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Molecular Cancer
Published in: Molecular Cancer 1/2003

Open Access 01-12-2003 | Review

Genetic abnormalities in pancreatic cancer

Authors: Patrick S Moore, Stefania Beghelli, Giuseppe Zamboni, Aldo Scarpa

Published in: Molecular Cancer | Issue 1/2003

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Abstract

The incidence and mortality of pancreatic adenocarcinoma are nearly coincident having a five-year survival of less than 5%. Enormous advances have been made in our knowledge of the molecular alterations commonly present in ductal cancer and other pancreatic malignancies. One significant outcome of these studies is the recognition that common ductal cancers have a distinct molecular fingerprint compared to other nonductal or endocrine tumors. Ductal carcinomas typically show alteration of K-ras, p53, p16INK 4, DPC4 and FHIT, while other pancreatic tumor types show different aberrations. Among those tumors arising from the exocrine pancreas, only ampullary cancers have a molecular fingerprint that may involve some of the same genes most frequently altered in common ductal cancers. Significant molecular heterogeneity also exists among pancreatic endocrine tumors. Nonfunctioning pancreatic endocrine tumors have frequent mutations in MEN-1 and may be further subdivided into two clinically relevant subgroups based on the amount of chromosomal alterations. The present review will provide a brief overview of the genetic alterations that have been identified in the various subgroups of pancreatic tumors. These results have important implications for the development of genetic screening tests, early diagnosis, and prognostic genetic markers.
Literature
1.
Rozenblum E, Schutte M, Goggins M, Hahn SA, Panzer S, Zahurak M, Goodman SN, Sohn TA, Hruban RH, Yeo CJ: Tumor-suppressive pathways in pancreatic carcinoma. Cancer Res. 1997, 57: 1731-4.PubMed
2.
Moore PS, Orlandini S, Zamboni G, Capelli P, Rigaud G, Falconi M, Bassi C, Lemoine NR, Scarpa A: Pancreatic tumours: molecular pathways implicated in ductal cancer are involved in ampullary but not in exocrine nonductal or endocrine tumorigenesis. Br J Cancer. 2001, 84: 253-62. 10.1054/bjoc.2000.1567.PubMedCentralCrossRefPubMed
3.
Sorio C, Baron A, Orlandini S, Zamboni G, Pederzoli P, Huebner K, Scarpa A: The FHIT gene is expressed in pancreatic ductular cells and is altered in pancreatic cancers. Cancer Res. 1999, 59: 1308-1314.PubMed
4.
Hiyama E, Kodama T, Shinbara K, Iwao T, Itoh M, Hiyama K, Shay JW, Matsuura Y, Yokoyama T: Telomerase activity is detected in pancreatic cancer but not in benign tumors. Cancer Res. 1997, 57: 326-31.PubMed
5.
Villanueva A, Garcia C, Paules AB, Vicente M, Megias M, Reyes G, de Villalonga P, Agell N, Lluis F, Bachs O: Disruption of the antiproliferative TGF-beta signaling pathways in human pancreatic cancer cells. Oncogene. 1998, 17: 1969-78. 10.1038/sj.onc.1202118.CrossRefPubMed
6.
Su GH, Hilgers W, Shekher MC, Tang DJ, Yeo CJ, Hruban RH, Kern SE: Alterations in pancreatic, biliary, and breast carcinomas support MKK4 as a genetically targeted tumor suppressor gene. Cancer Res. 1998, 58: 2339-42.PubMed
7.
Goggins M, Shekher M, Turnacioglu K, Yeo CJ, Hruban RH, Kern SE: Genetic alterations of the transforming growth factor beta receptor genes in pancreatic and biliary adenocarcinomas. Cancer Res. 1998, 58: 5329-32.PubMed
8.
Su GH, Hruban RH, Bansal RK, Bova GS, Tang DJ, Shekher MC, Westerman AM, Entius MM, Goggins M, Yeo CJ: Germline and somatic mutations of the STK11/LKB1 Peutz-Jeghers gene in pancreatic and biliary cancers. Am J Pathol. 1999, 154: 1835-40.PubMedCentralCrossRefPubMed
9.
Goggins M, Hruban RH, Kern SE: BRCA2 is inactivated late in the development of pancreatic intraepithelial neoplasia: evidence and implications. Am J Pathol. 2000, 156: 1767-71.PubMedCentralCrossRefPubMed
10.
