Best Practice & Research Clinical Endocrinology & Metabolism
Volume 21, Issue 1 , Pages 1-14 , March 2007

Molecular genetics of neuroendocrine tumors

  • Eva-Maria Duerr, MD (Research Fellow)
    • ,
  • Daniel C. Chung, MD (Assistant Professor of Medicine, Harvard Medical School)

      Affiliations

    • Corresponding Author InformationCorresponding author. Tel.: +1 617 726 8687; Fax: +1 617 726 5895.

References 

  1. Kloppel G, Perren A, Heitz PU. The gastroenteropancreatic neuroendocrine cell system and its tumors: the WHO classification. Annals of the New York Academy of Sciences. 2004;1014:13–27
  2. Chandrasekharappa SC, Guru SC, Manickam P, et al. Positional cloning of the gene for multiple endocrine neoplasia-type 1. Science. 1997;276(5311):404–407
  3. Zhuang Z, Vortmeyer AO, Pack S, et al. Somatic mutations of the MEN1 tumor suppressor gene in sporadic gastrinomas and insulinomas. Cancer Research. 1997;57(21):4682–4686
  4. Moore PS, Missiaglia E, Antonello D, et al. Role of disease-causing genes in sporadic pancreatic endocrine tumors: MEN1 and VHL. Genes, Chromosomes & Cancer. 2001;32(2):177–181
  5. Gortz B, Roth J, Krahenmann A, et al. Mutations and allelic deletions of the MEN1 gene are associated with a subset of sporadic endocrine pancreatic and neuroendocrine tumors and not restricted to foregut neoplasms. The American Journal of Pathology. 1999;154(2):429–436
  6. Cupisti K, Hoppner W, Dotzenrath C, et al. Lack of MEN1 gene mutations in 27 sporadic insulinomas. European Journal of Clinical Investigation. 2000;30(4):325–329
  7. Wang EH, Ebrahimi SA, Wu AY, et al. Mutation of the MENIN gene in sporadic pancreatic endocrine tumors. Cancer Research. 1998;58(19):4417–4420
  8. Shan L, Nakamura Y, Nakamura M, et al. Somatic mutations of multiple endocrine neoplasia type 1 gene in the sporadic endocrine tumors. Laboratory Investigation. 1998;78(4):471–475
  9. Yu F, Jensen RT, Lubensky IA, et al. Survey of genetic alterations in gastrinomas. Cancer Research. 2000;60(19):5536–5542
  10. Goebel SU, Heppner C, Burns AL, et al. Genotype/phenotype correlation of multiple endocrine neoplasia type 1 gene mutations in sporadic gastrinomas. The Journal of Clinical Endocrinology and Metabolism. 2000;85(1):116–123
  11. Perren A, Komminoth P, Heitz PU. Molecular genetics of gastroenteropancreatic endocrine tumors. Annals of the New York Academy of Sciences. 2004;1014:199–208
  12. Jakobovitz O, Nass D, DeMarco L, et al. Carcinoid tumors frequently display genetic abnormalities involving chromosome 11. The Journal of Clinical Endocrinology and Metabolism. 1996;81(9):3164–3167
  13. Debelenko LV, Brambilla E, Agarwal SK, et al. Identification of MEN1 gene mutations in sporadic carcinoid tumors of the lung. Human Molecular Genetics. 1997;6(13):2285–2290
  14. Debelenko LV, Emmert-Buck MR, Zhuang Z, et al. The multiple endocrine neoplasia type I gene locus is involved in the pathogenesis of type II gastric carcinoids. Gastroenterology. 1997;113(3):773–781
  15. Fujii T, Kawai T, Saito K, et al. MEN1 gene mutations in sporadic neuroendocrine tumors of foregut derivation. Pathology International. 1999;49(11):968–973
  16. Agarwal SK, Guru SC, Heppner C, et al. Menin interacts with the AP1 transcription factor JunD and represses JunD-activated transcription. Cell. 1999;96(1):143–152
