.
    Guo SS, Wu X, Shimoide AT, Wong J, Moatamed F, Sawicki MP: Frequent overexpression of cyclin D1 in sporadic pancreatic endocrine tumours. J Endocrinol 2003;179:73–79.PubMedCrossRefGoogle Scholar
  81. 81.
    Chung DC, Brown SB, Graeme-Cook F, et al.: Overexpression of cyclin D1 in sporadic pancreatic endocrine tumours. J Clin Endocrinol Metab 2000;85:4373–4378.PubMedCrossRefGoogle Scholar
  82. 82.
    Hervieu V, Lepinasse F, Gouysse G, et al.: J Clin Pathol 2006;59:1300–1304.PubMedCrossRefGoogle Scholar
  83. 83.
    Chetty R, Serra S, Asa SL. 2008;Am J Surg Pathol 32:413–419.PubMedCrossRefGoogle Scholar
  84. 84.
    Wang DG, Johnston CF, Anderson N, et al.: Overexpression of the tumour suppressor p53 is not implicated in neuroendocrine tumour carcinogenesis. J Pathol 1995;175:397–401.PubMedCrossRefGoogle Scholar
  85. 85.
    Yoshimoto K, Iwahana H, Fukuda A, et al.: Role of p53 mutations in endocrine tumourigenesis: mutation detection by polymerase chain reaction-single strand conformation polymorphism. Cancer Res 1992;52:5061–5064.PubMedGoogle Scholar
  86. 86.
    Lam KY, Lo CY: Role of p53 tumour suppressor gene in pancreatic endocrine tumours of Chinese patients. Am J Gastroenterol 1998;93:1232–1235.PubMedCrossRefGoogle Scholar
  87. 87.
    Bartz C, Ziske C, Wiedenmann B, et al.: p53 tumour suppressor gene expression in pancreatic neuroendocrine tumour cells. Gut 1996;38:403–409.PubMedCrossRefGoogle Scholar
  88. 88.
    Bartsch D, Hahn SA, Danichevski KD, et al.: Mutations of the DPC4/Smad4 gene in neuroendocrine pancreatic tumours. Oncogene 1999;18:2367–2371.PubMedCrossRefGoogle Scholar
  89. 89.
    Chung DC, Smith AP, Louis DN, et al.: Analysis of the retinoblastoma tumour suppressor gene in pancreatic endocrine tumours. Clin Endocrinol (Oxf) 1997;47:423–428.CrossRefGoogle Scholar
  90. 90.
    Bartsch D, Kersting M, Wild A: Low frequency of p16(INK4a) alterations in insulinomas. Digestion 2000;52:171–177.CrossRefGoogle Scholar
  91. 91.
    Serrano J, Goebel SU, Peghini PL, et al.: Alterations in the p16 INK4a/CDKN2A tumour suppressor gene in gastrinomas. J Clin Endocrinol Metab 2000;85:4146–4156.PubMedCrossRefGoogle Scholar
  92. 92.
    Wild A, Ramaswamy A, Langer P, Celik I, Fendrich V, Chaloupka B, Simon B, Bartsch DK: Frequent methylation-associated silencing of the tissue inhibitor of metalloproteinase-3 gene in pancreatic endocrine tumours. J Clin Endocrinol Metab 2003;88(3):1367–1373.PubMedCrossRefGoogle Scholar
  93. 93.
    Dammann R, Schagdarsurengin U, Liu L, Otto N, Gimm O, Dralle H, Boehm BO, Pfeifer GP, Hoang-Vu C: Frequent RASSF1A promoter hypermethylation and K-ras mutations in pancreatic carcinoma. Oncogene 2003;22(24):3806–3812.PubMedCrossRefGoogle Scholar
  94. 94.
    Pizzi S, Azzoni C, Bottarelli L, Campanini N, D’Adda T, Pasquali C, Rossi G, Rindi G, Bordi C: RASSF1A promoter methylation and 3p21.3 loss of heterozygosity are features of foregut, but not midgut and hindgut, malignant endocrine tumours. J Pathol 2005;206(4):409–416.PubMedGoogle Scholar
  95. 95.
