Advertisement

Pankreaskarzinom

  • Stephan A. Hahn
  • Wolff Schmiegel
Part of the Molekulare Medizin book series (MOLMED)

Zusammenfassung

Das Pankreaskarzinom, das 1936 durch Mondier zum 1. Mal beschrieben wurde, steht in Deutschland sowohl bei der Frau als auch beim Mann in der Sterbestatistik an 6. Stelle. 1997 starben in Deutschland 11319 Personen an dieser Erkrankung (Statistisches Bundesamt 1999). Trotz intensivster Anstrengungen überleben das 1. Jahr nach der Diagnosestellung auch heute nur < 20% der Patienten und die 5-J ahres-überlebensrate beträgt < 5%, weshalb sich für diese Tumorart die Mortalitätszahlen praktisch nicht von den Inzidenzwerten abheben. Darüber hinaus nimmt die Inzidenz dieses Tumors in Deutschland kontinuierlich zu, eine Tendenz, die sich auch in vielen anderen Ländern findet. Inwieweit diese Zunahme auf eine verbesserte und intensivierte Diagnostik zurückzuführen ist, kann nur schwer geklärt werden.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

Literatur

  1. Attisano L, Wrana JL (2000) Smads as transcriptional comodulators. Curr Opin Cell Biol 12:235–243PubMedGoogle Scholar
  2. Bansal P, Sonnenberg A (1995) Pancreatitis is a risk factor for pancreatic cancer. Gastroenterology 109:247–251PubMedGoogle Scholar
  3. Bartsch D, Skevlin DW, Tung WS, Visker O, Wills SA, Goodfellow PJ (1995) Frequent mutations of CDKN2 in primary pancreatic carcinomas. Genes Chromosomes Cancer 14:189–195PubMedGoogle Scholar
  4. Berman DB, Costalas J, Schultz DC, Grana G, Daly M, Godwin AK (1996) A common mutation in BRCA2 that predisposes to a variety of cancers is found in both Jewish Ashkenazi and non-Jewish individuals. Cancer Res 56:3409–3414PubMedGoogle Scholar
  5. Berthelemy P, Bouisson M, Escourrou J, Vaysse N, Rumeau JL, Pradayrol L (1995) Identification of K-ras mutations in pancreatic juice in the early diagnosis of pancreatic cancer. Ann Intern Med 123:188–191PubMedGoogle Scholar
  6. Bishop JM (1987) The molecular genetics of cancer. Science 235:305–311PubMedGoogle Scholar
  7. Boschman CR, Stryker S, Reddy J, Rao MS (1994) Expression of p53 protein in precursor lesions and adenocarcinoma of human pancreas. Am J PathoL 145:1291–1295PubMedCentralPubMedGoogle Scholar
  8. Brennan JA, Mao L, Hruban RH et al. (1995) Molecular assessment of histopathological staging in squamous-cell carcinoma of the head and neck. N Engl J Med 332:429–435PubMedGoogle Scholar
  9. Brentnall TA, Chen R, Lee JG et al. (1995) Microsatellite instability and K-ras mutations associated with pancreatic adenocarcinoma and pancreatitis. Cancer Res 55:4264–4267PubMedGoogle Scholar
  10. Caca K, Kolligs FT, Ji X et al. (1999) Beta-and gamma-catenin mutations, but not E-cadherin inactivation, underlie T-cell factor/lymphoid enhancer factor transcriptional deregulation in gastric and pancreatic cancer. Cell Growth Differ 10:369–376PubMedGoogle Scholar
  11. Caldas C, Hahn SA, Hruban RH, Redston MS, Yeo CJ, Kern SE (1994a) Detection of K-ras mutations in the stool of patients with pancreatic adenocarcinoma and pancreatic ductal hyperplasia. Cancer Res 54:3568–3573PubMedGoogle Scholar
  12. Caldas C, Hahn SA, Costa da LT et al. (1994b) Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet 8:27–32PubMedGoogle Scholar
  13. Calle EE, Murphy TK, Rodriguez C, Thun MI, Heath CJ (1998) Diabetes mellitus and pancreatic cancer mortality in a prospective cohort of United States adults. Cancer Causes Control 9:403–410PubMedGoogle Scholar
  14. Cheng JQ, Ruggeri B, Klein WM et al. (1996) Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci USA 93:3636–3641PubMedCentralPubMedGoogle Scholar
  15. Couch FI, Farid LM, DeShano ML et al. (1996) BRCA2 germline mutations in male breast cancer cases and breast cancer families. Nat Genet 13:123–125PubMedGoogle Scholar