  17. Gobl AE, Berg M, Lopez-Egido JR, et al. Menin represses JunD-activated transcription by a histone deacetylase-dependent mechanism. Biochimica et Biophysica Acta. 1999;1447(1):51–56
  18. Milne TA, Hughes CM, Lloyd R, et al. Menin and MLL cooperatively regulate expression of cyclin-dependent kinase inhibitors. Proceedings of the National Academy of Sciences of the United States of America. 2005;102(3):749–754
  19. Karnik SK, Hughes CM, Gu X, et al. Menin regulates pancreatic islet growth by promoting histone methylation and expression of genes encoding p27Kip1 and p18INK4c. Proceedings of the National Academy of Sciences of the United States of America. 2005;102(41):14659–14664
  20. Crabtree JS, Scacheri PC, Ward JM, et al. A mouse model of multiple endocrine neoplasia, type 1, develops multiple endocrine tumors. Proceedings of the National Academy of Sciences of the United States of America. 2001;98(3):1118–1123
  21. Franklin DS, Godfrey VL, O'Brien DA, et al. Functional collaboration between different cyclin-dependent kinase inhibitors suppresses tumor growth with distinct tissue specificity. Molecular and Cellular Biology. 2000;20(16):6147–6158
  22. Komminoth P, Roth J, Muletta-Feurer S, et al. RET proto-oncogene point mutations in sporadic neuroendocrine tumors. The Journal of Clinical Endocrinology and Metabolism. 1996;81(6):2041–2046
  23. Lubensky IA, Pack S, Ault D, et al. Multiple neuroendocrine tumors of the pancreas in von Hippel–Lindau disease patients: histopathological and molecular genetic analysis. The American Journal of Pathology. 1998;153(1):223–231
  24. Lott ST, Chandler DS, Curley SA, et al. High frequency loss of heterozygosity in von Hippel–Lindau (VHL)-associated and sporadic pancreatic islet cell tumors: evidence for a stepwise mechanism for malignant conversion in VHL tumorigenesis. Cancer Research. 2002;62(7):1952–1955
  25. Chung DC, Smith AP, Louis DN, et al. A novel pancreatic endocrine tumor suppressor gene locus on chromosome 3p with clinical prognostic implications. The Journal of Clinical Investigation. 1997;100(2):404–410
  26. Speel EJ, Richter J, Moch H, et al. Genetic differences in endocrine pancreatic tumor subtypes detected by comparative genomic hybridization. The American Journal of Pathology. 1999;155(6):1787–1794
  27. Speel EJ, Scheidweiler AF, Zhao J, et al. Genetic evidence for early divergence of small functioning and nonfunctioning endocrine pancreatic tumors: gain of 9Q34 is an early event in insulinomas. Cancer Research. 2001;61(13):5186–5192
  28. Zhao J, Moch H, Scheidweiler AF, et al. Genomic imbalances in the progression of endocrine pancreatic tumors. Genes, Chromosomes & Cancer. 2001;32(4):364–372
  29. Stumpf E, Aalto Y, Hoog A, et al. Chromosomal alterations in human pancreatic endocrine tumors. Genes, Chromosomes & Cancer. 2000;29(1):83–87
  30. Barghorn A, Komminoth P, Bachmann D, et al. Deletion at 3p25.3-p23 is frequently encountered in endocrine pancreatic tumours and is associated with metastatic progression. The Journal of Pathology. 2001;194(4):451–458
  31. Barghorn A, Speel EJ, Farspour B, et al. Putative tumor suppressor loci at 6q22 and 6q23-q24 are involved in the malignant progression of sporadic endocrine pancreatic tumors. The American Journal of Pathology. 2001;158(6):1903–1911
  32. Guo SS, Wu AY, Sawicki MP. Deletion of chromosome 1, but not mutation of MEN-1, predicts prognosis in sporadic pancreatic endocrine tumors. World Journal of Surgery. 2002;26(7):843–847