Yamamoto H, Itoh F, Nakamura H, Fukushima H, Sasaki S, Perucho M, Imai K: Genetic and clinical features of human pancreatic ductal adenocarcinomas with widespread microsatellite instability. Cancer Res. 2001, 61: 3139-44.PubMed
11.
Nakata B, Wang YQ, Yashiro M, Nishioka N, Tanaka H, Ohira M, Ishikawa T, Nishino H, Hirakawa K: Prognostic value of microsatellite instability in resectable pancreatic cancer. Clin Cancer Res. 2002, 8: 2536-40.PubMed
12.
Wilentz RE, Goggins M, Redston M, Marcus VA, Adsay NV, Sohn TA, Kadkol SS, Yeo CJ, Choti M, Zahurak M: Genetic, immunohistochemical, and clinical features of medullary carcinoma of the pancreas: A newly described and characterized entity. Am J Pathol. 2000, 156: 1641-51.PubMedCentralCrossRefPubMed
13.
Hruban RH, Adsay NV, Albores-Saavedra J, Compton C, Garrett ES, Goodman SN, Kern SE, Klimstra DS, Kloppel G, Longnecker DS: Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions. Am J Surg Pathol. 2001, 25: 579-86. 10.1097/00000478-200105000-00003.CrossRefPubMed
14.
Luttges J, Galehdari H, Brocker V, Schwarte-Waldhoff I, Henne-Bruns D, Kloppel G, Schmiegel W, Hahn SA: Allelic loss is often the first hit in the biallelic inactivation of the p53 and DPC4 genes during pancreatic carcinogenesis. Am J Pathol. 2001, 158: 1677-83.PubMedCentralCrossRefPubMed
15.
Klein WM, Hruban RH, Klein-Szanto AJ, Wilentz RE: Direct correlation between proliferative activity and dysplasia in pancreatic intraepithelial neoplasia (PanIN): additional evidence for a recently proposed model of progression. Mod Pathol. 2002, 15: 441-7.CrossRefPubMed
16.
van Heek NT, Meeker AK, Kern SE, Yeo CJ, Lillemoe KD, Cameron JL, Offerhaus GLA, Hicks JL, Wilentz RE, G MG: Telomere shortening is nearly universal in pancreatic intraepithelial neoplasia. Am J Pathol. 2002, 161: 1541-1547.PubMedCentralCrossRefPubMed
17.
Fukushima N, Sato N, Ueki T, Rosty C, Walter KM, Wilentz RE, Yeo CJ, Hruban RH, Goggins M: Aberrant methylation of preproenkephalin and p16 genes in pancreatic intraepithelial neoplasia and pancreatic ductal adenocarcinoma. Am J Pathol. 2002, 160: 1573-81.PubMedCentralCrossRefPubMed
18.
Sato N, Ueki T, Fukushima N, Iacobuzio-Donahue CA, Yeo CJ, Cameron JL, Hruban RH, Goggins M: Aberrant methylation of CpG islands in intraductal papillary mucinous neoplasms of the pancreas. Gastroenterology. 2002, 123: 365-72. 10.1053/gast.2002.34160.CrossRefPubMed
19.
Ueki T, Toyota M, Sohn T, Yeo CJ, Issa JP, Hruban RH, Goggins M: Hypermethylation of multiple genes in pancreatic adenocarcinoma. Cancer Res. 2000, 60: 1835-9.PubMed
20.
Ueki T, Toyota M, Skinner H, Walter KM, Yeo CJ, Issa JP, Hruban RH, Goggins M: Identification and characterization of differentially methylated CpG islands in pancreatic carcinoma. Cancer Res. 2001, 61: 8540-6.PubMed
21.
Gress TM, Muller-Pillasch F, Geng M, Zimmerhackl F, Zehetner G, Friess H, Buchler M, Adler G, Lehrach H: A pancreatic cancer-specific expression profile. Oncogene. 1996, 13: 1819-30.PubMed
22.
Michl P, Buchholz M, Rolke M, Kunsch S, Lohr M, McClane B, Tsukita S, Leder G, Adler G, Gress TM: Claudin-4: a new target for pancreatic cancer treatment using Clostridium perfringens enterotoxin. Gastroenterology. 2001, 121: 678-84.CrossRefPubMed
23.
Weber CK, Sommer G, Michl P, Fensterer H, Weimer M, Gansauge F, Leder G, Adler G, Gress TM: Biglycan is overexpressed in pancreatic cancer and induces G1-arrest in pancreatic cancer cell lines. Gastroenterology. 2001, 121: 657-67.CrossRefPubMed
24.
