This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Caldas, C. Articles by Kern, S. E. Search for Related Content PubMed PubMed Citation Articles by Caldas, C. Articles by Kern, S. E.

Detection of K-ras Mutations in the Stool of Patients with Pancreatic Adenocarcinoma and Pancreatic Ductal Hyperplasia¹

Departments of Oncology [C. C., S. E. K.], Pathology [S. A. H., R. H. H., M. S. R., S. E. K.], and Surgery [C. J. Y.], The Johns Hopkins University School of Medicine, Baltimore, Maryland 21205

Pancreatic adenocarcinoma is the fifth leading cause of cancer death in the United States. Mutations in the K-ras oncogene occur in 85% of pancreatic adenocarcinomas and have also been identified in 75% of pancreatic ducts with mucinous cell hyperplasia seen in association with chronic pancreatitis. We identified K-ras mutations in 65% of duct lesions associated not only with chronic pancreatitis but also with pancreatic adenocarcinoma and distal common bile duct carcinoma (cholangiocarcinoma). These observations make K-ras a potential candidate for a gene-based diagnostic test. Indeed, K-ras mutations have been demonstrated in the pancreatic secretions of patients with pancreatic carcinoma and pancreatic intraductal neoplasia. We analyzed stool specimens for mutated K-ras sequences using a plaque hybridization assay in patients with pancreatic adenocarcinoma, cholangiocarcinoma, and chronic pancreatitis. K-ras mutations were detected in stool specimens from 6 of 11 patients with pancreatic adenocarcinoma, from 2 of 3 patients with cholangiocarcinoma, and from 1 of 3 patients with chronic pancreatitis. The K-ras mutations found in stool specimens from patients with pancreatic carcinoma were identical to those in the primary cancer in five cases. Mutations found in the stool specimens from one patient with pancreatic cancer, one patient with chronic pancreatitis, and two patients with cholangiocarcinoma were the same as those identified in pancreatic ductal mucinous cell hyperplasia lesions present in the resected pancreas specimens. Our data suggest that the K-ras mutations originating from cells of pancreatic adenocarcinomas and from cells shed by abnormal pancreatic duct epithelium can be detected in the stool. These results support the further exploration of stool K-ras analysis as a potential screening assay for the early detection of pancreatic adenocarcinoma and precursor lesions such as pancreatic ductal mucinous cell hyperplasia.

¹ Supported by NIH Grants RO1-CA56130-03 and RO1-CA57345, by Deutschen Krebshilfe (to S. A. H.), and by the Medical Research Council of Canada (to M. S. R.).

² To whom requests for reprints should be addressed, at 628 Ross Research Building, The Johns Hopkins School of Medicine, Baltimore, MD 21205-2196.

Received 3/ 3/94. Accepted 5/17/94.

This article has been cited by other articles:

				C Brockschmidt, H Hirner, N Huber, T Eismann, A Hillenbrand, G Giamas, B Radunsky, O Ammerpohl, B Bohm, D Henne-Bruns, et al. Anti-apoptotic and growth-stimulatory functions of CK1 delta and epsilon in ductal adenocarcinoma of the pancreas are inhibited by IC261 in vitro and in vivo Gut, June 1, 2008; 57(6): 799 - 806. [Abstract] [Full Text] [PDF]

				Z. Ji, F. C. Mei, J. Xie, and X. Cheng Oncogenic KRAS Activates Hedgehog Signaling Pathway in Pancreatic Cancer Cells J. Biol. Chem., May 11, 2007; 282(19): 14048 - 14055. [Abstract] [Full Text] [PDF]

				U. Haug, T. Hillebrand, P. Bendzko, M. Low, D. Rothenbacher, C. Stegmaier, and H. Brenner Mutant-Enriched PCR and Allele-Specific Hybridization Reaction to Detect K-ras Mutations in Stool DNA: High Prevalence in a Large Sample of Older Adults Clin. Chem., April 1, 2007; 53(4): 787 - 790. [Abstract] [Full Text] [PDF]

				J Kim, H A Reber, S M Dry, D Elashoff, S L Chen, N Umetani, M Kitago, O J Hines, K K Kazanjian, S Hiramatsu, et al. Unfavourable prognosis associated with K-ras gene mutation in pancreatic cancer surgical margins Gut, November 1, 2006; 55(11): 1598 - 1605. [Abstract] [Full Text] [PDF]

				B. Levin Molecular Screening Testing for Colorectal Cancer Clin. Cancer Res., September 1, 2006; 12(17): 5014 - 5017. [Full Text] [PDF]

				N T van Heek, S J Clayton, P D J Sturm, J Walker, D J Gouma, L A Noorduyn, G J A Offerhaus, and J C Fox Comparison of the novel quantitative ARMS assay and an enriched PCR-ASO assay for K-ras mutations with conventional cytology on endobiliary brush cytology from 312 consecutive extrahepatic biliary stenoses J. Clin. Pathol., December 1, 2005; 58(12): 1315 - 1320. [Abstract] [Full Text] [PDF]