  16. Cubilla AL, Fitzgerald PJ (1976) Morphologicallesions associated with human primary invasive carcinoma nonendocrine pancreas cancer. Cancer Res 36:2690–2698PubMedGoogle Scholar
  17. Dai JL, Turnacioglu KK, Schutte M, Sugar AY, Kern SE (1998) Dpc4 transcriptional activation and dysfunction in cancer cells. Cancer Res 58:4592–4597PubMedGoogle Scholar
  18. Derynck R, Zhang Y, Feng X-H (1998) Smads: transcriptional activators of TGF-ß responses. Cell 95:737–740PubMedGoogle Scholar
  19. DiGuiseppe JA, Hruban RH, Offerhaus GJ et al. (1994a) Detection of K-ras mutation in mucinous pancreatic duct hyperplasia from a patient with a family history of pancreatic carcinoma. Am J Pathol 144:889–895Google Scholar
  20. DiGiuseppe JA, Hruban RH, Goodman SN et al. (1994b) Overexpression of p53 protein in adenocarcinoma of the pancreas. Am J Clin Pathol 101:684–688PubMedGoogle Scholar
  21. Doll R, Peto R (1976) Mortality in relation to smoking: 20 years’ observation on male British doctors. BMJ 2:1525–1536PubMedCentralPubMedGoogle Scholar
  22. El-Deiry WS, Tokino T, Velculescu VE et al. (1993) WAF1, a potential mediator of p53 tumor suppression. Cell 75:817–825PubMedGoogle Scholar
  23. El-Deiry WS, Harper JW, O’Connor PM et al. (1994) WAF1/CIP1 is induced in p53-mediated GI arrest and apoptosis. Cancer Res 54:1169–1174PubMedGoogle Scholar
  24. Eppert K, Scherer SW, Ozcelik H et al. (1996) MADR2 maps to 18q21 and encodes a TGF-ß-regulated MAD-related protein that is functionally mutated in colorectal carcinoma. Cell 86:543–552PubMedGoogle Scholar
  25. Everhart J, Wright D (1995) Diabetes mellitus as a risk factor for pancreatic cancer. JAMA 273:1605–1609PubMedGoogle Scholar
  26. Feig LA (1993) Strategies for suppressing the function of oncogenic Ras protein in tumors. J Natl Cancer Inst 85:1266–1268PubMedGoogle Scholar
  27. Ferbus D, Flechon A, Muleris M et al. (1999) Amplification and over-expression of OZF, a gene encoding a zinc finger protein, in human pancreatic carcinomas. Int J Cancer 80:369–372PubMedGoogle Scholar
  28. Friedl W, Kruse R, Uhlhaas S et al. (1999) Frequent 4-bp deletion in exon 9 of the SMAD4/MADH4 gene in familial juvenile polyposis patients. Genes Chromosomes Cancer 25:403–406PubMedGoogle Scholar
  29. Fukushige S, Furukawa T, Satoh K et al. (1998) Loss of chromosome 18q is an early event in pancreatic ductal tumorigenesis. Cancer Res 58:4222–4226PubMedGoogle Scholar
  30. Furuya N, Kawa S, Akamatsu T, Furihata K (1997) Longterm follow-up of patients with chronic pancreatitis and K-ras gene mutation detected in pancreatic juice. Gastroenterology 113:593–598PubMedGoogle Scholar
  31. Gapstur SM, Gann PH, Lowe W, Liu K, Colangelo L, Dyer A (2000) Abnormal glucose metabolism and pancreatic cancer mortality. JAMA 283:2552–2558PubMedGoogle Scholar
  32. Giardiello FM, Welsh SB, Hamilton SR et al. (1987) Increased risk of cancer in the Peutz-Jeghers syndrome. N Engl J Med 316:1511–1414PubMedGoogle Scholar
  33. Giardiello FM, Brensinger JD, Tersmette AC et al. (2000) Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology 119:1447–1453PubMedGoogle Scholar
  34. Goggins M, Schutte M, Lu J et al. (1996) Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res 56:5360–5364PubMedGoogle Scholar
  35. Goggins M, Offerhaus GJ, Hilgers W. et al. (1998a) Pancreatic adenocarcinomas with DNA replication errors (RER +) are associated with wild-type K-ras and characteristic histopathology. Poor differentiation, a syncytial growth pattern, and pushing borders suggest RER+. Am J Pathol 152:1501–1507PubMedCentralPubMedGoogle Scholar