    Rahman A, Maitra A, Ashfaq R, Yeo CJ, Cameron JL, Hansel DE: Loss of p27 nuclear expression in a prognostically favorable subset of well-differentiated pancreatic endocrine neoplasms. Am J Clin Pathol 2003;120(5):685–690.PubMedCrossRefGoogle Scholar
  96. 96.
    House MG, Herman JG, Guo MZ, Hooker CM, Schulick RD, Cameron JL, Hruban RH, Maitra A, Yeo CJ: Prognostic value of hMLH1 methylation and microsatellite instability in pancreatic endocrine neoplasms. Surgery 2003;134(6):902–908; discussion 909.PubMedCrossRefGoogle Scholar
  97. 97.
    Parangi S, O’Reilly M, Christofori G, Holmgren L, Grosfeld J, Folkman J, et al.: Antiangiogenic therapy of transgenic mice impairs de novo tumour growth. Proc Natl Acad Sci (USA) 1996;93(5):2002–2007.CrossRefGoogle Scholar
  98. 98.
    Zhang J, Jia Z, Li Q, Wang L, Rashid A, Zhu Z, et al.: Elevated expression of vascular endothelial growth factor correlates with increased angiogenesis and decreased progression-free survival among patients with low-grade neuroendocrine tumours. Cancer 2007;109(8):1478–1486.PubMedCrossRefGoogle Scholar
  99. 99.
    Couvelard A, O’Toole D, Turley H, Leek R, Sauvanet A, Degott C, Ruszniewski P, Belghiti J, Harris AL, Gatter K: Microvascular density and hypoxia-inducible factor pathway in pancreatic endocrine tumours: negative correlation of microvascular density and VEGF expression with tumour progression. Br J Cancer 2005;92:94–101.PubMedCrossRefGoogle Scholar
  100. 100.
    Wulbrand U, Wied M, Zofel P, Goke B, Arnold R, Fehmann H: Growth factor receptor expression in human gastroenteropancreatic neuroendocrine tumours. Eur J Clin Invest 1998;28(12):1038–1049.PubMedCrossRefGoogle Scholar
  101. 101.
    Srivastava A, Alexander J, Lomakin I, Dayal Y: Immunohistochemical expression of transforming growth factor alpha and epidermal growth factor receptor in pancreatic endocrine tumours. Hum Pathol 2001;32(11):1184–1189.PubMedCrossRefGoogle Scholar
  102. 102.
    Fjallskog ML, Lejonklou MH, Oberg KE, Eriksson BK, Janson ET: Expression of molecular targets for tyrosine kinase receptor antagonists in malignant endocrine pancreatic tumours. Clin Cancer Res 2003;9(4):1469–1473.PubMedGoogle Scholar
  103. 103.
    Welin S, Fjallskog ML, Saras J, Eriksson B, Janson ET. Expression of tyrosine kinase receptors in malignant midgut carcinoid tumours. Neuroendocrinology 2006;84(1):42–48.PubMedCrossRefGoogle Scholar
  104. 104.
    Papouchado B, Erickson LA, Rohlinger AL, Hobday TJ, Erlichman C, Ames MM, et al.: Epidermal growth factor receptor and activated epidermal growth factor receptor expression in gastrointestinal carcinoids and pancreatic endocrine carcinomas. Mod Pathol 2005;18(10):1329–1335.PubMedCrossRefGoogle Scholar
  105. 105.
    Koch CA, Gimm O, Vortmeyer AO, Al-Ali HK, Lamesch P, Ott R, et al.: Does the expression of c-kit (CD117) in neuroendocrine tumours represent a target for therapy? Ann NY Acad Sci 2006;1073:517–526.PubMedCrossRefGoogle Scholar
  106. 106.
