Predictive Factors for Pancreatic Cancer in Patients with Chronic Pancreatitis in Association with K-ras Gene Mutation

Background and Study Aims: Chronic pancreatitis is considered to be a predisposing factor for pancreatic ductal adenocarcinoma (PAC). The purpose of this study was to examine the prognostic value of a finding of mutated (K-ras) gene in predicting the development of PAC in patients with chronic pancreatitis. Patients and Methods: The pancreatic duct brushings of 146 patients with chronic pancreatitis were examined in order to identify K-ras gene mutations. A total of 112 patients were followed up (median duration 42 months) using clinical evaluation, serum CA19 - 9 levels, and imaging studies. Results: One or more K-ras mutations were found in 57 of the 146 patients with chronic pancreatitis (39 %). Patients harboring K-ras mutations had a higher incidence of persistent alcohol consumption (P = 0.041) and of prior rupture of the main pancreatic duct (P = 0.040). A finding of nuclear atypia in brushing cytology was also more common in patients with K-ras mutation (P = 0.048). Out of the 112 patients who were followed up, PAC occurred in four of the 44 patients who had a K-ras mutation, but in none of the 68 patients with the wild genotype (P = 0.022). PAC occurred in three of the 25 patients who did not have pancreatic calcifications (P = 0.034) and in four of the 54 patients who had demonstrated exocrine insufficiency, but in none of the 58 patients with preserved exocrine function (P = 0.051). Using stepwise logistic regression, the absence of calcifications, the presence of exocrine insufficiency, and the presence of K-ras mutation were identified as independent predictive factors for cancer development in all patients with chronic pancreatitis. Conclusions: K-ras gene mutations occur in chronic pancreatitis and are associated with evolution towards PAC. The absence of pancreatic calcifications and the presence of exocrine insufficiency were identified as additional predictive factors for the development of PAC.