  36. Goggins M, Shekher M, Turnacioglu K, Yeo CJ, Hruban RH, Kern SE (1998b) Genetic alterations of the transforming growth factor beta receptor genes in pancreatic and biliary adenocarcinomas. Cancer Res 58:5329–5332PubMedGoogle Scholar
  37. Goldstein AM, Fraser MC, Struewing JP et al. (1995) Increased risk of pancreatic cancer in melanoma-prone kindreds with p16 INK4 mutations. N Engl J Med 333:970–974PubMedGoogle Scholar
  38. Gruis NA, Sandkuijl LA, van der Velden PA et al. (1995) CDKN2 explains part of the clinical phenotype in Dutch familial atypical multiple-mole melanoma (FAMMM) syndrome families. Melanoma Res 5:169–177PubMedGoogle Scholar
  39. Grünewald K, Lyons J, Fröhlich A et al. (1989) High frequency of Ki-ras codon 12 mutations in pancreatic adenocarcinomas. Int J Cancer 43:1037–1041PubMedGoogle Scholar
  40. Gullo L (1999) Diabetes and the risk of pancreatic cancer. Ann Oncol [Suppl] 10:79–81PubMedGoogle Scholar
  41. Hahn SA, Seymour AB, Hoque ATMS et al. (1995) Allelotype of pancreatic adenocarcinoma using xenograft enrichment. Cancer Res 55:4670–4675PubMedGoogle Scholar
  42. Hahn SA, Hoque ATM, Moskaluk CA et al. (1996a) Homozygous deletion map at 18q21.1 in pancreatic cancer. Cancer Res 56:490–494PubMedGoogle Scholar
  43. Hahn SA, Schutte M, Hoque ATM et al. (1996b) DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science 271:350–353PubMedGoogle Scholar
  44. Hahn SA, Bartsch D, Schroers A et al. (1998) Mutations of the DPC4/Smad4 gene in biliary tract carcinoma. Cancer Res 58:1124–1126PubMedGoogle Scholar
  45. Hara M, Akasaka K, Akinaga S et al. (1993) Identification of Ras farnesyltransferase inhibitors by microbial screening. Proc Natl Acad Sci USA 90:2281–2285PubMedCentralPubMedGoogle Scholar
  46. Harper JW, Adami GR, Wei N, Keyomarsi K, Elledge SJ (1993) The p21 cdk-interacting protein Cipl is a potent inhibitor of GI cyclin-dependent kinases. Cell 75:805–816PubMedGoogle Scholar
  47. Harris CC, Hollstein M (1993) Clinical implications of the p53 tumor-suppressor gene. N Engl J Med 329:1318–1327PubMedGoogle Scholar
  48. Hayashi N, Ito I, Yanagisawa A et al. (1995) Genetic diagnosis of lymph-node metastasis in colorectal cancer. Lancet 345:1257–1259PubMedGoogle Scholar
  49. Heinmöller E, Dietmaier W, Zirngibl H et al. (2000) Molecular analysis of microdissected tumors and preneoplastic intraductal lesions in pancreatic carcinoma. Am J Pathol 157:83–92PubMedCentralPubMedGoogle Scholar
  50. Heldin C-H, Miyazono K, Dijke P ten (1997) TGF-ß signalling from cell membrane to nucleus through SMAD proteins. Nature 390:465–471PubMedGoogle Scholar
  51. Hemminki A, Markie D, Tomlinson I et al. (1998) A serine/threonine kinase gene defective in Peutz-Jeghers syndrome. Nature 391:184–187PubMedGoogle Scholar
  52. Hiyama E, Kodama T, Shinbara K et al. (1997) Telomerase activity is detected in pancreatic cancer but not in benign tumors. Cancer Res 57:326–331PubMedGoogle Scholar
  53. Hollstein M, Sidransky D, Vogelstein B, Harris CC (1991) p53 mutations in human cancers. Science 253:49–53PubMedGoogle Scholar
  54. Howe GR, Jain M, Burch JD et al. (1991) Cigarette smoking and cancer of the pancreas: evidence from a population-based control study in Toronto, Canada. Int J Cancer 47:323–328PubMedGoogle Scholar
  55. Howe JR, Roth S, Ringold JC et al. (1998) Mutations in the smad4/dpc4 gene in juvenile polyposis. Science 280: 1086–1088PubMedGoogle Scholar
  56. Hruban RH, Mansfeld ADM. van, Offerhaus GJ et al. (1993) K-ras oncogene activation in adenocarcinoma of the human pancreas. A study of 82 carcinomas using a combination of mutant-enriched polymerase chain reaction analysis and allele-specific oligonucleotide hybridization. Am J Pathol 143:545–554PubMedCentralPubMedGoogle Scholar
