[Frontiers in Bioscience 3, d1148-1160, November 15, 1998]
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MOLECULAR PATHOBIOLOGY OF PANCREATIC ADENOCARCINOMA

Shamlal Mangray and Thomas C King

Department of Pathology and Laboratory Medicine, Brown University School of Medicine, Providence, RI

Received 8/24/98 Accepted 9/4/98

9. REFERENCES

1. S.H.Laudis, T.Murray, S. Bolden & P.A. Wings: Cancer Statistics, 1998. CA Cancer J Clin 48, 6-29 (1998)

2. H. Safran, T.C. King, H. Choy, P. Hesketh, B. Wolf, E. Altenhein, W. Sikov, A. Rosmarin, W. Akerley, K. Radie-Keane, G. Cicchetti, F. Lopez, K. Bland & H.J. Wanebo: Paclitaxel and Concurrent Radiaton for Locally Advanced Pancreatic and Gastric Cancer: a Phase I Study. J Clin Onc 15, 901-907 (1997)

3. R.H Hruban, C.J. Yeo & S.E. Kern: Pancreatic cancer. In: Vogelstein B and Kinzler KW. Eds: The Genetic Basis of Human Cancer. McGraw-Hill, New York pp 603-613 (1997)

4. C.A. Moskaluk, R.H. Hruban, S.E. Kern: p16 and K-ras gene mutations in the intraductal precursors of human pancreatic adenocarcinoma. Cancer Res 57, 2140-2143 (1997)

5. K. Z’graggen, J.A. Rivera, C.C. Compton, M. Pins, J. Werner, C. Fernandez del Castillo, D.W. Rattner, K.B. Lewandrowski, A.K. Rustgi & A.L. Warshaw: Prevalence of activating K-ras mutations in the evolutionary stages of neoplasia in intraductal papillary mucinous tumors of the pancreas. Ann Surg 26, 491-498 (1997)

6. M. Tada, M. Omata & M. Ohto: Ras gene mutations in intraductal papillary neoplasms of the pancreas. Cancer 64 634-638 (1991)

7. D.C. Whitcomb, R.A. Preston, C.E. Aston, M.J. Sossenheimer, P.S. Barua, Y. Zhang, A. Wong-Chong, G.J. White, P.G. Wood, L.K. Gates, C. Ulrich, S.P. Martin, J.C. Post & G.D. Ehrlich: A gene for hereditary pancreatitis maps to chromosome 7q35. Gastroenterology 110, 1975-1980 (1996)

8. A.M. Goldstein, M.C. Fraser, J.P. Struewing, C.J. Hussassian, K. Ranade, D.P. Zametkin, L.S. Fontaine, S.M. Organic, N.C. Dracopoli, W.H.C. Clark & M.A. Tucker: Increased risk of pancreatic cancer in melanoma-prone kindred with p16INK4 mutation. New Engl J Med 333, 970-974 (1995)

9. M. Nystrom-Lahti, R. Parsons, P. Sistonen, L. Pyilkkanen, L.A. Aaltonen, F.S. Leach, S.R. Hamilton, P. Watson, E. Bronson & R Fusaro: Mismatch repair genes on chromosome 2p and 3p account for a major share of hereditrary nonpolyposis colorectal cancer families evaluable by linkage. Am J Hum Genet 55, 659-665 (1994)

10. J.A. Lumadue, C.A. Griffin, M. Osman & R.H. Hruban: Familial pancreatic cancer and the genetics of pancreatic cancer. Surg Clin North Am 75(5), 845-855 (1995)

11. L.A. Aaltonen, P. Peltomaki, J.P. Mecklin, H. Jarvinen, J.R. Jass, J.S. Green, H.T. Lynch, P. Watson, G. Tallqvist, M. Juhola, P. Sistonen, S.R. Hamilton, K.W. Kinzler, B. Vogelstein & A. de la Chapelle: Replication errors in benign and malignant tumors from hereditary nonpolyposis colorectal cancer patients. Cancer Res 54, 1645-1648 (1994)

12. S.N. Thibodeau, G. Bren & C. Schaid D: Microsatellite instability incancer of the proximal colon. Science 260, 816-819 (1993)