References

• 1 Gudjonsson B. Cancer of the pancreas: 50 years of surgery.  Cancer. 1987;  60 2284-2303
• 2 Ahmad N A, Lewis J D, Ginsberg G G. et al . Long-term survival after pancreatic resection for pancreatic carcinoma.  Am J Gastroenterol. 2001;  96 2609-2615
• 3 Lowenfels A B, Maisonneuve P, Cavallini G. et al . and the International Pancreatitis Study Group. Pancreatitis and the risk of pancreatic cancer.  N Engl J Med. 1993;  328 1433-1437
• 4 Malka D, Hammel P, Maire F. et al . Risk of pancreatic adenocarcinoma in chronic pancreatitis.  Gut. 2002;  51 849-852
• 5 McGrath J P, Capon D J, Smith D H. et al . Structure and organization of the human Ki-ras proto-oncogene and a related processed pseudogene.  Nature. 1983;  304 501-506
• 6 Garrington T P, Johnson G L. Organization and regulation of mitogen-activated protein-kinase signaling pathways.  Curr Opin Cell Biol. 1999;  11 211-218
• 7 Almoguera C, Shibata D, Forrester K. et al . Most human carcinomas of the exocrine pancreas contain mutant c-K-ras genes.  Cell. 1988;  53 549-554
• 8 Kondo H, Sugano K, Fukayama N. et al . Detection of point mutations in the K-ras oncogene at codon 12 in pure pancreatic juice for diagnosis of pancreatic carcinoma.  Cancer. 1994;  73 1589-1594
• 9 Nakamura Y, Onda M, Uchida E. Analysis of K-ras codon 12 point mutations using duodenal lavage fluid for diagnosis of pancreatic carcinoma.  Pancreas. 1999;  18 133-140
• 10 Van Laethem J L, Vertongen P, Deviere J. et al . Detection of c-Ki-ras gene codon 12 mutations from pancreatic duct brushings in the diagnosis of pancreatic tumors.  Gut. 1995;  36 781-787
• 11 Cerny W L, Mangold K A, Scarpelli D G. K-ras mutation is an early event in pancreatic duct carcinogenesis in the Syrian golden hamster.  Cancer Res. 1992;  52 4507-4513
• 12 Tada M, Ohashi M, Shiratori Y. et al . Analysis of K-ras gene mutation in hyperplasic duct cells of the pancreas without pancreatic disease.  Gastroenterology. 1996;  110 227-231
• 13 Lüttges J, Schlehe B, Menke M A. et al . The K-ras mutation pattern in pancreatic ductal adenocarcinoma usually is identical to that in associated normal, hyperplasic, and metaplasic ductal epithelium.  Cancer. 1999;  85 1703-1710
• 14 Banerjee S, Zoubine M N, Mullick M. et al . Tumor angiogenesis in chronic pancreatitis and pancreatic adenocarcinoma: impact of K-ras mutations.  Pancreas. 2000;  20 248-255
• 15 Moore P S, Sipos B, Orlandini S. et al . Genetic profile of 22 pancreatic carcinoma cell lines: analysis of K-ras, p53, p16 and DPC4/Smad4.  Virchows Arch.. 2001;  439 798-802
• 16 Furuya N, Kawa S, Akamatsu T, Furihata K. Long-term follow-up of patients with chronic pancreatitis and K-ras gene mutation detected in pancreatic juice.  Gastroenterology. 1997;  113 593-598
• 17 Boadas J, Mora J, Urgell E. et al . Clinical usefulness of K-ras mutation detection and cytology in pancreatic juice in the diagnosis and screening of pancreatic cancer.  Eur J Gastroenterol Hepatol. 2001;  13 1153-1159
• 18 Löhr M, Müller P, Mora J. et al . p53 and K-ras mutations in pancreatic juice samples from patients with chronic pancreatitis.  Gastrointest Endosc. 2001;  53 734-743
• 19 Van Laethem J L, Bourgeois V, Parma J. et al . Relative contribution of Ki-ras gene analysis and brush cytology during ERCP for the diagnosis of biliary and pancreatic diseases.  Gastrointest Endosc. 1998;  47 479-485
• 20 Queneau P E, Adessi G L, Thibault P. et al . Early detection of pancreatic cancer in patients with chronic pancreatitis: diagnostic utility of a K-ras point mutation in the pancreatic juice.  Am J Gastroenterol. 2001;  96 700-704
• 21 Barthelemy P, Bouisson M, Escourou J. et al . Identification of K-ras mutation in pancreatic juice in the early diagnosis of pancreatic cancer.  Ann Intern Med. 1995;  123 188-191
• 22 Einarsson K, Bjökhem I, Eklöf R, Blomstrand R. 14C triolein breath test as a rapid and convenient screening test for fat malabsorption.  Scand J Gastroenterol. 1983;  18 9-12
• 23 Cremer M. Les pancreatiques chroniques primitives.  Acta Gastroenterol Belg. 1976;  39 522-546
• 24 Axon A T, Classen M, Cotton P B. et al . Pancreatography in chronic pancreatitis: international definition.  Gut. 1984;  25 1107-1112
• 25 Telford J J, Farrell J J, Saltzman J R. et al . Pancreatic stent placement for duct disruption.  Gastrointest Endosc. 2002;  56 18-24
• 26 Jiang W, Kahn S M, Guillem J G. et al . Rapid detection of ras oncogenes in human tumors: application to colon, esophageal, and gastric cancer.  Oncogene. 1989;  4 923-928
• 27 Verlaan-de Vries M, Bogaard M E, van den Elst H. et al . A dot-blot screening procedure for mutated ras oncogenes using synthetic oligodeoxynucleotides.  Gene. 1986;  50 313-320
• 28 Löhr M, Maisonneuve P, Lowenfels A B. K-ras mutations and benign pancreatic disease.  Int J Pancreatol. 2000;  27 93-103
• 29 Gansauge S, Schmidt R M, Muller J. et al . Genetic alterations in chronic pancreatitis: evidence for early occurrence of p53 but not K-ras mutations.  Br J Surg. 1998;  85 337-340
• 30 Behn M, Qun S, Pankow W. et al . Frequent detection of ras and p53 mutations in brush cytology samples from lung cancer patients by a restriction fragment length polymorphism-based ”enriched PCR” technique.  Clin Cancer Res. 1998;  4 361-371
• 31 Van Laethem J L. Ki-ras oncogene mutations in chronic pancreatitis: which have discriminating ability for malignant potential.  Ann NY Acad Sci. 1999;  880 210-218
• 32 Hruban R H, Adsay N V, Albores-Saavedra J. et al . Pancreatic intraepithelial neoplasia: a new nomenclature and classification system for pancreatic duct lesions.  Am J Surg Path. 2001;  25 579-586
• 33 Apple S K, Hecht J R, Lewin D N. et al . 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;  30 123-129
• 34 Layer P, Yamamoto H, Kalthoff L. et al . The different courses of early- and late-onset idiopathic and alcoholic chronic pancreatitis.  Gastroenterology. 1994;  107 1481-1487
• 35 Etemad B, Whitcomb D C. Chronic pancreatitis: diagnosis, classification and new genetic developments.  Gastroenterology. 2001;  120 682-707
• 36 Biankin A V, Kench J G, Morey A L. et al . Overexpression of p21 (WAF1/CIP1) is an early event in the development of pancreatic intraepithelial neoplasia.  Cancer Res. 2001;  61 8830-8837
• 37 Costentin L, Pages P, Bouisson M. et al . Frequent deletions of tumor suppressor genes in pure pancreatic juice from patients with tumoral or nontumoral pancreatic disease.  Pancreatology. 2002;  2 17-25