  57. Hruban RH, Adsay NV, Albores-Saavedra J et al. (2001) Pancreatic intraepithelial neoplasia (PanIN): a new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol, in pressGoogle Scholar
  58. Huang L, Goodrow TL, Zhang S-Y, Klein-Szanto AJP, Chang H, Ruggeri BA (1996) Deletion and mutation analyses of the P16/MTS-1 tumor suppressor gene in human ductal pancreatic cancer reveals a higher frequency of abnormalities in tumor-derived cell lines than in primary ductal adenocarcinoma. Cancer Res 56:1137–1141PubMedGoogle Scholar
  59. Huntsman DG, Chin SF, Muleris M et al. (1999) MLL2, the second human homolog of the Drosophila tri thorax gene, maps to 19q13.1 and is amplified in solid tumor cell lines. Oncogene 18:7975–7984PubMedGoogle Scholar
  60. James GL, Goldstein JL, Brown MS et al. (1993) Benzodiazepine peptidomimetics: potent inhibitors of Ras farnesylation in animal cells. Science 260:1937–1942PubMedGoogle Scholar
  61. Jenne DE, Reimann H, Nezu J et al. (1998) Peutz-Jeghers syndrome is caused by mutations in a novel serine threonine kinase. Nat Genet 18:38–43PubMedGoogle Scholar
  62. Johnson K, Kirkpatrick H, Corner A, Hoffmann FM, Laughon A (1999) Interaction of Smad complexes with tri-partite DNA-binding sites. J Biol Chem 274:20709–20716PubMedGoogle Scholar
  63. Jones JB, Kern SE (2000) Functional mapping of the MHI DNA-binding domain of DPC4/SMAD4. Nucleic Acids Res 28:2363–2368PubMedCentralPubMedGoogle Scholar
  64. Kahn SM, Jiang W, Culbertson TA et al. (1991) Rapid and sensitive nonradioactive detection of mutant K-ras genes via’ enriched’ PCR amplification. Oncogene 6:1079–1083PubMedGoogle Scholar
  65. Kalthoff H, Schmiegel W, Roeder C et al. (1993) p53 and K-RAS alterations in pancreatic epithelial cell lesions. Oncogene8:289–298PubMedGoogle Scholar
  66. Karlson B-M, Ekbom A, Josefsson S, McLaughlin JK, Fraumeni JF, Nyren O (1997) The risk of pancreatic cancer following pancreatitis: an association due to confounding? Gastroenterology 113:587–592PubMedGoogle Scholar
  67. Kastan MB, Onyekwere O, Sidransky D, Vogelstein B, Craig RW (1991) Participation of p53 protein in the cellular response to DNA damage. Cancer Res 51:6304–6311PubMedGoogle Scholar
  68. Kim NW, Piatyszek MA, Prowse KR et al. (1994) Specific association of human telomerase activity with immortal cells and cancer. Science 266:2011–2015PubMedGoogle Scholar
  69. Kim SK, Fan Y, Papadimitrakopoulou V et al. (1996) DPC4, a candidate tumor suppressor gene, is altered infrequently in head and neck squamous cell carcinoma. Cancer Res 56:2519–2521PubMedGoogle Scholar
  70. Kingsley DM (1994) The TGF-ß superfamily: new members, new receptors, and new genetic tests of function in different organisms. Genes Dev 8:133–146PubMedGoogle Scholar
  71. Klöppel G, Solcia E, Longnecker DS, Capella C, Sobin LH (1996) World Health Organization international histological classification of tumors, 2nd edn. Springer, Berlin Heidelberg New YorkGoogle Scholar
  72. Knudson JAG (1985) Hereditary cancer, oncogenes, and antioncogenes. Cancer Res 45:1437–1443PubMedGoogle Scholar
  73. Kohl NE, Mosser SD, de Solms SJ et al. (1993) Selective inhibition of ras-dependent transformation by a farnesyltransferase inhibitor. Science 260:1934–1937PubMedGoogle Scholar
  74. Kondo H, Sugano K, Fukayama N et al. (1994) Detection of point mutations in the K-ras oncogene at codon 12 in pure pancreatic juice for diagnosis of pancreatic carcinoma. Cancer 73:1589–1594PubMedGoogle Scholar
  75. Kozuka S, Sassa R, Takai T et al. (1979) Relation of pancreatic duct hyperplasia to carcinoma. Cancer 43:1418–1428PubMedGoogle Scholar
  76. Lagna G, Hata A, Hemmati BA, Massague J (1996) Partnership between DPC4 and SMAD proteins in TGF-ß signalling pathways. Nature 383:832–836PubMedGoogle Scholar