				M. Goggins Molecular Markers of Early Pancreatic Cancer J. Clin. Oncol., July 10, 2005; 23(20): 4524 - 4531. [Abstract] [Full Text] [PDF]

				H. Zou, N. K. Osborn, J. J. Harrington, K. K. Klatt, J. R. Molina, L. J. Burgart, and D. A. Ahlquist Frequent Methylation of Eyes Absent 4 Gene in Barrett's Esophagus and Esophageal Adenocarcinoma Cancer Epidemiol. Biomarkers Prev., April 1, 2005; 14(4): 830 - 834. [Abstract] [Full Text] [PDF]

				S. E. Dowen, T. Crnogorac-Jurcevic, R. Gangeswaran, M. Hansen, J. J. Eloranta, V. Bhakta, T. A. Brentnall, J. Luttges, G. Kloppel, and N. R. Lemoine Expression of S100P and Its Novel Binding Partner S100PBPR in Early Pancreatic Cancer Am. J. Pathol., January 1, 2005; 166(1): 81 - 92. [Abstract] [Full Text] [PDF]

				C.-Y. Chen, S.-C. Shiesh, and S.-J. Wu Rapid Detection of K-ras Mutations in Bile by Peptide Nucleic Acid-mediated PCR Clamping and Melting Curve Analysis: Comparison with Restriction Fragment Length Polymorphism Analysis Clin. Chem., March 1, 2004; 50(3): 481 - 489. [Abstract] [Full Text] [PDF]

				S.-X. Qiao, M. Yuan, Y.-L. Liu, X.-S. Lin, X.-P. Zhang, and M. Tobi Detection of Gastric Cancer and Premalignant Lesions by Novel Marker Glycoprotein 87 Using Monoclonal Antibody Adnab-9 Cancer Epidemiol. Biomarkers Prev., October 1, 2003; 12(10): 1095 - 1099. [Abstract] [Full Text] [PDF]

				J. F. Parker, S. R. Florell, A. Alexander, J. A. DiSario, P. J. Shami, and S. A. Leachman Pancreatic Carcinoma Surveillance in Patients With Familial Melanoma Arch Dermatol, August 1, 2003; 139(8): 1019 - 1025. [Abstract] [Full Text] [PDF]

				C. H.W. Klaassen, M. A.F. Jeunink, C. F.M. Prinsen, T. J.M. Ruers, A. C.I.T.L. Tan, L. J.A. Strobbe, and F. B.J.M. Thunnissen Quantification of Human DNA in Feces as a Diagnostic Test for the Presence of Colorectal Cancer Clin. Chem., July 1, 2003; 49(7): 1185 - 1187. [Full Text] [PDF]

				C. Rosty, L. Christa, S. Kuzdzal, W. M. Baldwin, M. L. Zahurak, F. Carnot, D. W. Chan, M. Canto, K. D. Lillemoe, J. L. Cameron, et al. Identification of Hepatocarcinoma-Intestine-Pancreas/Pancreatitis-associated Protein I as a Biomarker for Pancreatic Ductal Adenocarcinoma by Protein Biochip Technology Cancer Res., March 1, 2002; 62(6): 1868 - 1875. [Abstract] [Full Text] [PDF]

				L. Prix, P. Uciechowski, B. Bockmann, M. Giesing, and A. J. Schuetz Diagnostic Biochip Array for Fast and Sensitive Detection of K-ras Mutations in Stool Clin. Chem., March 1, 2002; 48(3): 428 - 435. [Abstract] [Full Text] [PDF]

				R. E. Wilentz, P. Argani, and R. H. Hruban Loss of Heterozygosity or Intragenic Mutation, Which Comes First? Am. J. Pathol., May 1, 2001; 158(5): 1561 - 1563. [Full Text] [PDF]

				S Kubicka, F Kuhnel, P Flemming, B Hain, N Kezmic, K L Rudolph, M Manns, and P N Meier K-ras mutations in the bile of patients with primary sclerosing cholangitis Gut, March 1, 2001; 48(3): 403 - 408. [Abstract] [Full Text] [PDF]

				R. H. Hruban, M. Goggins, J. Parsons, and S. E. Kern Progression Model for Pancreatic Cancer Clin. Cancer Res., August 1, 2000; 6(8): 2969 - 2972. [Full Text]

				E. Heinmoller, W. Dietmaier, H. Zirngibl, P. Heinmoller, W. Scaringe, K.-W. Jauch, F. Hofstadter, and J. Ruschoff Molecular Analysis of Microdissected Tumors and Preneoplastic Intraductal Lesions in Pancreatic Carcinoma Am. J. Pathol., July 1, 2000; 157(1): 83 - 92. [Abstract] [Full Text] [PDF]

				R. H. Hruban, R. E. Wilentz, and S. E. Kern Genetic Progression in the Pancreatic Ducts Am. J. Pathol., June 1, 2000; 156(6): 1821 - 1825. [Abstract] [Full Text] [PDF]