  33. Rindi G, Villanacci V, Ubiali A, Scarpa A. Endocrine tumors of the digestive tract and pancreas: histogenesis, diagnosis and molecular basis. Expert Review of Molecular Diagnostics. 2001;1(3):323–333
  34. Tonnies H, Toliat MR, Ramel C, et al. Analysis of sporadic neuroendocrine tumours of the enteropancreatic system by comparative genomic hybridisation. Gut. 2001;48(4):536–541
  35. Zhao J, de Krijger RR, Meier D, et al. Genomic alterations in well-differentiated gastrointestinal and bronchial neuroendocrine tumors (carcinoids): marked differences indicating diversity in molecular pathogenesis. The American Journal of Pathology. 2000;157(5):1431–1438
  36. Wang GG, Yao JC, Worah S, et al. Comparison of genetic alterations in neuroendocrine tumors: frequent loss of chromosome 18 in ileal carcinoid tumors. Modern Pathology. 2005;18(8):1079–1087
  37. Stancu M, Wu TT, Wallace C, et al. Genetic alterations in goblet cell carcinoids of the vermiform appendix and comparison with gastrointestinal carcinoid tumors. Modern Pathology. 2003;16(12):1189–1198
  38. Lollgen RM, Hessman O, Szabo E, et al. Chromosome 18 deletions are common events in classical midgut carcinoid tumors. International Journal of Cancer. 2001;92(6):812–815
  39. Kytola S, Hoog A, Nord B, et al. Comparative genomic hybridization identifies loss of 18q22-qter as an early and specific event in tumorigenesis of midgut carcinoids. The American Journal of Pathology. 2001;158(5):1803–1808
  40. Chan AO, Kim SG, Bedeir A, et al. CpG island methylation in carcinoid and pancreatic endocrine tumors. Oncogene. 2003;22(6):924–934
  41. House MG, Herman JG, Guo MZ, et al. Aberrant hypermethylation of tumor suppressor genes in pancreatic endocrine neoplasms. Annals of Surgery. 2003;238(3):423–431[discussion 431–432]
  42. House MG, Herman JG, Guo MZ, et al. Prognostic value of hMLH1 methylation and microsatellite instability in pancreatic endocrine neoplasms. Surgery. 2003;134(6):902–908[discussion 909]
  43. Pfeifer GP, Dammann R. Methylation of the tumor suppressor gene RASSF1A in human tumors. Biochemistry. Biokhimiia. 2005;70(5):576–583
  44. Shivakumar L, Minna J, Sakamaki T, et al. The RASSF1A tumor suppressor blocks cell cycle progression and inhibits cyclin D1 accumulation. Molecular and Cellular Biology. 2002;22(12):4309–4318
  45. Pizzi S, Azzoni C, Bottarelli LC, et al. RASSF1A promoter methylation and 3p21.3 loss of heterozygosity are features of foregut, but not midgut and hindgut, malignant endocrine tumours. The Journal of Pathology. 2005;206(4):409–416
  46. Dammann R, Schagdarsurengin U, Liu L, et al. Frequent RASSF1A promoter hypermethylation and K-ras mutations in pancreatic carcinoma. Oncogene. 2003;22(24):3806–3812
  47. McCormick F. Ras-related proteins in signal transduction and growth control. Molecular Reproduction and Development. 1995;42(4):500–506
  48. Yashiro T, Fulton N, Hara H, et al. Comparison of mutations of ras oncogene in human pancreatic exocrine and endocrine tumors. Surgery. 1993;114(4):758–763[discussion 763–764]
  49. Younes N, Fulton N, Tanaka R, et al. The presence of K-12 ras mutations in duodenal adenocarcinomas and the absence of ras mutations in other small bowel adenocarcinomas and carcinoid tumors. Cancer. 1997;79(9):1804–1808
  50. Pavelic K, Hrascan R, Kapitanovic S, et al. Molecular genetics of malignant insulinoma. Anticancer Research. 1996;16(4A):1707–1717
