Skip to main content
Top
Published in: Molecular Cancer 1/2003

Open Access 01-12-2003 | Review

Genetic alterations in pancreatic carcinoma

Authors: Gunter Schneider, Roland M Schmid

Published in: Molecular Cancer | Issue 1/2003

Login to get access

Abstract

Cancer of the exocrine pancreas represents the fifth leading cause of cancer death in the Western population with an average survival after diagnosis of 3 to 6 months and a five-year survival rate under 5%. Our understanding of the molecular carcinogenesis has improved in the last few years due to the development of novel molecular biological techniques. Pancreatic cancer is a multi-stage process resulting from the accumulation of genetic changes in the somatic DNA of normal cells. In this article we describe major genetic alterations of pancreatic cancer, mutations in the proto-oncogene K-RAS and the tumor suppressors INK4A, TP53 and DPC4/SMAD4. The accumulation of these genetic changes leads to a profound disturbance in cell cycle regulation and continuous growth. The knowledge of the underlying molecular mechanisms will offer new therapeutic and diagnostic options and hopefully improve the outcome of this aggressive disease.
Appendix
Available only for authorised users
Literature
1.
2.
go back to reference 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 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
4.
go back to reference Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M: Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell. 1988, 53: 549-54.CrossRefPubMed Almoguera C, Shibata D, Forrester K, Martin J, Arnheim N, Perucho M: Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes. Cell. 1988, 53: 549-54.CrossRefPubMed
5.
go back to reference Caldas C, Kern SE: K-ras mutation and pancreatic adenocarcinoma. Int J Pancreatol. 1995, 18: 1-6.PubMed Caldas C, Kern SE: K-ras mutation and pancreatic adenocarcinoma. Int J Pancreatol. 1995, 18: 1-6.PubMed
6.
go back to reference Terhune PG, Phifer DM, Tosteson TD, Longnecker DS: K-ras mutation in focal proliferative lesions of human pancreas. Cancer Epidemiol Biomarkers Prev. 1998, 7: 515-21.PubMed Terhune PG, Phifer DM, Tosteson TD, Longnecker DS: K-ras mutation in focal proliferative lesions of human pancreas. Cancer Epidemiol Biomarkers Prev. 1998, 7: 515-21.PubMed
7.
go back to reference Shields JM, Pruitt K, McFall A, Shaub A, Der CJ: Understanding Ras: 'it ain't over 'til it's over'. Trends Cell Biol. 2000, 10: 147-54. 10.1016/S0962-8924(00)01740-2.CrossRefPubMed Shields JM, Pruitt K, McFall A, Shaub A, Der CJ: Understanding Ras: 'it ain't over 'til it's over'. Trends Cell Biol. 2000, 10: 147-54. 10.1016/S0962-8924(00)01740-2.CrossRefPubMed
8.
go back to reference Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW: Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997, 88: 593-602. 10.1016/S0092-8674(00)81902-9.CrossRefPubMed Serrano M, Lin AW, McCurrach ME, Beach D, Lowe SW: Oncogenic ras provokes premature cell senescence associated with accumulation of p53 and p16INK4a. Cell. 1997, 88: 593-602. 10.1016/S0092-8674(00)81902-9.CrossRefPubMed
9.
go back to reference Biankin AV, Kench JG, Morey AL, Lee CS, Biankin SA, Head DR, Hugh TB, Henshall SM, Sutherland RL: Overexpression of p21(WAF1/CIP1) is an early event in the development of pancreatic intraepithelial neoplasia. Cancer Res. 2001, 61: 8830-7.PubMed Biankin AV, Kench JG, Morey AL, Lee CS, Biankin SA, Head DR, Hugh TB, Henshall SM, Sutherland RL: Overexpression of p21(WAF1/CIP1) is an early event in the development of pancreatic intraepithelial neoplasia. Cancer Res. 2001, 61: 8830-7.PubMed
10.
go back to reference LaBaer J, Garrett MD, Stevenson LF, Slingerland JM, Sandhu C, Chou HS, Fattaey A, Harlow E: New functional activities for the p21 family of CDK inhibitors. Genes Dev. 1997, 11: 847-62.CrossRefPubMed LaBaer J, Garrett MD, Stevenson LF, Slingerland JM, Sandhu C, Chou HS, Fattaey A, Harlow E: New functional activities for the p21 family of CDK inhibitors. Genes Dev. 1997, 11: 847-62.CrossRefPubMed
11.
go back to reference Tada M, Omata M, Kawai S, Saisho H, Ohto M, Saiki RK, Sninsky JJ: Detection of ras gene mutations in pancreatic juice and peripheral blood of patients with pancreatic adenocarcinoma. Cancer Res. 1993, 53: 2472-4.PubMed Tada M, Omata M, Kawai S, Saisho H, Ohto M, Saiki RK, Sninsky JJ: Detection of ras gene mutations in pancreatic juice and peripheral blood of patients with pancreatic adenocarcinoma. Cancer Res. 1993, 53: 2472-4.PubMed
12.