				M. Yamano, H. Fujii, T. Takagaki, N. Kadowaki, H. Watanabe, and T. Shirai Genetic Progression and Divergence in Pancreatic Carcinoma Am. J. Pathol., June 1, 2000; 156(6): 2123 - 2133. [Abstract] [Full Text] [PDF]

				M. Goggins, R. H. Hruban, and S. E. Kern BRCA2 Is Inactivated Late in the Development of Pancreatic Intraepithelial Neoplasia : Evidence and Implications Am. J. Pathol., May 1, 2000; 156(5): 1767 - 1771. [Abstract] [Full Text] [PDF]

				R. E. Wilentz, C. A. Iacobuzio-Donahue, P. Argani, D. M. McCarthy, J. L. Parsons, C. J. Yeo, S. E. Kern, and R. H. Hruban Loss of Expression of Dpc4 in Pancreatic Intraepithelial Neoplasia: Evidence That DPC4 Inactivation Occurs Late in Neoplastic Progression Cancer Res., April 1, 2000; 60(7): 2002 - 2006. [Abstract] [Full Text]

				T. Adell, A. Gómez-Cuadrado, A. Skoudy, O. S. Pettengill, D. S. Longnecker, and F. X. Real Role of the Basic Helix-Loop-Helix Transcription Factor p48 in the Differentiation Phenotype of Exocrine Pancreas Cancer Cells Cell Growth Differ., March 1, 2000; 11(3): 137 - 147. [Abstract] [Full Text]

				P. C. de Groen, G. J. Gores, N. F. LaRusso, L. L. Gunderson, and D. M. Nagorney Biliary Tract Cancers N. Engl. J. Med., October 28, 1999; 341(18): 1368 - 1378. [Full Text] [PDF]

				A. R Hart Classic diseases revisited: Pancreatic cancer: any prospects for prevention? Postgrad. Med. J., September 1, 1999; 75(887): 521 - 526. [Abstract] [Full Text]

				D. S. LONGNECKER Molecular Pathology of Invasive Carcinoma Ann. N.Y. Acad. Sci., June 30, 1999; 880(1): 74 - 82. [Abstract] [Full Text] [PDF]

				J. L. VAN LAETHEM Ki-Ras Oncogene Mutations in Chronic Pancreatitis: Which Discriminating Ability for Malignant Potential? Ann. N.Y. Acad. Sci., June 30, 1999; 880(1): 210 - 218. [Abstract] [Full Text] [PDF]

				L. KADAJA, R. JESNOWSKI, T. MAIMETS, S. LIEBE, and M. LOHR Construction of Recombinant Retroviruses Expressing Mutated k-ras or Mutated p53 Genes Ann. N.Y. Acad. Sci., June 30, 1999; 880(1): 371 - 373. [Full Text] [PDF]

				G. H. Su, R. H. Hruban, R. K. Bansal, G. S. Bova, D. J. Tang, M. C. Shekher, A. M. Westerman, M. M. Entius, M. Goggins, C. J. Yeo, et al. Germline and Somatic Mutations of the STK11/LKB1 Peutz-Jeghers Gene in Pancreatic and Biliary Cancers Am. J. Pathol., June 1, 1999; 154(6): 1835 - 1840. [Abstract] [Full Text] [PDF]

				P. D. J. Sturm, E. A. J. Rauws, R. H. Hruban, E. Caspers, T. B. Ramsoekh, K. Huibregtse, L. A. Noorduyn, and G. J. A. Offerhaus Clinical Value of K-ras Codon 12 Analysis and Endobiliary Brush Cytology for the Diagnosis of Malignant Extrahepatic BileDuct Stenosis Clin. Cancer Res., March 1, 1999; 5(3): 629 - 635. [Abstract] [Full Text] [PDF]

				A. Castells, P. Puig, J. Mora, J. Boadas, L. Boix, E. Urgell, M. Sole, G. Capella, F. Lluis, L. Fernandez-Cruz, et al. K-ras Mutations in DNA Extracted From the Plasma of Patients With Pancreatic Carcinoma: Diagnostic Utility and Prognostic Significance J. Clin. Oncol., February 1, 1999; 17(2): 578 - 578. [Abstract] [Full Text] [PDF]

				C. Berndt, K. Haubold, F. Wenger, B. Brux, J. Muller, P. Bendzko, T. Hillebrand, E. Kottgen, and J. Zanow K-ras mutations in stools and tissue samples from patients with malignant and nonmalignant pancreatic diseases Clin. Chem., October 1, 1998; 44(10): 2103 - 2107. [Abstract] [Full Text] [PDF]

				C. Caldas Science, medicine, and the future: Molecular assessment of cancer BMJ, May 2, 1998; 316(7141): 1360 - 1363. [Full Text]

				D. Sidransky Nucleic Acid-Based Methods for the Detection of Cancer Science, November 7, 1997; 278(5340): 1054 - 1058. [Abstract] [Full Text]

				W. F. Maule, G. Ramadori, H. Munke, R. M. Schmid, G. Adler, and D. Seidler Chronic Pancreatitis N. Engl. J. Med., November 2, 1995; 333(18): 1221 - 1222. [Full Text]