  51. Fujimori M, Ikeda S, Shimizu Y, et al. Accumulation of beta-catenin protein and mutations in exon 3 of beta-catenin gene in gastrointestinal carcinoid tumor. Cancer Research. 2001;61(18):6656–6659
  52. Gerdes B, Ramaswamy A, Simon B, et al. Analysis of beta-catenin gene mutations in pancreatic tumors. Digestion. 1999;60(6):544–548
  53. Stalberg P, Granberg D, Carling T, et al. In situ RNA-RNA hybridisation of phospholipase C beta 3 shows lack of expression in neuroendocrine tumours. Anticancer Research. 2003;23(3B):2227–2232
  54. Goke R, Gregel C, Goke A, et al. Programmed cell death protein 4 (PDCD4) acts as a tumor suppressor in neuroendocrine tumor cells. Annals of the New York Academy of Sciences. 2004;1014:220–221
  55. Evers BM, Rady PL, Sandoval K, et al. Gastrinomas demonstrate amplification of the HER-2/neu proto-oncogene. Annals of Surgery. 1994;219(6):596–601[discussion 602–604]
  56. Goebel SU, Iwamoto M, Raffeld M, et al. Her-2/neu expression and gene amplification in gastrinomas: correlations with tumor biology, growth, and aggressiveness. Cancer Research. 2002;62(13):3702–3710
  57. Bartsch D, Hahn SA, Danichevski KD, et al. Mutations of the DPC4/Smad4 gene in neuroendocrine pancreatic tumors. Oncogene. 1999;18(14):2367–2371
  58. Perren A, Saremaslani P, Schmid S, et al. DPC4/Smad4: no mutations, rare allelic imbalances, and retained protein expression in pancreatic endocrine tumors. Diagnostic Molecular Pathology. 2003;12(4):181–186
  59. Sherr CJ. The Pezcoller lecture: cancer cell cycles revisited. Cancer Research. 2000;60(14):3689–3695
  60. Sherr CJ, Roberts JM. Inhibitors of mammalian G1 cyclin-dependent kinases. Genes & Development. 1995;9(10):1149–1163
  61. Quelle DE, Zindy F, Ashmun RA, Sherr CJ. Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell. 1995;83(6):993–1000
  62. Chung DC, Smith AP, Louis DN, et al. Analysis of the retinoblastoma tumour suppressor gene in pancreatic endocrine tumours. Clinical Endocrinology. 1997;47(5):523–528
  63. Williams BO, Remington L, Albert DM, et al. Cooperative tumorigenic effects of germline mutations in Rb and p53. Nature Genetics. 1994;7(4):480–484
  64. Yoshimoto K, Iwahana H, Fukuda A, et al. Role of p53 mutations in endocrine tumorigenesis: mutation detection by polymerase chain reaction-single strand conformation polymorphism. Cancer Research. 1992;52(18):5061–5064
  65. Tomita T. p53 and proliferating cell nuclear antigen in endocrine tumors of pancreas and intestinal carcinoids. Pathology. 1997;29(2):147–153
  66. Lam KY, Lo CY. Role of p53 tumor suppressor gene in pancreatic endocrine tumors of Chinese patients. The American Journal of Gastroenterology. 1998;93(8):1232–1235
  67. Rane SG, Cosenza SC, Mettus RV, Reddy EP. Germ line transmission of the Cdk4(R24C) mutation facilitates tumorigenesis and escape from cellular senescence. Molecular and Cellular Biology. 2002;22(2):644–656
  68. 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. The Journal of Endocrinology. 2003;178(2):301–310
  69. Muscarella P, Melvin WS, Fisher WE, et al. Genetic alterations in gastrinomas and nonfunctioning pancreatic neuroendocrine tumors: an analysis of p16/MTS1 tumor suppressor gene inactivation. Cancer Research. 1998;58(2):237–240
  70. Lubomierski N, Kersting M, Bert T, et al. Tumor suppressor genes in the 9p21 gene cluster are selective targets of inactivation in neuroendocrine gastroenteropancreatic tumors. Cancer Research. 2001;61(15):5905–5910