13. A. Hemminki, I. Tomlinson, D. Markie, H. Jarvinen, P. Siswtonen, A.M. Bjorkqvist, S.Knuutila, R. Salovaara, W. Bodmer, D. Shibita, A. de la Chapelle & L. A. Aaltonen LA: Localization of a susceptibility locus for Peutz-Jeghers syndrome to 19p using comparative genomic hybridization and targeted linkage analysis. Nat Genet 15,87-90 (1997)

14. D.E. Jenne, H. Reimann, J. Nezu, W. Freidel, S. Loff, R. Jeschke, O. Muller, W. Back & M. Zimmer: Peutz-Jeghers syndrome is cxaused by mutations in a novel serine threonine kinase. Nat Genet 18, 38-43 (1998)

15. F.M. Giardello, S.B. Welsh, S.R. Hamilton, G.J.A. Offerhaus, A.M. Gittelsohn, S.V. Booker, A.J. Krush, J.H. Yardley & G.D. Luk: Increased risk of cancer in the Peutz-Jeghers Syndrome. New EngJ Med 316, 1511-1514 (1987)

16. H.T. Lynch, T. Smyrk, S.E. Kern, R.H. Hruban, C.J. Lightdale, S.J. Lemon, J.F. Lynch, R.M. Fusaro & P. Ghadirian: Familial pancreatic cancer: a review. Semin Onc 23, 251-275 (1996)

17. H. Tulinius, G.H. Olafsdottir, G.H. Sigvaldason, L. Tryggvadottir & K. Bjarnadottir: Neoplastic diseases in families of breast cancer patients. J Med Genet 31, 618-621 (1994)

18. R.A. Kerber & M.L. Slattery: The impact of family history on ovarian cancer risk. Arch Int Med 155, 905-912 (1995)

19. R. Porschen, U. Remy, G. Bevers, S Schauseil, K.J. Hengels & F. Borchard: Prognostic significance of DNA ploidy in adenocarcinoma of the pancreas. A flow cytometric study of paraffin-embedded specimens. Cancer 71,3846-3850 (1993)

20. S.T. Dergham, M.C. Dugan, P. Arlauskas, W. Du, V.K. Vaitkevicius, J.D. Crissman & F.H. Sarkar: Relationship of family cancer history to the expression of p53, p21WAF, HER-2/neu, and K-ras mutation in pancreatic adenocarcinoma. Int J Pancreatol 21, 225-234 (1997).

21. E. Rozenblum, M. Schutte, M. Goggins, S.A. Hahn, S. Panzer, M. Zahurak, S.N. Goodman, T.A. Sohn , R.H. Hruban, C.J. Yeo & S.E. Kern: Tumor suppressive pathways in pancreatic cancer. Cancer Res 57, 1731-1734 (1997)

22. L. Huang, T.L. Goodrow, S.Y. Zhang, A.J. Klein-Szanto, H. Chang & B.A. Ruggeri: Deletion and mutational analyses of the p16/MTS-1 tumor-suppressor gene in human ductal pancreatic cancer reveals a high frequency of abnormalities in tumor-derived cell lines than in primary ductal adenocarcinomas. Cancer Res 56, 1137-1141 (1996)

23. B. Simon, D. Bartsch, P. Barth, N. Prasnikar, K. Munch, A. Blum, R. Arnold & B. Goke: Frequent abnormalities of the putative suppressor gene FHIT at 3p14.2 in pancreatic carcinoma cell lines. Cancer Res 58, 1583-1587 (1998)

24. S.T. Dergham, M.C. Dugan, R. Kucway, W. Du, D.S. Kamarauskiene, V.K. Vaitkevicius, J.D. Crissman & F.H. Sarkar: Prevalence and clinical significance of combined K-ras mutation and p53 aberration in pancreatic adenocarcinoma. Int J Pancreatol 21, 127-143 (1997)

25. G. Reyes, A. Villanueva, C. Garcia, F.J. Sancho, J. Puilats, F. Lluis & G.Capella: Orthotopic xenografts of human pancreatic carcinomas acquire genetic aberrations during dissemination in nude mice. Cancer Res 56, 5713-5719 (1996)

26. R.H. Hruban, A.D.M. van Mansfield, G.J.A. Offerhaus, D.J.H. van Weering, D.C. Allison, S.N. Goodman, T.W. Kensler, K.K. Bose, J.L. Cameron & J.L. Bos: K-ras oncogene activation in adenocarcinoma of the human aancreas : a study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. Am J Pathol 143, 545-554 (1993)

