title: Frequency of K-ras mutations in pancreatic intraductal neoplasias associated with pancreatic ductal adenocarcinoma and chronic pancreatitis: a meta-analysis.
abstract: Molecular analyses have demonstrated mutations in the K-ras gene at codon 12 in the majority of pancreatic ductal adenocarcinomas (PDACs). In order to determine whether the K-ras mutation rate increases parallel to the grade of dysplasia in duct lesions, we performed a meta-analysis of the studies published between 1988 and 2003 that provide information on K-ras mutations in hyperplastic and dysplastic duct lesions in the pancreas. The described duct lesions were reclassified according to the nomenclature for pancreatic intraepithelial neoplasia (PanIN), and the molecular methods for detecting K-ras were reviewed. In PanIN lesions from pancreata of patients with PDAC, there was a stepwise increase in K-ras mutations that correlated with the grade of dysplasia of the PanIN lesion. K-ras mutations were found in 36%, 44%, and 87% of PanIN-1a, 1b, and 2-3 lesions, respectively (trend statistic P <.001). Mutation-enriched polymerase chain reaction (PCR) resulted in higher rates of K-ras mutations in PanIN than plain PCR did. The incidence of K-ras mutations in PanIN lesions associated with chronic pancreatitis (CP) or normal pancreas was low (around 10%). In CP, K-ras mutations were only found after a disease duration of 3 years. The correlation of the incidence of K-ras mutations with the grade of dysplasia in PanIN and the occurrence of these mutations in CP with a duration of more than 3 years underlines the importance of this genetic change for the development of PDAC.
authors.affiliation: Department of Medicine II, Medical Faculty Mannheim, University of Heidelberg, Heidelberg, Germany. matthias.loehr@med.ma.uni-heidelberg.de
authors.forename: Matthias
authors.initials: M
authors.lastname: Löhr
authors.forename: Günter
authors.initials: G
authors.lastname: Klöppel
authors.forename: Patrick
authors.initials: P
authors.lastname: Maisonneuve
authors.forename: Albert B
authors.initials: AB
authors.lastname: Lowenfels
authors.forename: Jutta
authors.initials: J
authors.lastname: Lüttges
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics*; D011905:Genes, ras / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics*; D010183:Pancreatic Ducts / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D010195:Pancreatitis / Q000235:genetics*
references.citation: Am J Pathol. 2002 Nov;161(5):1541-7
references.pmid: 12414502
references.citation: Nature. 1999 Jul 29;400(6743):464-8
references.pmid: 10440377
references.citation: Gastroenterology. 2003 Jun;124(7):1958-64
references.pmid: 12806629
references.citation: Eur J Surg Oncol. 2003 Aug;29(6):491-6
references.pmid: 12875854
references.citation: Pancreas. 2003 Oct;27(3):e57-62
references.pmid: 14508142
references.citation: Int J Cancer. 2003 Nov 20;107(4):635-41
references.pmid: 14520703
references.citation: Mod Pathol. 2003 Oct;16(10):996-1006
references.pmid: 14559982
references.citation: Virchows Arch. 2003 Oct;443(4):508-17
references.pmid: 12942322
references.citation: Proc Natl Acad Sci U S A. 2003 Nov 25;100(24):14247-52
references.pmid: 14603032
references.citation: Am J Surg Pathol. 2003 Dec;27(12):1495-501
references.pmid: 14657708
references.citation: Cancer Cell. 2003 Dec;4(6):437-50
references.pmid: 14706336
references.citation: Curr Gastroenterol Rep. 2004 Apr;6(2):111-8
references.pmid: 15191688
references.citation: Carcinogenesis. 2004 Jul;25(7):1243-7
references.pmid: 14963016
references.citation: Int J Cancer. 2004 Sep 10;111(4):480-3
references.pmid: 15239123
references.citation: Mol Cancer. 2003 Jan 7;2:7
references.pmid: 12537585
references.citation: Gastroenterology. 1992 Jan;102(1):230-6
references.pmid: 1309358
references.citation: Ann Surg. 1993 Feb;217(2):138-43