go back to reference Tada M, Ohashi M, Shiratori Y, Okudaira T, Komatsu Y, Kawabe T, Yoshida H, Machinami R, Kishi K, Omata M: Analysis of K-ras gene mutation in hyperplastic duct cells of the pancreas without pancreatic disease. Gastroenterology. 1996, 110: 227-31.CrossRefPubMed Tada M, Ohashi M, Shiratori Y, Okudaira T, Komatsu Y, Kawabe T, Yoshida H, Machinami R, Kishi K, Omata M: Analysis of K-ras gene mutation in hyperplastic duct cells of the pancreas without pancreatic disease. Gastroenterology. 1996, 110: 227-31.CrossRefPubMed
13.
go back to reference Yanagisawa A, Ohtake K, Ohashi K, Hori M, Kitagawa T, Sugano H, Kato Y: Frequent c-Ki-ras oncogene activation in mucous cell hyperplasias of pancreas suffering from chronic inflammation. Cancer Res. 1993, 53: 953-6.PubMed Yanagisawa A, Ohtake K, Ohashi K, Hori M, Kitagawa T, Sugano H, Kato Y: Frequent c-Ki-ras oncogene activation in mucous cell hyperplasias of pancreas suffering from chronic inflammation. Cancer Res. 1993, 53: 953-6.PubMed
14.
go back to reference Moskaluk CA, Hruban RH, Kern SE: p16 and K-ras gene mutations in the intraductal precursors of human pancreatic adenocarcinoma. Cancer Res. 1997, 57: 2140-3.PubMed Moskaluk CA, Hruban RH, Kern SE: p16 and K-ras gene mutations in the intraductal precursors of human pancreatic adenocarcinoma. Cancer Res. 1997, 57: 2140-3.PubMed
15.
go back to reference Johnson L, Mercer K, Greenbaum D, Bronson RT, Crowley D, Tuveson DA, Jacks T: Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature. 2001, 410: 1111-6. 10.1038/35074129.CrossRefPubMed Johnson L, Mercer K, Greenbaum D, Bronson RT, Crowley D, Tuveson DA, Jacks T: Somatic activation of the K-ras oncogene causes early onset lung cancer in mice. Nature. 2001, 410: 1111-6. 10.1038/35074129.CrossRefPubMed
16.
go back to reference Spandidos DA, Frame M, Wilkie NM: Expression of the normal H-ras1 gene can suppress the transformed and tumorigenic phenotypes induced by mutant ras genes. Anticancer Res. 1990, 10: 1543-54.PubMed Spandidos DA, Frame M, Wilkie NM: Expression of the normal H-ras1 gene can suppress the transformed and tumorigenic phenotypes induced by mutant ras genes. Anticancer Res. 1990, 10: 1543-54.PubMed
17.
go back to reference Zhang Z, Wang Y, Vikis HG, Johnson L, Liu G, Li J, Anderson MW, Sills RC, Hong HL, Devereux TR: Wildtype Kras2 can inhibit lung carcinogenesis in mice. Nat Genet. 2001, 29: 25-33. 10.1038/ng721.CrossRefPubMed Zhang Z, Wang Y, Vikis HG, Johnson L, Liu G, Li J, Anderson MW, Sills RC, Hong HL, Devereux TR: Wildtype Kras2 can inhibit lung carcinogenesis in mice. Nat Genet. 2001, 29: 25-33. 10.1038/ng721.CrossRefPubMed
18.
go back to reference Hamad NM, Elconin JH, Karnoub AE, Bai W, Rich JN, Abraham RT, Der CJ, Counter CM: Distinct requirements for Ras oncogenesis in human versus mouse cells. Genes Dev. 2002, 16: 2045-57. 10.1101/gad.993902.PubMedCentralCrossRefPubMed Hamad NM, Elconin JH, Karnoub AE, Bai W, Rich JN, Abraham RT, Der CJ, Counter CM: Distinct requirements for Ras oncogenesis in human versus mouse cells. Genes Dev. 2002, 16: 2045-57. 10.1101/gad.993902.PubMedCentralCrossRefPubMed
19.
go back to reference Wilentz RE, Geradts J, Maynard R, Offerhaus GJ, Kang M, Goggins M, Yeo CJ, Kern SE, Hruban RH: Inactivation of the p16 (INK4A) tumor-suppressor gene in pancreatic duct lesions: loss of intranuclear expression. Cancer Res. 1998, 58: 4740-4.PubMed Wilentz RE, Geradts J, Maynard R, Offerhaus GJ, Kang M, Goggins M, Yeo CJ, Kern SE, Hruban RH: Inactivation of the p16 (INK4A) tumor-suppressor gene in pancreatic duct lesions: loss of intranuclear expression. Cancer Res. 1998, 58: 4740-4.PubMed
20.
go back to reference Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Hruban RH, Yeo CJ, Kern SE: Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet. 1994, 8: 27-32.CrossRefPubMed Caldas C, Hahn SA, da Costa LT, Redston MS, Schutte M, Seymour AB, Weinstein CL, Hruban RH, Yeo CJ, Kern SE: Frequent somatic mutations and homozygous deletions of the p16 (MTS1) gene in pancreatic adenocarcinoma. Nat Genet. 1994, 8: 27-32.CrossRefPubMed
21.