27. M. Serrano, G.J. Hannon & D. Beach D: A new regulatory motif in cell-cycle control causing specific inhibition of cyclin D/cdk-4. Nature 386, 704-707 (1993)

28. T. Hunter & J. Pines: Cyclins and cancer II: cyclin D and CDK inhibitors come of age. Cell 79, 573-582 (1994)

29. S.A. Hahn & S.E. Kern: Molecular genetic of exocrine pancreatic neoplasms. Surg Arch NA 75, 857-869 (1995)

30. T. Nobori, K.K. Miura, D.J. Wu A. Lois, K. Takabayashi & D.A. Carson: Deletions of the cyclin-dependent kinase-4 inhibitor gene in multiple human cancers. Nature 368, 753-756 (1994)

31. M. Park: Oncogenes. In: The Genetic Basis Of Human Cancer. Eds: Vogelstein B, Kinzler KW, Mc Graw-Hill, New York, pp 205-228 (1997)

32. K.S.J. Elenitoba-Johnson, R.D. Gascoyne, M.S. Lim, M. Chhanabai, E.S. Jaffe, M. Raffeld: Homozygous deletions at chromosome 9p21 involving p16 and p15 are associated with histologic progression in follicle center lymohoma. Blood 91, 4677-4685 (1998)

33. S. Taga, T. Osaki, A. Ohgami, H. Imoto, T. Yoshimatus, I. Yoshino, K. Yano, R. Nakanishi, Y. Ichiyoshi & K. Yasumoto: Prognostic value of the immunohistochemical detection of p16INK4a expression in nonsamll cell lung carcinoma. Cancer 80, 389-395 (1997)

34. J.G. Herman, C.I. Civin, J.P. Issa, M.I. Collector, S.J. Sharkis & S.B. Baylin: Distinct patterns of inactivation of the p15INK4B and p16INK4A characterize the major types of hematological malignancies. Cancer Res 57, 837-841 (1997)

35. A. Kamb, N.A. Gruis & J.W. Feldhaus: A cell cycle regulator potentially involved in genesis of many tumor types. Science 264, 436-439, (1993)

36. G. Hannon & D. Beach: p15INK4B is a potential effector of TGF-B-induced cell cycle arrest. Nature 371, 257-261 (1994)

37. D.E. Quelle, R. Zindy, R.A. Ashmun & C.J. Sherr: Alternative reading frames of the INK4a tumor suppressor gene encode two unrelated proteins capable of inducing cell cycle arrest. Cell 83, 993-1000 (1995)

38. J. Pomerantz, N. Schreiber-Agus, N.J. Leigeois, A. Silverman, L. Alland, L. Chin, J. Potes, K. Chen, I. Orlow, H.W. Lee, C. Cordon-Cardo & R.A. Depinho: The Ink4a tumor suppressor gene product p19ARF, interacts with MDM2 and neutralizes MDM2's inhibition of p53. Cell 92, 713-723 (1998)

39. T. Kamiho, F. Zindy, M.F. Roussel, D.E. Quelle, J.R. Downing, R.A. Ashmun, G. Grosvel & C.J. Sherr: Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell 91, 649-659 (1997)

40. C. Caldas, S.A. Hahn, L.T. da Costa, M.S. Redston, M. Schutte, A.B. Seymour, C.L. Weinstein, R.H. Hruban, C.J. Yeo & S.E. Kern: Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nature Genet 8, 27-32 (1994)

41. M. Schutte, R.H. Hruban, J. Geradts, R. Maynard, W. Hilgers, S.K. Rabindran, C.A Moskaluk, H.A. Hahn, I. Schwarte-Waldhoff , W. Schmiegel, S.B. Baylin, S.E. Kern & J.G. Herman: Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res 57:3126-3130 (1997)

42. D. Bartsch, D.W. Shevlin & W.S. Tung: Frequent mutations of CDKN2 in primary pancreatic adenocarcinomas. Genes Chromosomes Cancer 14, 189-195 (1995)

43. J. Marx: A challenge to p16 gene as a major tumor suppressor. Science 264, 1846 (1994)

44. F.P. Li, J.F. Fraumeni, J.J. Mulvihill, W.A. Blattner, M.G. Dreyfus, M.A. Tucker & R.W. Miller: A cancer family syndrome in twenty-four kindreds. Cancer Res 48, 5358-5362 (1988).