Wallrapp C, Hahnel S, Muller-Pillasch F, Burghardt B, Iwamura T, Ruthenburger M, Lerch MM, Adler G, Gress TM: A novel transmembrane serine protease (TMPRSS3) overexpressed in pancreatic cancer. Cancer Res. 2000, 60: 2602-6.PubMed
25.
Crnogorac-Jurcevic T, Efthimiou E, Capelli P, Blaveri E, Baron A, Terris B, Jones M, Tyson K, Bassi C, Scarpa A: Gene expression profiles of pancreatic cancer and stromal desmoplasia. Oncogene. 2001, 20: 7437-46. 10.1038/sj.onc.1204935.CrossRefPubMed
26.
Friess H, Ding J, Kleeff J, Liao Q, Berberat PO, Hammer J, Buchler MW: Identification of disease-specific genes in chronic pancreatitis using DNA array technology. Ann Surg. 2001, 234: 769-78. 10.1097/00000658-200112000-00008.PubMedCentralCrossRefPubMed
27.
Argani P, Rosty C, Reiter RE, Wilentz RE, Murugesan SR, Leach SD, Ryu B, Skinner HG, Goggins M, Jaffee EM: Discovery of new markers of cancer through serial analysis of gene expression: prostate stem cell antigen is overexpressed in pancreatic adenocarcinoma. Cancer Res. 2001, 61: 4320-4.PubMed
28.
Argani P, Iacobuzio-Donahue C, Ryu B, Rosty C, Goggins M, Wilentz RE, Murugesan SR, Leach SD, Jaffee E, Yeo CJ: Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE). Clin Cancer Res. 2001, 7: 3862-8.PubMed
29.
Ryu B, Jones J, Hollingsworth MA, Hruban RH, Kern SE: Invasion-specific genes in malignancy: serial analysis of gene expression comparisons of primary and passaged cancers. Cancer Res. 2001, 61: 1833-8.PubMed
30.
Rosty C, Ueki T, Argani P, Jansen M, Yeo CJ, Cameron JL, Hruban RH, Goggins M: Overexpression of S100A4 in Pancreatic Ductal Adenocarcinomas Is Associated with Poor Differentiation and DNA Hypomethylation. Am J Pathol. 2002, 160: 45-50.PubMedCentralCrossRefPubMed
31.
Crnogorac-Jurcevic T, Efthimiou E, Nielsen T, Loader J, Terris B, Stamp G, Baron A, Scarpa A, Lemoine NR: Expression profiling of microdissected pancreatic adenocarcinomas. Oncogene. 2002, 21: 4587-94. 10.1038/sj.onc.1205570.CrossRefPubMed
32.
Murphy KM, Brune KA, Griffin C, Sollenberger JE, Petersen GM, Bansal R, Hruban RH, Kern SE: Evaluation of candidate genes MAP2K4, MADH4, ACVR1B, and BRCA2 in familial pancreatic cancer: deleterious BRCA2 mutations in 17%. Cancer Res. 2002, 62: 3789-93.PubMed
33.
Moore PS, Zamboni G, Falconi M, Bassi C, Scarpa A: A novel germline mutation, P48T, in the CDKN2A/p16 gene in a patient with pancreatic carcinoma. Hum Mutat. 2000, 16: 447-8. 10.1002/1098-1004(200011)16:5<447::AID-HUMU18>3.0.CO;2-J.CrossRefPubMed
34.
Goggins M, Kern SE, Offerhaus JA, Hruban RH: Progress in cancer genetics: lessons from pancreatic cancer. Ann Oncol. 1999, 10: 4-8. 10.1023/A:1008307913019.CrossRefPubMed
35.
Pellegata N, Sessa F, Renault B, Bonato M, Leone B, Solcia E, Ranzani G: K-ras and p53 mutations in pancreatic cancer: ductal and non-ductal tumors progress through different genetic lesions. Cancer Res. 1994, 54: 1556-1560.PubMed
36.
Rigaud G, Moore P, Zamboni G, Taruscio D, Paradisi S, Falconi M, Klöppel G, Scarpa A: Allelotype of pancreatic acinar cell carcinoma. Int J Cancer. 2000, 88: 772-777. 10.1002/1097-0215(20001201)88:5<772::AID-IJC14>3.0.CO;2-W.CrossRefPubMed
37.
Abraham SC, Wu TT, Hruban RH, Lee JH, Yeo CJ, Conlon K, Brennan M, Cameron JL, Klimstra DS: Genetic and immunohistochemical analysis of pancreatic acinar cell carcinoma: frequent allelic loss on chromosome 11p and alterations in the APC/beta-catenin pathway. Am J Pathol. 2002, 160: 953-62.PubMedCentralCrossRefPubMed
38.