go back to reference 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 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
22.
go back to reference Sherr CJ: The INK4a/ARF network in tumour suppression. Nat Rev Mol Cell Biol. 2001, 2: 731-7. 10.1038/35096061.CrossRefPubMed Sherr CJ: The INK4a/ARF network in tumour suppression. Nat Rev Mol Cell Biol. 2001, 2: 731-7. 10.1038/35096061.CrossRefPubMed
23.
go back to reference Serrano M, Lee H, Chin L, Cordon-Cardo C, Beach D, DePinho RA: Role of the INK4a locus in tumor suppression and cell mortality. Cell. 1996, 85: 27-37.CrossRefPubMed Serrano M, Lee H, Chin L, Cordon-Cardo C, Beach D, DePinho RA: Role of the INK4a locus in tumor suppression and cell mortality. Cell. 1996, 85: 27-37.CrossRefPubMed
24.
go back to reference Kamijo T, Zindy F, Roussel MF, Quelle DE, Downing JR, Ashmun RA, Grosveld G, Sherr CJ: Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell. 1997, 91: 649-59.CrossRefPubMed Kamijo T, Zindy F, Roussel MF, Quelle DE, Downing JR, Ashmun RA, Grosveld G, Sherr CJ: Tumor suppression at the mouse INK4a locus mediated by the alternative reading frame product p19ARF. Cell. 1997, 91: 649-59.CrossRefPubMed
25.
go back to reference Sharpless NE, Bardeesy N, Lee KH, Carrasco D, Castrillon DH, Aguirre AJ, Wu EA, Horner JW, DePinho RA: Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature. 2001, 413: 86-91. 10.1038/35092592.CrossRefPubMed Sharpless NE, Bardeesy N, Lee KH, Carrasco D, Castrillon DH, Aguirre AJ, Wu EA, Horner JW, DePinho RA: Loss of p16Ink4a with retention of p19Arf predisposes mice to tumorigenesis. Nature. 2001, 413: 86-91. 10.1038/35092592.CrossRefPubMed
26.
go back to reference Krimpenfort P, Quon KC, Mooi WJ, Loonstra A, Berns A: Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice. Nature. 2001, 413: 83-6. 10.1038/35092584.CrossRefPubMed Krimpenfort P, Quon KC, Mooi WJ, Loonstra A, Berns A: Loss of p16Ink4a confers susceptibility to metastatic melanoma in mice. Nature. 2001, 413: 83-6. 10.1038/35092584.CrossRefPubMed
27.
go back to reference Gruis NA, van der Velden PA, Sandkuijl LA, Prins DE, Weaver-Feldhaus J, Kamb A, Bergman W, Frants RR: Homozygotes for CDKN2 (p16) germline mutation in Dutch familial melanoma kindreds. Nat Genet. 1995, 10: 351-3.CrossRefPubMed Gruis NA, van der Velden PA, Sandkuijl LA, Prins DE, Weaver-Feldhaus J, Kamb A, Bergman W, Frants RR: Homozygotes for CDKN2 (p16) germline mutation in Dutch familial melanoma kindreds. Nat Genet. 1995, 10: 351-3.CrossRefPubMed
28.
go back to reference Goldstein AM, Fraser MC, Struewing JP, Hussussian CJ, Ranade K, Zametkin DP, Fontaine LS, Organic SM, Dracopoli NC, Clark WH: Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations. N Engl J Med. 1995, 333: 970-4. 10.1056/NEJM199510123331504.CrossRefPubMed Goldstein AM, Fraser MC, Struewing JP, Hussussian CJ, Ranade K, Zametkin DP, Fontaine LS, Organic SM, Dracopoli NC, Clark WH: Increased risk of pancreatic cancer in melanoma-prone kindreds with p16INK4 mutations. N Engl J Med. 1995, 333: 970-4. 10.1056/NEJM199510123331504.CrossRefPubMed
29.
go back to reference Whelan AJ, Bartsch D, Goodfellow PJ: Brief report: a familial syndrome of pancreatic cancer and melanoma with a mutation in the CDKN2 tumor-suppressor gene. N Engl J Med. 1995, 333: 975-7. 10.1056/NEJM199510123331505.CrossRefPubMed Whelan AJ, Bartsch D, Goodfellow PJ: Brief report: a familial syndrome of pancreatic cancer and melanoma with a mutation in the CDKN2 tumor-suppressor gene. N Engl J Med. 1995, 333: 975-7. 10.1056/NEJM199510123331505.CrossRefPubMed
30.
go back to reference Lynch HT, Fitzsimmons ML, Smyrk TC, Lanspa SJ, Watson P, McClellan J, Lynch JF: Familial pancreatic cancer: clinicopathologic study of 18 nuclear families. Am J Gastroenterol. 1990, 85: 54-60.PubMed Lynch HT, Fitzsimmons ML, Smyrk TC, Lanspa SJ, Watson P, McClellan J, Lynch JF: Familial pancreatic cancer: clinicopathologic study of 18 nuclear families. Am J Gastroenterol. 1990, 85: 54-60.PubMed
31.