45. A.J. Levine, J. Momand & C.A. Finlay: The p53 tumour suppressor gene. Nature 351, 453-456 (1991)

46. S.W. Lowe, H.E. Ruley & T. Jacks: p53-dependent apoptosis modulates the cytotoxicity of anticancer agents. Cell 74, 957-967 (1993)

47. E. Wattel, C. Preudomme & B. Gecquet B: p53 mutations are associated with resistance to chemotherapy and short survival in hematologic malignancies. Blood 84, 3148-3157 (1994)

48. S.W. Lowe, S. Bodis & A.McClatchey: p53 status and the efficacy of cancer therapy in vivo. Science 266, 807-810 (1994)

49. H. Choy, T.C. King, W. Akerley & H. Safran: Paclitaxel and concurrent radiation for lung, pancreatic, and gastric carcinomas: significance of p53 gene mutations for treatment response. Semin Rad Onc 7, 77-81 (1997)

50. D. Lang, S.J. Miknyoczki, L. Huang & B.A. Ruggeri: Stable reintroduction of wild-type p53 (MTmp53ts) causes the induction of apoptosis and neuroendocrine-like Differentiation in human ductal pancreatic carcinoma cells. Oncogene 16, 1593-1602 (1998)

51. S .E. Kern SE, J.A. Pietenpol & S. Thiagalingam: Oncogenic forms of p53 inhibit p53-regulated gene expression. Science 256, 827-830 (1992).

52. P.L. Porter, A.M. Gown, S.G. Kramp & M.D. Coltrera: Widespread p53 overexpression in human malignant tumors. Am J Path 140, 145-153 (1991)

53. K.S.J. Elenitoba-Johnson, L.J. Medeiros, J. Khorsand & T.C. King: p53 expression in Reed-Sternberg cells does not correlate with gene mutations in Hodgkin's disease. Amer J Clin Path 106, 728-738 (1996)

54. D. Coppola, L. Lu, J.P. Fruehauf, A. Kyshtoobayeva, R.C. Karl, S.V. Nicosia & T.J. Yeatman: Analysis of p53. p21WAF, and TGF-beta 1 in human ductal adenocarcinoma of the pancreas. TGF-beta 1 protein expression predicts longer survival. Am J Clin Pathol 110, 16-23 (1998)

55. L.L. Kisselev, J. Justesen, A.D. Wolfson & L.Y. Frolova: Oligophosphates (Ap(n)A), a novel class of signalling molecules: FEBS Let 427, 157-163 (1998)

56. R. Shridhar, V. Shridhar, X. Wang, W. Paradee, M. Dugan, F. Sarkar, C. Wilke, T.W. Glover, V.K. Vaitkevicuis & D.I. Smith: Frequent breakpoints in the 3p14.2 fragile site, FRA3B, in pancretic tumors. Cancer Res 56, 4347-4350 (1996)

57. M. Ohta, H. Inoue, G.M. Corticelli, K. Kastury, R. Baffa, J. Palazzo, Z. Siprashvilli, M. Mori, P. McCue, T. Druck, C.M Croce & K. Huebner: The FHIT gene, spanning chromosome 3p14.2FRA3B site identified by homozygous deletions in tumor cell lines. Cancer Res 56, 978-983 (1996)

58. L. Mao: Tumor Suppressor Genes : Does FHIT Fit?. J Natl Cancer Inst 90, 412-413 (1998)

59. L. Mao, J.S. Lee, Y.H. Fan, J.Y. Ro, J.G. Batsakis, S. Lippman, W. Hittelman & W.K. Hong: Frequent microsatellite altertations at chromosomes 9p21 and 3p14 in oral premalignant lesions and their value in cancer risk. Nat Med 2, 682-685 (1996)

60. G.A Otterson, X. Guang-Hui, J. Geradts, G. Jin, W. Chen, W. Niklinska, F.J. Kaye & R.S. Yeung: Protein expression and functional analysis of the FHIT gene in human tumor cells. J Natl Cancer Inst 90, 426-432 (1998)

61. Z. Siprashvili, G. Sozzi, L.D. Barnes, P. McCue, A.K. Robinson & V. Eryomin: Replacement of FHIT in cancer cells suppresses tumorigenicity. Proc Natl Acad Sci USA 94, 13771-13776 (1997)