  71. Bartsch DK, Kersting M, Wild A, et al. Low frequency of p16(INK4a) alterations in insulinomas. Digestion. 2000;62(2-3):171–177
  72. Krimpenfort P, Quon KC, Mooi WJ, et al. Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice. Nature. 2001;413(6851):83–86
  73. Sharpless NE, Bardeesy N, Lee KH, et al. Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature. 2001;413(6851):86–91
  74. Kamijo T, Bodner S, van de Kamp E, et al. Tumor spectrum in ARF-deficient mice. Cancer Research. 1999;59(9):2217–2222
  75. Kawahara M, Kammori M, Kanauchi H, et al. Immunohistochemical prognostic indicators of gastrointestinal carcinoid tumours. European Journal of Surgical Oncology. 2002;28(2):140–146
  76. Guo SS, Wu X, Shimoide AT, et al. Anomalous overexpression of p27(Kip1) in sporadic pancreatic endocrine tumors. The Journal of Surgical Research. 2001;96(2):284–288
  77. Canavese G, Azzoni C, Pizzi S, et al. p27: a potential main inhibitor of cell proliferation in digestive endocrine tumors but not a marker of benign behavior. Human Pathology. 2001;32(10):1094–1101
  78. Chung DC, Brown SB, Graeme-Cook F, et al. Overexpression of cyclin D1 occurs frequently in human pancreatic endocrine tumors. The Journal of Clinical Endocrinology and Metabolism. 2000;85(11):4373–4378
  79. Guo SS, Wu X, Shimoide AT, et al. Frequent overexpression of cyclin D1 in sporadic pancreatic endocrine tumours. The Journal of Endocrinology. 2003;179(1):73–79
  80. von Wichert G, Jehle PM, Hoeflich A, et al. Insulin-like growth factor-I is an autocrine regulator of chromogranin A secretion and growth in human neuroendocrine tumor cells. Cancer Research. 2000;60(16):4573–4581
  81. Christofori G, Naik P, Hanahan D. A second signal supplied by insulin-like growth factor II in oncogene-induced tumorigenesis. Nature. 1994;369(6479):414–418
  82. Zhang X, Gaspard JP, Mizukami Y, et al. Overexpression of cyclin D1 in pancreatic beta-cells in vivo results in islet hyperplasia without hypoglycemia. Diabetes. 2005;54(3):712–719
  83. Imanishi Y, Hosokawa Y, Yoshimoto K, et al. Primary hyperparathyroidism caused by parathyroid-targeted overexpression of cyclin D1 in transgenic mice. The Journal of Clinical Investigation. 2001;107(9):1093–1102
  84. Maitra A, Hansel DE, Argani P, et al. Global expression analysis of well-differentiated pancreatic endocrine neoplasms using oligonucleotide microarrays. Clinical Cancer Research. 2003;9(16 Pt 1):5988–5995
  85. Bloomston M, Durkin A, Yang I, et al. Identification of molecular markers specific for pancreatic neuroendocrine tumors by genetic profiling of core biopsies. Annals of Surgical Oncology. 2004;11(4):413–419
  86. Dilley WG, Kalyanaraman S, Verma S, et al. Global gene expression in neuroendocrine tumors from patients with the MEN1 syndrome. Molecular Cancer Research. 2005;4(1):9
  87. Hansel DE, Rahman A, House H, et al. 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
  88. Capurso G, Lattimore S, Crnogorac-Jurcevic T, et al. Gene expression profiles of progressive pancreatic endocrine tumours and their liver metastases reveal potential novel markers and therapeutic targets. Endocrine-Related Cancer. 2006;13(2):541–558

PII: S1521-690X(06)00110-2

doi: 10.1016/j.beem.2006.12.001

Best Practice & Research Clinical Endocrinology & Metabolism
Volume 21, Issue 1 , Pages 1-14 , March 2007

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