go back to reference Liu L, Dilworth D, Gao L, Monzon J, Summers A, Lassam N, Hogg D: Mutation of the CDKN2A 5' UTR creates an aberrant initiation codon and predisposes to melanoma. Nat Genet. 1999, 21: 128-32. 10.1038/5082.CrossRefPubMed Liu L, Dilworth D, Gao L, Monzon J, Summers A, Lassam N, Hogg D: Mutation of the CDKN2A 5' UTR creates an aberrant initiation codon and predisposes to melanoma. Nat Genet. 1999, 21: 128-32. 10.1038/5082.CrossRefPubMed
32.
go back to reference Lal G, Liu L, Hogg D, Lassam NJ, Redston MS, Gallinger S: Patients with both pancreatic adenocarcinoma and melanoma may harbor germline CDKN2A mutations. Genes Chromosomes Cancer. 2000, 27: 358-61. 10.1002/(SICI)1098-2264(200004)27:4<358::AID-GCC4>3.0.CO;2-O.CrossRefPubMed Lal G, Liu L, Hogg D, Lassam NJ, Redston MS, Gallinger S: Patients with both pancreatic adenocarcinoma and melanoma may harbor germline CDKN2A mutations. Genes Chromosomes Cancer. 2000, 27: 358-61. 10.1002/(SICI)1098-2264(200004)27:4<358::AID-GCC4>3.0.CO;2-O.CrossRefPubMed
33.
go back to reference Randerson-Moor JA, Harland M, Williams S, D Cuthbert-Heavens, Sheridan E, Aveyard J, Sibley K, Whitaker L, Knowles M, Bishop JN: A germline deletion of p14(ARF) but not CDKN2A in a melanoma-neural system tumour syndrome family. Hum Mol Genet. 2001, 10: 55-62. 10.1093/hmg/10.1.55.CrossRefPubMed Randerson-Moor JA, Harland M, Williams S, D Cuthbert-Heavens, Sheridan E, Aveyard J, Sibley K, Whitaker L, Knowles M, Bishop JN: A germline deletion of p14(ARF) but not CDKN2A in a melanoma-neural system tumour syndrome family. Hum Mol Genet. 2001, 10: 55-62. 10.1093/hmg/10.1.55.CrossRefPubMed
34.
go back to reference Schutte M, Hruban RH, Geradts J, Maynard R, Hilgers W, Rabindran SK, Moskaluk CA, Hahn SA, Schwarte-Waldhoff I, Schmiegel W: Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res. 1997, 57: 3126-30.PubMed Schutte M, Hruban RH, Geradts J, Maynard R, Hilgers W, Rabindran SK, Moskaluk CA, Hahn SA, Schwarte-Waldhoff I, Schmiegel W: Abrogation of the Rb/p16 tumor-suppressive pathway in virtually all pancreatic carcinomas. Cancer Res. 1997, 57: 3126-30.PubMed
35.
go back to reference Boschman CR, Stryker S, Reddy JK, Rao MS: Expression of p53 protein in precursor lesions and adenocarcinoma of human pancreas. Am J Pathol. 1994, 145: 1291-5.PubMedCentralPubMed Boschman CR, Stryker S, Reddy JK, Rao MS: Expression of p53 protein in precursor lesions and adenocarcinoma of human pancreas. Am J Pathol. 1994, 145: 1291-5.PubMedCentralPubMed
36.
go back to reference Apple SK, Hecht JR, Lewin DN, Jahromi SA, Grody WW, Nieberg RK: Immunohistochemical evaluation of K-ras, p53, and HER-2/neu expression in hyperplastic, dysplastic, and carcinomatous lesions of the pancreas: evidence for multistep carcinogenesis. Hum Pathol. 1999, 30: 123-9.CrossRefPubMed Apple SK, Hecht JR, Lewin DN, Jahromi SA, Grody WW, Nieberg RK: Immunohistochemical evaluation of K-ras, p53, and HER-2/neu expression in hyperplastic, dysplastic, and carcinomatous lesions of the pancreas: evidence for multistep carcinogenesis. Hum Pathol. 1999, 30: 123-9.CrossRefPubMed
37.
go back to reference DiGiuseppe JA, Hruban RH, Goodman SN, Polak M, van den Berg FM, Allison DC, Cameron JL, Offerhaus GJ: Overexpression of p53 protein in adenocarcinoma of the pancreas. Am J Clin Pathol. 1994, 101: 684-8.PubMed DiGiuseppe JA, Hruban RH, Goodman SN, Polak M, van den Berg FM, Allison DC, Cameron JL, Offerhaus GJ: Overexpression of p53 protein in adenocarcinoma of the pancreas. Am J Clin Pathol. 1994, 101: 684-8.PubMed
38.