62. Y. Yamanaka, H. Freiss, M.S. Kobrin, M. Buchler, J. Kunz, H.G. Beger & M. Korc: Overexpression of Her-2/neu oncogene in human pancreatic carcinoma. Human Path 24, 1127-1134 (1993)

63.J.D. Day, G. Di Guiseppe, C.J. Yeo, M. Liu-Goldman, S.M. Anderson, S.N. Goodman, S.E. Kern & R.H. HrubaN; Immunohistochemical evaluation of HER-2/neu expression in pancreatic adenocarcinoma and intraepithelial neoplasms. Human Path 27, 119-124 (1996)

64.M.C. Dugan, S.T. Dergham, R. Kucway, K. Singh, L. Biernat, W. Du, V.K. Vaitkevicius, J.D. Crissman & F.H. Sarkar: HER-2/neu expression in pancreatic adenocarcinoma: relation to tumor differentiation and survival. Pancreas 14, 229-236 (1997)

65.M. Goggins, M. Schutte, J. Lu, C.A. Moskaluk, C.L. Weinstein, G.M. Petersen, C.J. Yeo, C.E. Jackson, H.T. Lynch, R.H. Hruban & S.E. Kern: Germline BRCA2 gene mutations in patients with apparently sporadic pancretic carcinomas. Cancer Res 56, 5360-5364 (1996)

66.C.M. Barton, A.B. McKie, A. Hogg, B. Bia, G. Elia, S.M. Phillips, S.F. Ding & N.R. Lemoine:Abnormalities of the RB1 and DCC tumor suppressor genes: uncommon in pancreatic adenocarcinoma. Mol Carcinog 13, 61-69 (1995)

67.L. Huang, D. Lang, J. Geradts, T. Obara, A.J. Klein-Szanto, H.T. Lynch & B.A. Ruggeri: Molecular and immunochemical analyses of RB1 and cyclin D1 in human ductal pancreatic carcinomas and cell lines. Molec Carcinog 15, 85-95 (1996)

68.C. Caldas, S.A. Hahn, R.H. Hruban, M.S. Redston, C.J. Yeo & S.E. Kern: Detection of K-ras mutations in the stools of patients with pancreatic adenocarcinoma and pancreatic ductal hyperplasia. Cancer Res 54, 3568-3573 (1994)

69. S. Nomoto, A. Nakao, N. Ando, S. Takeda, Y. Kasai, S. Inoue, T. Kaneko & H. Takagi: Clinical application of K-ras oncogene mutations in pancreatic carcinoma: detection of micrometastases. Semin Surg Onc 15, 40-46 (1998)

70. D. Van der Velde-Zimmermann, J.F.M. Roijers, A. Bouwens-Rombouts, R.A De Weger, P.W. De Graaf, M.G.J. Tilanus & J.G. Van den Tweel: Molecular test for the detection of tumor cells in blood and sentinel nodes of melanoma patients. Am J Pathol 149, 759-764 (1996)

71.T. Iwao, K. Hanada, A. Tsuchida, M. Hirata, N. Eguchi, G. Kajiyama: The establishment of a pre-operative diagnosis of pancreatic carcinoma using cell specimens from pancreatic duct brushing with special attention to p53 mutations. Cancer 82, 1487-1494 (1998)

72.S. Gansauge, F. Gansauge, G. Negri, P. Galle, J. Muller, A.K. Nussler, B. Pock & H.G. Berger: The role of anti-p53 autoantibodies in pancreatic disorders. Int J Pancreatol 19, 171-178 (1996)

73.J Raedle, G. Oremek, M. Welker, W.K. Roth, W.F. Caspary & S. Zeurem: 53 Autoantibodies in patients with pancreatitis and pancreatic carcinoma. Pancreas 13, 241-246 (1996)

74.S. Takeda, A. Nakao, K. Miyoshi & H. Takagi: Gene therapy for pancreatic cancer. Semin Surg Oncol 15, 57-61 (1998)

75.T.M. McCarty, X. Liu, J. Sun, E.A. Preatta, D.J. Diamond & J.D.I. Ellenhorn: Targeting p53 for adoptive T-cell immunotherapy. Cancer Res 58, 2601-2605 (1998)