references.pmid: 8439212
references.citation: Cancer Res. 1993 Mar 1;53(5):953-6
references.pmid: 8439969
references.citation: Am J Pathol. 1993 Aug;143(2):545-54
references.pmid: 8342602
references.citation: Int J Pancreatol. 1993 Dec;14(3):237-44
references.pmid: 8113625
references.citation: BMJ. 1994 Sep 10;309(6955):648-51
references.pmid: 8086990
references.citation: Gastroenterology. 1996 Jan;110(1):227-31
references.pmid: 8536861
references.citation: Gastroenterology. 1996 Jan;110(1):306-10
references.pmid: 8536876
references.citation: Jpn J Cancer Res. 1999 Aug;90(8):841-8
references.pmid: 10543256
references.citation: Virchows Arch. 1999 Nov;435(5):461-8
references.pmid: 10592048
references.citation: J Epidemiol Community Health. 1999 Nov;53(11):702-9
references.pmid: 10656099
references.citation: Cancer Res. 2000 Apr 1;60(7):2002-6
references.pmid: 10766191
references.citation: Am J Pathol. 2000 May;156(5):1767-71
references.pmid: 10793087
references.citation: Histopathology. 2000 Jun;36(6):481-7
references.pmid: 10849088
references.citation: Am J Pathol. 2000 Jun;156(6):1821-5
references.pmid: 10854204
references.citation: Am J Pathol. 2000 Jun;156(6):2123-33
references.pmid: 10854233
references.citation: Int J Pancreatol. 2000 Apr;27(2):93-103
references.pmid: 10862508
references.citation: Cancer. 2000 Jun 1;88(11):2495-504
references.pmid: 10861425
references.citation: Am J Pathol. 2000 Jul;157(1):83-92
references.pmid: 10880379
references.citation: J Pathol. 2000 Sep;192(1):81-9
references.pmid: 10951404
references.citation: Am J Pathol. 2000 Sep;157(3):755-61
references.pmid: 10980115
references.citation: Dig Dis. 2001;19(1):15-23
references.pmid: 11385247
references.citation: Virchows Arch. 2001 Jun;438(6):581-90
references.pmid: 11469690
references.citation: Virchows Arch. 2001 Dec;439(6):798-802
references.pmid: 11787853
references.citation: Mod Pathol. 2002 Apr;15(4):441-7
references.pmid: 11950919
references.citation: Hematol Oncol Clin North Am. 2002 Feb;16(1):1-16
references.pmid: 12063821
references.citation: Pancreatology. 2001;1(5):405-15
references.pmid: 12120217
references.citation: Pancreatology. 2001;1(6):581-6
references.pmid: 12120240
references.citation: Br J Cancer. 2002 Aug 27;87(5):551-4
references.pmid: 12189555
references.citation: Mod Pathol. 2001 Mar;14(3):139-46
references.pmid: 11266517
references.citation: Clin Cancer Res. 2001 Apr;7(4):812-7
references.pmid: 11309327
references.citation: Am J Pathol. 2001 May;158(5):1677-83
references.pmid: 11337365
references.citation: Am J Surg Pathol. 2001 May;25(5):579-86
references.pmid: 11342768
references.citation: Gastrointest Endosc. 2001 Jun;53(7):734-43
references.pmid: 11375580
references.citation: Int J Pancreatol. 1996 Oct;20(2):85-93
references.pmid: 8968863
references.citation: Surgery. 1997 Jan;121(1):42-9
references.pmid: 9001550
references.citation: Cancer Res. 1997 Jun 1;57(11):2140-3
references.pmid: 9187111
references.citation: Int J Pancreatol. 1997 Jun;21(3):205-17
references.pmid: 9322119
references.citation: Ann Surg. 1997 Oct;226(4):491-8; discussion 498-500
references.pmid: 9351717
references.citation: Cancer Epidemiol Biomarkers Prev. 1998 Jun;7(6):515-21
references.pmid: 9641496
references.citation: Mutat Res. 1998 Sep 20;405(2):125-33
references.pmid: 9748537
references.citation: Pancreas. 1998 Nov;17(4):323-4
references.pmid: 9821172
references.citation: Cancer. 1999 Jan 15;85(2):326-32
references.pmid: 10023699
references.citation: Int J Cancer. 1999 Mar 15;80(6):827-41
references.pmid: 10074914
references.citation: Cancer. 1999 Apr 15;85(8):1703-10
references.pmid: 10223563
references.citation: Hum Pathol. 1999 Jun;30(6):602-10
references.pmid: 10374765
references.citation: Int J Clin Pharmacol Ther. 2002 Aug;40(8):354-67
references.pmid: 12467304