Moore P, Zamboni G, Brighenti A, Lissandrini D, Antonello D, Capelli P, Rigaud G, Falconi M, Scarpa A: Molecular characterization of pancreatic serous microcystic adenomas: evidence for a tumor suppressor gene on chromosome 10q. Am J Pathol. 2001, 158: 317-321.PubMedCentralCrossRefPubMed
39.
Zamboni G, Scarpa A, Bogina G, Iacono C, Bassi C, Talamini G, Sessa F, Capella C, Solcia E, Rickaert F: Mucinous cystic tumors of the pancreas: clinicopathological features, prognosis, and relationship to other mucinous cystic tumors. Am J Surg Pathol. 1999, 23: 410-22. 10.1097/00000478-199904000-00005.CrossRefPubMed
40.
Iacobuzio-Donahue CA, Wilentz RE, Argani P, Yeo CJ, Cameron JL, Kern SE, Hruban RH: Dpc4 protein in mucinous cystic neoplasms of the pancreas: frequent loss of expression in invasive carcinomas suggests a role in genetic progression. Am J Surg Pathol. 2000, 24: 1544-8. 10.1097/00000478-200011000-00011.CrossRefPubMed
41.
Sessa F, Solcia E, Capella C, Bonato M, Scarpa A, Zamboni G, Pellegata N, Ranzani G, Rickaert F, Klöppel G: Intraductal papillary-mucinous pancreatic tumors are phenotypically, genetically and behaviorally distinct growths. An analysis of tumor cell phenotype, K-ras and p53 genes' mutations. Virchows Archiv. 1994, 425: 357-367.CrossRefPubMed
42.
Terris B, Blaveri E, Crnogorac-Jurcevic T, Jones M, Missiaglia E, Ruszniewski P, Sauvanet A, Lemoine NR: Characterization of gene expression profiles in intraductal papillary-mucinous tumors of the pancreas. Am J Pathol. 2002, 160: 1745-54.PubMedCentralCrossRefPubMed
43.
Tanaka Y, Kato K, Notohara K, Hojo H, Ijiri R, Miyake T, Nagahara N, Sasaki F, Kitagawa N, Nakatani Y: Frequent beta-catenin mutation and cytoplasmic/nuclear accumulation in pancreatic solid-pseudopapillary neoplasm. Cancer Res. 2001, 61: 8401-4.PubMed
44.
Abraham SC, Klimstra DS, Wilentz RE, Yeo CJ, Conlon K, Brennan M, Cameron JL, Wu TT, Hruban RH: Solid-pseudopapillary tumors of the pancreas are genetically distinct from pancreatic ductal adenocarcinomas and almost always harbor beta-catenin mutations. Am J Pathol. 2002, 160: 1361-9.PubMedCentralCrossRefPubMed
45.
Scarpa A, Capelli P, Zamboni G, Oda T, Mukai K, Bonetti F, Martignoni G, Iacono C, Serio G, Hirohashi S: Neoplasia of the ampulla of Vater: Ki-ras and p53 mutations. Am J Pathol. 1993, 142: 1163-1172.PubMedCentralPubMed
46.
Scarpa A, Zamboni G, Achille A, Capelli P, Bogina G, Iacono C, Serio G, Accolla R: Ras-family gene mutations in neoplasia of the ampulla of Vater. Int J Cancer. 1994, 59: 39-42.CrossRefPubMed
47.
Howe JR, Klimstra DS, Cordon-Cardo C, Paty PB, Park PY, Brennan MF: K-ras mutation in adenomas and carcinomas of the ampulla of vater. Clin Cancer Res. 1997, 3: 129-33.PubMed
48.
Beghelli S, Orlandini S, Moore PS, Talamini G, Capelli P, Zamboni G, Falconi M, Scarpa A: Ampulla of vater cancers: T-stage and histological subtype but not Dpc4 expression predict prognosis. Virchows Arch. 2002, 441: 19-24. 10.1007/s00428-002-0625-x.CrossRefPubMed
49.
Scarpa A, Di Pace C, Talamini G, Falconi M, Lemoine N, Iacono C, Achille A, Baron A, Zamboni G: Cancer of the ampulla of Vater: chromosome 17p allelic loss is associated with poor prognosis. Gut. 2000, 46: 842-848. 10.1136/gut.46.6.842.PubMedCentralCrossRefPubMed
50.