go back to reference Redston MS, Caldas C, Seymour AB, Hruban RH, da Costa L, Yeo CJ, Kern SE: p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res. 1994, 54: 3025-33.PubMed Redston MS, Caldas C, Seymour AB, Hruban RH, da Costa L, Yeo CJ, Kern SE: p53 mutations in pancreatic carcinoma and evidence of common involvement of homocopolymer tracts in DNA microdeletions. Cancer Res. 1994, 54: 3025-33.PubMed
39.
go back to reference Barton CM, Staddon SL, Hughes CM, Hall PA, O'Sullivan C, Kloppel G, Theis B, Russell RC, Neoptolemos J, RC Williamson: Abnormalities of the p53 tumour suppressor gene in human pancreatic cancer. Br J Cancer. 1991, 64: 1076-82.PubMedCentralCrossRefPubMed Barton CM, Staddon SL, Hughes CM, Hall PA, O'Sullivan C, Kloppel G, Theis B, Russell RC, Neoptolemos J, RC Williamson: Abnormalities of the p53 tumour suppressor gene in human pancreatic cancer. Br J Cancer. 1991, 64: 1076-82.PubMedCentralCrossRefPubMed
40.
41.
go back to reference Harada T, Okita K, Shiraishi K, Kusano N, Kondoh S, Sasaki K: Interglandular cytogenetic heterogeneity detected by comparative genomic hybridization in pancreatic cancer. Cancer Res. 2002, 62: 835-9.PubMed Harada T, Okita K, Shiraishi K, Kusano N, Kondoh S, Sasaki K: Interglandular cytogenetic heterogeneity detected by comparative genomic hybridization in pancreatic cancer. Cancer Res. 2002, 62: 835-9.PubMed
42.
go back to reference Gorunova L, Hoglund M, Andren-Sandberg A, Dawiskiba S, Jin Y, Mitelman F, Johansson B: Cytogenetic analysis of pancreatic carcinomas: intratumor heterogeneity and nonrandom pattern of chromosome aberrations. Genes Chromosomes Cancer. 1998, 23: 81-99. 10.1002/(SICI)1098-2264(199810)23:2<81::AID-GCC1>3.0.CO;2-0.CrossRefPubMed Gorunova L, Hoglund M, Andren-Sandberg A, Dawiskiba S, Jin Y, Mitelman F, Johansson B: Cytogenetic analysis of pancreatic carcinomas: intratumor heterogeneity and nonrandom pattern of chromosome aberrations. Genes Chromosomes Cancer. 1998, 23: 81-99. 10.1002/(SICI)1098-2264(199810)23:2<81::AID-GCC1>3.0.CO;2-0.CrossRefPubMed
43.
go back to reference Strong LC, Stine M, Norsted TL: Cancer in survivors of childhood soft tissue sarcoma and their relatives. J Natl Cancer Inst. 1987, 79: 1213-20.PubMed Strong LC, Stine M, Norsted TL: Cancer in survivors of childhood soft tissue sarcoma and their relatives. J Natl Cancer Inst. 1987, 79: 1213-20.PubMed
44.
go back to reference Li FP, Fraumeni JF, Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA, Miller RW: A cancer family syndrome in twenty-four kindreds. Cancer Res. 1988, 48: 5358-62.PubMed Li FP, Fraumeni JF, Mulvihill JJ, Blattner WA, Dreyfus MG, Tucker MA, Miller RW: A cancer family syndrome in twenty-four kindreds. Cancer Res. 1988, 48: 5358-62.PubMed
45.
go back to reference Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH: DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science. 1996, 271: 350-3.CrossRefPubMed Hahn SA, Schutte M, Hoque AT, Moskaluk CA, da Costa LT, Rozenblum E, Weinstein CL, Fischer A, Yeo CJ, Hruban RH: DPC4, a candidate tumor suppressor gene at human chromosome 18q21.1. Science. 1996, 271: 350-3.CrossRefPubMed
46.
go back to reference Massague J, Blain SW, Lo RS: TGFbeta signaling in growth control, cancer, and heritable disorders. Cell. 2000, 103: 295-309.CrossRefPubMed Massague J, Blain SW, Lo RS: TGFbeta signaling in growth control, cancer, and heritable disorders. Cell. 2000, 103: 295-309.CrossRefPubMed
47.
go back to reference Wilentz RE, Iacobuzio-Donahue CA, Argani P, McCarthy DM, Parsons JL, Yeo CJ, Kern SE, Hruban RH: Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res. 2000, 60: 2002-6.PubMed Wilentz RE, Iacobuzio-Donahue CA, Argani P, McCarthy DM, Parsons JL, Yeo CJ, Kern SE, Hruban RH: Loss of expression of Dpc4 in pancreatic intraepithelial neoplasia: evidence that DPC4 inactivation occurs late in neoplastic progression. Cancer Res. 2000, 60: 2002-6.PubMed
48.
go back to reference Schwarte-Waldhoff I, Volpert OV, Bouck NP, Sipos B, Hahn SA, Klein-Scory S, Luttges J, Kloppel G, Graeven U, C Eilert-Micus: Smad4/DPC4-mediated tumor suppression through suppression of angiogenesis. Proc Natl Acad Sci U S A. 2000, 97: 9624-9. 10.1073/pnas.97.17.9624.PubMedCentralCrossRefPubMed Schwarte-Waldhoff I, Volpert OV, Bouck NP, Sipos B, Hahn SA, Klein-Scory S, Luttges J, Kloppel G, Graeven U, C Eilert-Micus: Smad4/DPC4-mediated tumor suppression through suppression of angiogenesis. Proc Natl Acad Sci U S A. 2000, 97: 9624-9. 10.1073/pnas.97.17.9624.PubMedCentralCrossRefPubMed
49.