    Mita MM, Mita A, Rowinsky EK: The molecular target of rapamycin (mTOR) as a therapeutic target against cancer. Cancer Biol Ther 2003;4(Suppl 1):S169–S177.Google Scholar
  107. 107.
    Averous J, Proud CG: When translation meets transformation: the mTOR story. Oncogene 2006;25:6423–6435.PubMedCrossRefGoogle Scholar
  108. 108.
    Tan PK, Downey TJ, Spitznagel EL Jr., Xu P, Fu D, Dimitrov DS, Lempicki RA, Raaka BM, Cam MC: Evaluation of gene expression measurements from commercial microarray platforms. Nucleic Acids Res 2003;31(19):5676–5684.PubMedCrossRefGoogle Scholar
  109. 109.
    Maitra A, Hansel DE, Argani P, Ashfaq R, Rahman A, Naji A, Deng S, Geradts J, Hawthorne L, House MG: Global expression analysis of well-differentiated pancreatic endocrine neoplasms using oligonucleotide microarrays. Clin Cancer Res 2003;95:988–995.Google Scholar
  110. 110.
    Dilley WG, Kalyanaraman S, Verma S, Cobb JP, Laramie JM, Lairmore TC: Global gene expression in neuroendocrine tumours from patients with MEN-I syndrome. Mol Cancer 2005;4(1):9.PubMedCrossRefGoogle Scholar
  111. 111.
    Bloomston M, Durkin A, Yang I, Rojiani M, Rosemurgy AS, Enkmann S, Yeatman TJ, Zervos EE: Identification of molecular markers specific for pancreatic neuroendocrine tumours by genetic profiling of core biopsies. Ann Surg Oncol 2004;11:413–419.PubMedCrossRefGoogle Scholar
  112. 112.
    Duerr EM, Mizukami Y, Ng A, Xavier RJ, Kikuchi H, Deshpande V, Warshaw AL, Glickman J, Kulke MH, Chung DC: Defining molecular classifications and targets in gastroenteropancreatic neuroendocrine tumours through DNA microarray analysis. Endocr Relat Cancer 2008;15(1):243–256.PubMedCrossRefGoogle Scholar
  113. 113.
    Hansel DE, Rahman A, House M, Ashfaq R, Berg K, Yeo CJ, Maitra A: Met proto-oncogene and insulin-like growth factor binding protein 3 overexpression correlates with metastatic ability in well-differentiated pancreatic endocrine neoplasms. Clin Cancer Res 2004;10:6152–6158.PubMedCrossRefGoogle Scholar
  114. 114.
    Couvelard A, Hu J, Steers G, O’Toole D, Sauvanet A, Belghiti J, Bedossa P, Gatter K, Ruszniewski P, Pezzella F: Identification of potential therapeutic targets by gene-expression profiling in pancreatic endocrine tumours. Gastroenterology 2006;131(5):1597–1610.PubMedCrossRefGoogle Scholar
  115. 115.
    Grützmann R, Saeger HD, Lüttges J, Schackert HK, Kalthoff H, Klöppel G, Pilarsky C: Microarray-based gene expression profiling in pancreatic ductal carcinoma: status quo and perspectives. Int J Colorectal Dis 2004;19(5):401–413.PubMedCrossRefGoogle Scholar
  116. 116.
    Roldo C, Missiaglia E, Hagan JP, Falconi M, Capelli P, Bersani S, Calin GA, Volinia S, Liu CG, Scarpa A, Croce CM: MicroRNA expression abnormalities in pancreatic endocrine and acinar tumours are associated with distinctive pathologic features and clinical behaviour. Clin Oncol 2006;24(29):4677–4684.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • Gabriele Capurso
    • 1
  • Stefano Festa
    • 1
  • Matteo Piciucchi
    • 1
  • Roberto Valente
    • 1
  • Gianfranco Delle Fave
    • 1
  1. 1.Digestive and Liver Disease Unit, II Medical School“Sapienza,” University of Rome, S. Andrea HospitalRomeItaly

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