  77. Lindemann F, Schlimok G, Dirschedl P, Witte J, Riethmüller G (1992) Prognostic significance of micrometastatic tumour cells in bone marrow of colorectal cancer patients. Lancet 340:685–689PubMedGoogle Scholar
  78. Longnecker DS (1994) The quest for preneoplastic lesions in the pancreas. Arch Pathol Lab Med 118:226PubMedGoogle Scholar
  79. Lowenfels AB, Maisonneuve P, Cavallini G et al. (1993) Pancreatitis and the risk of pancreatic cancer. N Engl J Med 328:1433–1437PubMedGoogle Scholar
  80. Lowenfels AB, Maisonneuve P, DiMagno EP et al. (1997) Hereditary pancreatitis and the risk of pancreatic cancer. International Hereditary Pancreatitis Study Group. J Natl Cancer Inst 89:442–446Google Scholar
  81. Lüttges J, Möllmann B, Menke MAOH et al. (1999) Duct changes and K-ras mutations in the disease-free pancreas: analysis of type, age relation and spatial distribution. Virchows Arch 435:461–468PubMedGoogle Scholar
  82. Lüttges J, Diederichs A, Menke MAOH, Vogel I, Kremer B, Klöppel G (2000) Ductal lesions in patients with chronic pancreatitis show K-ras mutations in a frequency similar to that in the normal pancreas and lack nudear immunoreactivity for p53. Cancer 88:2495–2504PubMedGoogle Scholar
  83. Lüttges J, Galehdari H, Bröcker V et al. (2001) Allelic loss is often the first hit in the biallelic inactivation of the p53 and DPC4 genes during pancreatic careinogenesis. Am J Pathol in pressGoogle Scholar
  84. Lynch HT, Fusaro RM (1991) Pancreatic cancer and the familial atypical multiple mole melanoma (FAMMM) syndrome. Pancreas 6:127–131PubMedGoogle Scholar
  85. Massague J (1992) Receptors for the TGF-ß family. Cell 69: 1069–1070Google Scholar
  86. McKie AB, Filipe MI, Lemoine NR (1993) Abnormalities affecting the APC and MCC tumour suppressor gene loci on chromosome 5q occur frequently in gastric cancer but not in pancreatic cancer. Int J Cancer 55:598–603PubMedGoogle Scholar
  87. Miyaki M, Iijima T, Konishi M et al. (1999) Higher frequency of Smad4 gene mutation in human colorectal cancer with distant metastasis. Oncogene 18:3098–3103PubMedGoogle Scholar
  88. Mizumoto K, Suehara N, Muta T et al. (1996) Semi-quantitative analysis of telomerase in pancreatic ductal adenocarcinoma. J Gastroenterol 31:894–897PubMedGoogle Scholar
  89. Morin PJ, Sparks AB, Korinek V et al. (1997) Activation of beta-catenin-Tcf signaling in colon cancer by mutations in beta-catenin or APC. Science 275:1787–1790PubMedGoogle Scholar
  90. Moskaluk CA, Hruban RH, Lietman A et al. (1997a) Novel germline p16(INK4) allele (Asp145Cys) in a family with multiple pancreatic carcinomas. Hum Mutat 12:70–77Google Scholar
  91. Moskaluk CA, Hruban RH, Kern SE (1997b) p16 and K-ras mutations in the intraductal precursors of human pancreaticadenocarcinoma. Cancer Res 57:2140–2143PubMedGoogle Scholar
  92. Nagasu T, Yoshimatsu K, Rowell C, Lewis MD, Garcia AM (1995) Inhibition of human tumor xenograft growth by treatment with the farnesyl transferase inhibitor B956. Cancer Res 55:5310–5314PubMedGoogle Scholar
  93. Nagatake M, Takagi Y, Osada H et al. (1996) Somatic in vivo alterations of the DPC4 gene at 18q21 in human lung cancers. Cancer Res 56:2718–2720PubMedGoogle Scholar
  94. Naumann M, Savitkaia N, Eilert C, Schramm A, Kalthoff H, Schmiegel W (1996) Frequent codeletions of p16/MTS1 and p1S/TS2 and genetic alterations in p16/MTS1 in pancreatic tumors. Gastroenterology 110:1215–1224PubMedGoogle Scholar
  95. Pantel K, Izbicki J, Passlick B et al. (1996) Frequency and prognostic significance of isolated tumor cells in bone marrow of patients with non-small lung cancer without overt metastasis. Lancet 347:649–653PubMedGoogle Scholar