50.
go back to reference Tascilar M, Skinner HG, Rosty C, Sohn T, Wilentz RE, Offerhaus GJ, Adsay V, Abrams RA, Cameron JL, Kern SE: The SMAD4 protein and prognosis of pancreatic ductal adenocarcinoma. Clin Cancer Res. 2001, 7: 4115-21.PubMed Tascilar M, Skinner HG, Rosty C, Sohn T, Wilentz RE, Offerhaus GJ, Adsay V, Abrams RA, Cameron JL, Kern SE: The SMAD4 protein and prognosis of pancreatic ductal adenocarcinoma. Clin Cancer Res. 2001, 7: 4115-21.PubMed
51.
go back to reference Biankin AV, Morey AL, Lee CS, Kench JG, Biankin SA, Hook HC, Head DR, Hugh TB, Sutherland RL, Henshall SM: DPC4/Smad4 Expression and Outcome in Pancreatic Ductal Adenocarcinoma. J Clin Oncol. 2002, 20: 4531-42. 10.1200/JCO.2002.12.063.CrossRefPubMed Biankin AV, Morey AL, Lee CS, Kench JG, Biankin SA, Hook HC, Head DR, Hugh TB, Sutherland RL, Henshall SM: DPC4/Smad4 Expression and Outcome in Pancreatic Ductal Adenocarcinoma. J Clin Oncol. 2002, 20: 4531-42. 10.1200/JCO.2002.12.063.CrossRefPubMed
52.
go back to reference Venkitaraman AR: Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002, 108: 171-82.CrossRefPubMed Venkitaraman AR: Cancer susceptibility and the functions of BRCA1 and BRCA2. Cell. 2002, 108: 171-82.CrossRefPubMed
53.
go back to reference Lancaster JM, Wooster R, Mangion J, Phelan CM, Cochran C, Gumbs C, Seal S, Barfoot R, Collins N, Bignell G: BRCA2 mutations in primary breast and ovarian cancers. Nat Genet. 1996, 13: 238-40.CrossRefPubMed Lancaster JM, Wooster R, Mangion J, Phelan CM, Cochran C, Gumbs C, Seal S, Barfoot R, Collins N, Bignell G: BRCA2 mutations in primary breast and ovarian cancers. Nat Genet. 1996, 13: 238-40.CrossRefPubMed
54.
go back to reference Ozcelik H, Schmocker B, Di Nicola N, Shi XH, Langer B, Moore M, Taylor BR, Narod SA, Darlington G, Andrulis IL: Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients. Nat Genet. 1997, 16: 17-8.CrossRefPubMed Ozcelik H, Schmocker B, Di Nicola N, Shi XH, Langer B, Moore M, Taylor BR, Narod SA, Darlington G, Andrulis IL: Germline BRCA2 6174delT mutations in Ashkenazi Jewish pancreatic cancer patients. Nat Genet. 1997, 16: 17-8.CrossRefPubMed
55.
go back to reference Goggins M, Schutte M, Lu J, Moskaluk CA, Weinstein CL, Petersen GM, Yeo CJ, Jackson CE, Lynch HT, Hruban RH: Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res. 1996, 56: 5360-4.PubMed Goggins M, Schutte M, Lu J, Moskaluk CA, Weinstein CL, Petersen GM, Yeo CJ, Jackson CE, Lynch HT, Hruban RH: Germline BRCA2 gene mutations in patients with apparently sporadic pancreatic carcinomas. Cancer Res. 1996, 56: 5360-4.PubMed
56.
go back to reference 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 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
57.
go back to reference Bowlby LS: Pancreatic adenocarcinoma in an adolescent male with Peutz-Jeghers syndrome. Hum Pathol. 1986, 17: 97-9.CrossRefPubMed Bowlby LS: Pancreatic adenocarcinoma in an adolescent male with Peutz-Jeghers syndrome. Hum Pathol. 1986, 17: 97-9.CrossRefPubMed
58.
go back to reference Giardiello FM, Welsh SB, Hamilton SR, Offerhaus GJ, Gittelsohn AM, Booker SV, Krush AJ, Yardley JH, Luk GD: Increased risk of cancer in the Peutz-Jeghers syndrome. N Engl J Med. 1987, 316: 1511-4.CrossRefPubMed Giardiello FM, Welsh SB, Hamilton SR, Offerhaus GJ, Gittelsohn AM, Booker SV, Krush AJ, Yardley JH, Luk GD: Increased risk of cancer in the Peutz-Jeghers syndrome. N Engl J Med. 1987, 316: 1511-4.CrossRefPubMed
59.