Achille A, Scupoli M, Magalini A, Zamboni G, Romanelli M, Orlandini S, Biasi M, Lemoine N, Accolla R, Scarpa A: APC gene mutations and allelic losses in sporadic ampullary tumours: evidence of genetic difference from tumours associated with familial adenomatous polyposis. Int J Cancer. 1996, 68: 305-312. 10.1002/(SICI)1097-0215(19961104)68:3<305::AID-IJC7>3.0.CO;2-5.CrossRefPubMed
51.
Achille A, Biasi MO, Zamboni G, Bogina G, Iacono C, Talamini G, Capella G, Scarpa A: Cancers of the papilla of Vater: mutator phenotype is associated with good prognosis. Clin Cancer Res. 1997, 3: 1841-1847.PubMed
52.
Gumbs AA, Moore PS, Falconi M, Bassi C, Beghelli S, Modlin I, Scarpa A: Review of the clinical, histological, and molecular aspects of pancreatic endocrine neoplasms. J Surg Oncol. 2002, 81: 45-53. 10.1002/jso.10142.CrossRefPubMed
53.
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: 41-50. 10.1002/(SICI)1096-9896(199809)186:1<41::AID-PATH172>3.0.CO;2-L.CrossRefPubMed
54.
Scarpa A, Orlandini S, Moore P, Lemoine N, Beghelli S, Baron A, Falconi M, Zamboni G: Dpc-4 is expressed in virtually all primary and metastatic pancreatic endocrine tumors. Virchows Arch. 2002, 440: 155-159. 10.1007/s00428-001-0569-6.CrossRefPubMed
55.
Moore PS, Missiaglia E, Antonello D, Zamo A, Zamboni G, Corleto V, Falconi M, Scarpa A: Role of disease-causing genes in sporadic pancreatic endocrine tumors: MEN1 and VHL. Genes Chromosomes Cancer. 2001, 32: 177-81. 10.1002/gcc.1180.CrossRefPubMed
56.
Chung DC, Smith AP, Louis DN, Graeme-Cook F, Warshaw AL, Arnold A: A novel pancreatic endocrine tumor suppressor gene locus on chromosome 3p with clinical prognostic implications. J Clin Invest. 1997, 100: 404-10.PubMedCentralCrossRefPubMed
57.
Rigaud G, Missiaglia E, Moore PS, Zamboni G, Falconi M, Talamini G, Pesci A, Baron A, Lissandrini D, Rindi G: High resolution allelotype of nonfunctional pancreatic endocrine tumors: identification of two molecular subgroups with clinical implications. Cancer Res. 2001, 61: 285-92.PubMed
58.
Hahn SA, Seymour AB, Hoque AT, Schutte M, da Costa LT, Redston MS, Caldas C, Weinstein CL, Fischer A, Yeo CJ: Allelotype of pancreatic adenocarcinoma using xenograft enrichment. Cancer Res. 1995, 55: 4670-5.PubMed
59.
Rigaud G, Moore PS, Zamboni G, Orlandini S, Taruscio D, Paradisi S, Lemoine NR, Kloppel G, Scarpa A: Allelotype of pancreatic acinar cell carcinoma. Int J Cancer. 2000, 88: 772-7. 10.1002/1097-0215(20001201)88:5<772::AID-IJC14>3.0.CO;2-W.CrossRefPubMed
60.
Moore PS, Zamboni G, Brighenti A, Lissandrini D, Antonello D, Capelli P, Rigaud G, Falconi M, Scarpa A: Molecular characterization of pancreatic serous microcystic adenomas: evidence for a tumor suppressor gene on chromosome 10q. Am J Pathol. 2001, 158: 317-21.PubMedCentralCrossRefPubMed
61.
Chung DC, Brown SB, Graeme-Cook F, Tillotson LG, Warshaw AL, Jensen RT, Arnold A: Localization of putative tumor suppressor loci by genome-wide allelotyping in human pancreatic endocrine tumors. Cancer Res. 1998, 58: 3706-11.PubMed
62.
Missiaglia E, Moore PS, Williamson J, Lemoine NR, Falconi M, Zamboni G, Scarpa A: Sex chromosome anomalies in pancreatic endocrine tumors. Int J Cancer. 2002, 98: 532-8. 10.1002/ijc.10223.CrossRefPubMed
Metadata
Title
Genetic abnormalities in pancreatic cancer
Authors
Patrick S Moore
Stefania Beghelli
Giuseppe Zamboni
Aldo Scarpa
Publication date
01-12-2003
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2003
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-2-7

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