  96. Pellegata NS, Sessa F, Renault B et al. (1994) K-ras and pS3 gene mutations in pancreatic cancer: ductal and nonductal tumors progress through different genetic lesions. Cancer Res 54:1556–1560PubMedGoogle Scholar
  97. Peters M, Herskowitz I (1994) Joining the complex: cydindependent kinase inhibitory proteins and the cell cycle. Cell 79:181–184Google Scholar
  98. Phelan CM, Lancaster JM, Tonin P et al. (1996) Mutation analysis of the BRCA2 gene in 49 site-specific breast cancer families. Nat Genet 13:120–122PubMedGoogle Scholar
  99. Polyak K, Lee M-H, Erdjument-Bromage H et al. (1994) Cloning of p27Kip1 a cydin-dependent kinase inhibitor and a potential mediator of extracellular antimitogenic signals. Cell 78:59–66PubMedGoogle Scholar
  100. Raftery LA, Twombly V, Wharton K, Gelbart WM (1996) Genetic screens to identify elements of the decapentaplegic signaling pathway in drosophila. Genetics 139:241–254Google Scholar
  101. Redston MS, Caldas C, Seymour AB et al. (1994) p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res 54:3025–3033PubMedGoogle Scholar
  102. Riggins GJ, Kinzier KW, Vogelstein B, Thiagalingam S (1997) Frequency of Smad gene mutations in human cancer. Cancer Res 57:2578–2580PubMedGoogle Scholar
  103. Roder JD, Thorban S, Pantel K, Siewert JR (1999) Micrometastases in bone marrow: prognostic indicators for pancreatic cancer. World J Surg 23:888–891PubMedGoogle Scholar
  104. Rozenblum E, Schutte M, Goggins M et al. (1997) Tumorsuppressive pathways in pancreatic carcinoma. Cancer Res 57:1731–1734PubMedGoogle Scholar
  105. Ruggeri BA, Huang L, Wood M, Cheng JQ, Testa JR (1998) Amplification and overexpression of the AKT2 oncogene in a subset of human pancreatic ductal adenocarcinomas. Mol Carcinog 21:81–86PubMedGoogle Scholar
  106. Rustgi AK (1996) MAD about colorectal cancer. Gastroenterology 111:1387–1389PubMedGoogle Scholar
  107. Savage C, Das P, Finelli AL, Townsend SR, Sun C.Y., Baird SE (1996) Caenorhabditis elegans genes sma-2, sma-3, and sma-4 define a conserved family of transforming growth factor ß pathway components. Proc Natl Acad Sci USA 93:790–794PubMedCentralPubMedGoogle Scholar
  108. Schutte M, Hruban RH, Hedrick L et al. (1996) DPC4 gene in various tumor types. Cancer Res 56:2527–2530PubMedGoogle Scholar
  109. Schutte M, Hruban RH, Geradts J et al. (1997) Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res 57:3126–3130PubMedGoogle Scholar
  110. Schwarte-Waldhoff I, Klein S, Blass-Kampmann S et al. (1999) DPC4/SMA4 mediated tumor suppression of colorectal carcinoma is associated with reduced urokinase expression. Oncogene 18:3152–3158PubMedGoogle Scholar
  111. Schwarte-Waldhoff I, Volpert OV, Bouck NP et al. (2000) Smad4/DPC4-mediated tumor suppression through suppression of angiogenesis. Proc Natl Acad Sci USA 97: 9624–9629PubMedCentralPubMedGoogle Scholar
  112. Sekelsky JJ, Newfeld SJ, Raftery LA, Chartoff EH, Gelbart WM (1995) Genetic characterization and cloning of Mothers against dpp, a gene required for decapentaplegic function in Drosophila melanogaster. Genetics 139:1347–1358PubMedCentralPubMedGoogle Scholar
  113. Sepp-Lorenzino L, Ma Z, Rands E et al. (1995) A peptidomimetic inhibitor of farnesyl: protein transferase blocks the anchorage-dependent and independent growth of human tumor cell lines. Cancer Res 55:5302–5309PubMedGoogle Scholar
  114. Serrano M, Hannon GJ, Beach D (1993) A new regulatory motif in cell-cycle control causing specific inhibition of cydin D/CDK4. Nature 366:704–707PubMedGoogle Scholar
  115. Seymour AB, Hruban RH, Redston M et al. (1994) Allelo-type of pancreatic adenocarcinoma. Cancer Res 54:2761–2764PubMedGoogle Scholar
  116. Sherr CJ (1993) Mammalian G1 cyclins. Cell 73:1059–1065PubMedGoogle Scholar