go back to reference Giardiello FM, Brensinger JD, Tersmette AC, Goodman SN, Petersen GM, Booker SV, Cruz-Correa M, Offerhaus JA: Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology. 2000, 119: 1447-53.CrossRefPubMed Giardiello FM, Brensinger JD, Tersmette AC, Goodman SN, Petersen GM, Booker SV, Cruz-Correa M, Offerhaus JA: Very high risk of cancer in familial Peutz-Jeghers syndrome. Gastroenterology. 2000, 119: 1447-53.CrossRefPubMed
61.
go back to reference Sato N, Rosty C, Jansen M, Fukushima N, Ueki T, Yeo CJ, Cameron JL, Iacobuzio-Donahue CA, Hruban RH, Goggins M: STK11/LKB1 Peutz-Jeghers gene inactivation in intraductal papillary-mucinous neoplasms of the pancreas. Am J Pathol. 2001, 159: 2017-22.PubMedCentralCrossRefPubMed Sato N, Rosty C, Jansen M, Fukushima N, Ueki T, Yeo CJ, Cameron JL, Iacobuzio-Donahue CA, Hruban RH, Goggins M: STK11/LKB1 Peutz-Jeghers gene inactivation in intraductal papillary-mucinous neoplasms of the pancreas. Am J Pathol. 2001, 159: 2017-22.PubMedCentralCrossRefPubMed
62.
go back to reference 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 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
63.
go back to reference Cheng JQ, Ruggeri B, Klein WM, Sonoda G, Altomare DA, Watson DK, Testa JR: Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci U S A. 1996, 93: 3636-41. 10.1073/pnas.93.8.3636.PubMedCentralCrossRefPubMed Cheng JQ, Ruggeri B, Klein WM, Sonoda G, Altomare DA, Watson DK, Testa JR: Amplification of AKT2 in human pancreatic cells and inhibition of AKT2 expression and tumorigenicity by antisense RNA. Proc Natl Acad Sci U S A. 1996, 93: 3636-41. 10.1073/pnas.93.8.3636.PubMedCentralCrossRefPubMed
64.
go back to reference Miwa W, Yasuda J, Murakami Y, Yashima K, Sugano K, Sekine T, Kono A, Egawa S, Yamaguchi K, Hayashizaki Y: Isolation of DNA sequences amplified at chromosome 19q13.1-q13.2 including the AKT2 locus in human pancreatic cancer. Biochem Biophys Res Commun. 1996, 225: 968-74. 10.1006/bbrc.1996.1280.CrossRefPubMed Miwa W, Yasuda J, Murakami Y, Yashima K, Sugano K, Sekine T, Kono A, Egawa S, Yamaguchi K, Hayashizaki Y: Isolation of DNA sequences amplified at chromosome 19q13.1-q13.2 including the AKT2 locus in human pancreatic cancer. Biochem Biophys Res Commun. 1996, 225: 968-74. 10.1006/bbrc.1996.1280.CrossRefPubMed
65.
go back to reference Ruggeri BA, Huang L, Wood M, Cheng JQ, Testa JR: Amplification and overexpression of the AKT2 oncogene in a subset of human pancreatic ductal adenocarcinomas. Mol Carcinog. 1998, 21: 81-6. 10.1002/(SICI)1098-2744(199802)21:2<81::AID-MC1>3.0.CO;2-R.CrossRefPubMed Ruggeri BA, Huang L, Wood M, Cheng JQ, Testa JR: Amplification and overexpression of the AKT2 oncogene in a subset of human pancreatic ductal adenocarcinomas. Mol Carcinog. 1998, 21: 81-6. 10.1002/(SICI)1098-2744(199802)21:2<81::AID-MC1>3.0.CO;2-R.CrossRefPubMed
66.
go back to reference Franke TF, Yang SI, Chan TO, Datta K, Kazlauskas A, Morrison DK, Kaplan DR, Tsichlis PN: The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell. 1995, 81: 727-36.CrossRefPubMed Franke TF, Yang SI, Chan TO, Datta K, Kazlauskas A, Morrison DK, Kaplan DR, Tsichlis PN: The protein kinase encoded by the Akt proto-oncogene is a target of the PDGF-activated phosphatidylinositol 3-kinase. Cell. 1995, 81: 727-36.CrossRefPubMed
67.
go back to reference Friess H, Berberat P, Schilling M, Kunz J, Korc M, Buchler MW: Pancreatic cancer: the potential clinical relevance of alterations in growth factors and their receptors. J Mol Med. 1996, 74: 35-42.CrossRefPubMed Friess H, Berberat P, Schilling M, Kunz J, Korc M, Buchler MW: Pancreatic cancer: the potential clinical relevance of alterations in growth factors and their receptors. J Mol Med. 1996, 74: 35-42.CrossRefPubMed
68.