  117. Shi Y, Wang Y.F., Jayaraman L, Yang H, Massague J, Pavletich NP (1998) Crystal structure of a Smad MH1 domain bound to DNA: insights on DNA binding in TGF-beta signaling. Cell 94:585–594PubMedGoogle Scholar
  118. Sidransky D, Tokino T, Hamilton SR et al. (1992) Identification of ras oncogene mutations in the stool of patients with curable colorectal tumors. Science 256:102–105PubMedGoogle Scholar
  119. Silvermann DT, Dunn JA, Hoover RN et al. (1994) Cigarette smoking and pancreas cancer: a case-control study based on direct interviews. J Natl Cancer Inst 86:1510–1516Google Scholar
  120. Solinas TS, Wallrapp C, Muller PF, Bentz M, Gress T, Lichter P (1996) Mapping of chromosomal imbalances in pancreatic carcinoma by comparative genomic hybridization. Cancer Res 56:3803–3807Google Scholar
  121. Sparks AB, Morin PJ, Vogelstein B, Kinzier KW (1998) Mutational analysis of the APC/beta-catenin/Tcf pathway in colorectal cancer. Cancer Res 58: 1130–1134PubMedGoogle Scholar
  122. Statistisches Bundesamt (1999) Gesundheitswesen. In: Statistisches Bundesamt(Hrsg) Statistisches Jahrbuch 1999. Metzler-Poeschel, Stuttgart, S 424–425Google Scholar
  123. Stein GH, Beeson M, Gordon L (1990) Failure to phosphorylate the retinoblastoma gene product in senescent human fibroblasts. Science 249:666–669PubMedGoogle Scholar
  124. Strumberg D, Wilke H, Illiger HJ, Klempnauer J (1999) Karzinom des exokrinen Pankreas. In: Schmoll HJ, Höffken K, Possinger K (Hrsg) Kompendium internistischer Onkologie, 3. Aufl. Springer, Berlin Heidelberg New York, S 1111Google Scholar
  125. Su GH, Hilgers W, Shekher MC, Tang DJ, Yeo CJ, Hruban RH, Kern SE (1998) Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene. Cancer Res 58:2339–2342PubMedGoogle Scholar
  126. Su GH, Hruban RH, Bansal RK et al. (1999) Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers. Am J Pathol 154:1835–1840PubMedCentralPubMedGoogle Scholar
  127. Suehara N, Mizumoto K, Tanaka M et al. (1997) Telomerase activity in pancreatic juice differentiates ductal carcinoma from adenoma and pancreatitis. Clin Cancer Res: 2479–2483Google Scholar
  128. Suehara N, Mizumoto K, Kusumoto M et al. (1998) Telomerase activity detected in pancreatic juice 19 months before a tumor is detected in a patient with pancreatic cancer. Am J Gastroenterol 93:1967–1971PubMedGoogle Scholar
  129. Sugio K, Molberg K, Albores SJ, Virmani AK, Kishimoto Y, Gazdar AF (1997) K-ras mutations and allelic loss at 5q and 18q in the development of human pancreatic cancers. Int J Pancreatol21:205–217PubMedGoogle Scholar
  130. Suzuki H, Yoshida S, Ichikawa Y et al. (1994) K-ras mutations in pancreatic secretions and aspirates from two patients without pancreatic cancer. J Natl Cancer Inst 86:1547–1549PubMedGoogle Scholar
  131. Tada M, Omata M, Kawai S et al. (1993) Detection of ras gene mutations in pancreatic juice and peripheral blood of patients with pancreatic adenocarcinoma. Cancer Res 53:2472–2474PubMedGoogle Scholar
  132. Tada M, Ohashi M, Shiratori Y et al. (1996) Analysis of K-ras gene mutation in hyperplastic duct cells of the pancreas without pancreatic disease. Gastroenterology 110:227–231PubMedGoogle Scholar
  133. Takagi Y, Kohmura H, Futamura M et al. (1996) Somatic alterations of the DPC4 gene in human colorectal cancers in vivo. Gastroenterology 111:1369–1372PubMedGoogle Scholar
  134. Takaku K, Oshima M, Miyoshi H, Matsui M, Seldin MF, Taketo MM (1998) Intestinal tumorigenesis in compound mutant mice of both Dpc4 (Smad4) and Apc genes. Cell 92:645–656PubMedGoogle Scholar
  135. Thiagalingam S, Lengauer C, Leach FS et al. (1996) Evaluation of candidate tumor suppressor genes on chromosome 18 in colorectal cancers. Nat Genet 13:342–346Google Scholar
  136. Thorlaeius S, Olafsdottir G, Tryggvadottir L et al. (1996) A single BRCA2 mutation in male and female breast cancer families from Iceland with varied cancer phenotypes. Nat Genet 13:117–119Google Scholar
  137. Toyoshima H, Hunter T (1994) p27, a novel inhibitor of G1 cyclin-Cdk protein kinase activity, is related to p21. Cell 78:67–74PubMedGoogle Scholar
  138. Tulinius H, Olafsdottir GH, Sigvaldason H, Tryggvadottir L, Bjarnadottir K (1994) Neoplastic diseases in families of breast cancer patients. J Med Genet 31:618–621PubMedCentralPubMedGoogle Scholar
  139. Uehara H, Nakaizumi A, Tatsuta M et al. (1999) Diagnosis of pancreatic cancer by detecting telomerase activity in pancreatic juice: comparison with K-ras mutations. Am J Gastroenterol 94:2513–2518PubMedGoogle Scholar
  140. Wallrapp C, Muller PF, Solinas TS et al. (1997) Characterization of a high copy number amplification at 6q24 in pancreatic cancer identifies c-myb as a candidate oncogene. Cancer Res 57:3135–3139PubMedGoogle Scholar
  141. Warshaw AL, Castillo del CF (1992) Pancreatic carcinoma. N Engl J Med 326:455–465PubMedGoogle Scholar
  142. Watanabe H, Sawabu N, Ohta H et al. (1993) Identification of K-ras oncogene mutations in the pure pancreatic juice of patients with ductal pancreatic cancers. Jpn J Cancer Res 84:961–965PubMedGoogle Scholar
  143. Weinberg RA (1989) Oncogenes, antioncogenes, and the molecular basis of multistep carcinogenesis. Cancer Res 49:3713–3721PubMedGoogle Scholar
  144. Whelan AJ, Bartsch D, Goodfellow PJ (1995) A familial syndrome of pancreatic carcinoma and melanoma with a mutation in the CDKN2 tumor suppressor gene. N Engl J Med 333:975–977PubMedGoogle Scholar
  145. Whitcomb DC, Gorry MC, Preston RA et al. (1996) Hereditary pancreatitis is caused by a mutation in the cationic trypsinogen gene. Nat Genet 14:141–145PubMedGoogle Scholar
  146. Wilentz RE, Hruban RH (1998) Pathology of cancer of the pancreas. Surg Oncol Clin N Am 7:43–65PubMedGoogle Scholar
  147. Wilentz RE, Geradts J, Maynard R et al. (1998) Inactivation of the p16 (INK4A) tumor-suppressor gene in pancreatic duct lesions: loss of intranuclear expression. Cancer Res 58:4740–4744PubMedGoogle Scholar
  148. Wilentz RE, Goggins M, Redston M et al. (2000a) Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: a newly described and characterized entity. Am J Pathol 156:1641–1651PubMedCentralPubMedGoogle Scholar
  149. Wilentz RE, Iacobuzio DC, Argani P et al. (2000b) Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res 60:2002–2006PubMedGoogle Scholar
  150. Xiong Y, Hannon GJ, Zhang H, Casso D, Kobayashi R, Beach D (1993) p21 is a universal inhibitor of cyclin kinases. Nature 366:701–704PubMedGoogle Scholar
  151. Yamano M, Fujii H, Takagaki T, Kadowaki N, Watanabe H, Shirai T (2000) Genetic progression and divergence in pancreatic carcinoma. Am J Pathol 156:2123–2133PubMedCentralPubMedGoogle Scholar
  152. Yanagisawa A, Ohtake K, Ohashi K et al. (1993) Frequent cKi-ras oncogene activation in mucous cell hyperplasias of pancreas suffering from chronic inflammation. Cancer Res 53:953–956PubMedGoogle Scholar
  153. Zawel L, Dai JL, Buckhaults P et al. (1998) Human Smad3 and Smad4 are sequence-specific transcription activators. Mol Cell 1:611–617PubMedGoogle Scholar
  154. Zhou S, Buckhaults P, Zawel L et al. (1998) Targeted deletion of Smad4 shows it is required for transforming growth factor beta and activin signaling in colorectal cancer cells. Proc Natl Acad Sci USA 95:2412–2416PubMedCentralPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2002

Authors and Affiliations

  • Stephan A. Hahn
  • Wolff Schmiegel

There are no affiliations available

Personalised recommendations