go back to reference Tanno S, Mitsuuchi Y, Altomare DA, Xiao GH, Testa JR: AKT activation up-regulates insulin-like growth factor I receptor expression and promotes invasiveness of human pancreatic cancer cells. Cancer Res. 2001, 61: 589-93.PubMed Tanno S, Mitsuuchi Y, Altomare DA, Xiao GH, Testa JR: AKT activation up-regulates insulin-like growth factor I receptor expression and promotes invasiveness of human pancreatic cancer cells. Cancer Res. 2001, 61: 589-93.PubMed
69.
go back to reference Lynch HT, Lynch JF: Hereditary nonpolyposis colorectal cancer. Semin Surg Oncol. 2000, 18: 305-13. 10.1002/(SICI)1098-2388(200006)18:4<305::AID-SSU5>3.0.CO;2-A.CrossRefPubMed Lynch HT, Lynch JF: Hereditary nonpolyposis colorectal cancer. Semin Surg Oncol. 2000, 18: 305-13. 10.1002/(SICI)1098-2388(200006)18:4<305::AID-SSU5>3.0.CO;2-A.CrossRefPubMed
70.
go back to reference Aarnio M, Mecklin JP, Aaltonen LA, M Nystrom-Lahti, Jarvinen HJ: Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer. 1995, 64: 430-3.CrossRefPubMed Aarnio M, Mecklin JP, Aaltonen LA, M Nystrom-Lahti, Jarvinen HJ: Life-time risk of different cancers in hereditary non-polyposis colorectal cancer (HNPCC) syndrome. Int J Cancer. 1995, 64: 430-3.CrossRefPubMed
71.
go back to reference Watson P, Lynch HT: Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer. 1993, 71: 677-85.CrossRefPubMed Watson P, Lynch HT: Extracolonic cancer in hereditary nonpolyposis colorectal cancer. Cancer. 1993, 71: 677-85.CrossRefPubMed
72.
go back to reference 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 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
73.
go back to reference Goggins M, Offerhaus GJ, Hilgers W, Griffin CA, Shekher M, Tang D, Sohn TA, Yeo CJ, Kern SE, Hruban RH: 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. 1998, 152: 1501-7.PubMedCentralPubMed Goggins M, Offerhaus GJ, Hilgers W, Griffin CA, Shekher M, Tang D, Sohn TA, Yeo CJ, Kern SE, Hruban RH: 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. 1998, 152: 1501-7.PubMedCentralPubMed
74.
go back to reference 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 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
75.
go back to reference Nakata B, Yashiro M, Nishioka N, Aya M, Yamada S, Takenaka C, Ohira M, Ishikawa T, Nishino H, Wakasa K: Very low incidence of microsatellite instability in intraductal papillary-mucinous neoplasm of the pancreas. Int J Cancer. 2002, 102: 655-9. 10.1002/ijc.10771.CrossRefPubMed Nakata B, Yashiro M, Nishioka N, Aya M, Yamada S, Takenaka C, Ohira M, Ishikawa T, Nishino H, Wakasa K: Very low incidence of microsatellite instability in intraductal papillary-mucinous neoplasm of the pancreas. Int J Cancer. 2002, 102: 655-9. 10.1002/ijc.10771.CrossRefPubMed
76.
go back to reference Ghimenti C, Tannergard P, Wahlberg S, Liu T, Giulianotti PG, Mosca F, Fornaciari G, Bevilacqua G, Lindblom A, Caligo MA: Microsatellite instability and mismatch repair gene inactivation in sporadic pancreatic and colon tumours. Br J Cancer. 1999, 80: 11-6. 10.1038/sj.bjc.6690314.PubMedCentralCrossRefPubMed Ghimenti C, Tannergard P, Wahlberg S, Liu T, Giulianotti PG, Mosca F, Fornaciari G, Bevilacqua G, Lindblom A, Caligo MA: Microsatellite instability and mismatch repair gene inactivation in sporadic pancreatic and colon tumours. Br J Cancer. 1999, 80: 11-6. 10.1038/sj.bjc.6690314.PubMedCentralCrossRefPubMed
77.
go back to reference Kondo E, Furukawa T, Yoshinaga K, Kijima H, Semba S, Yatsuoka T, Yokoyama T, Fukushige S, Horii A: Not hMSH2 but hMLH1 is frequently silenced by hypermethylation in endometrial cancer but rarely silenced in pancreatic cancer with microsatellite instability. Int J Oncol. 2000, 17: 535-41.PubMed Kondo E, Furukawa T, Yoshinaga K, Kijima H, Semba S, Yatsuoka T, Yokoyama T, Fukushige S, Horii A: Not hMSH2 but hMLH1 is frequently silenced by hypermethylation in endometrial cancer but rarely silenced in pancreatic cancer with microsatellite instability. Int J Oncol. 2000, 17: 535-41.PubMed
Metadata
Title
Genetic alterations in pancreatic carcinoma
Authors
Gunter Schneider
Roland M Schmid
Publication date
01-12-2003
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2003
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/1476-4598-2-15

Other articles of this Issue 1/2003

Molecular Cancer 1/2003 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine