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K-ras Mutations in DNA Extracted From the Plasma of Patients With Pancreatic Carcinoma: Diagnostic Utility and Prognostic Significance

From the Institut Clínic de Malalties Digestives and Department of Pathology, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic i Provincial, University of Barcelona; and Departments of Biochemistry, Gastroenterology, and Surgery, and Laboratori d'Investigació Gastrointestinal, Hospital de la Santa Creu i Sant Pau, Barcelona, Catalonia, Spain.

Address reprint requests to Antoni Castells, MD, Molecular Neurogenetics Unit, Massachusetts General Hospital, 149 13th St, 6th Floor, Charlestown, MA 02129; email castells{at}helix.mgh.harvard.edu

PURPOSE: Previous studies have demonstrated the presence of K-ras mutations in the plasma of patients with pancreatic carcinoma. However, the diagnostic utility and the prognostic significance of this finding have never been addressed.

PATIENTS AND METHODS: Forty-four consecutive patients with histologically confirmed primary pancreatic ductal adenocarcinoma were included. A control group of 37 patients with chronic pancreatitis, 10 patients with other tumors of the pancreatic area, nine patients with acute pancreatitis, and four healthy volunteers was also included. Plasma DNA was isolated and K-ras codon-12 mutations were analyzed by means of restriction fragment length polymorphism-polymerase chain reaction and single-strand conformation polymorphism techniques. Patients were followed up to establish their clinical outcome.

RESULTS: The mutant-type K-ras gene was found in plasma DNA samples of 12 (27%) of 44 patients with pancreatic ductal adenocarcinoma; this finding was related to the tumor stage (P = .05), mainly in the presence of distant metastases (P = .02). In addition, K-ras mutations were detected in the plasma DNA of two (5%) of 37 patients with chronic pancreatitis. In the subset of patients with pancreatic masses, the sensitivity and specificity of plasma K-ras analysis for pancreatic adenocarcinoma were 27% and 100%, respectively. Finally, pancreatic carcinoma patients with the mutant-type K-ras gene in plasma DNA exhibited a shorter survival time than patients with the wild-type gene (P < .005), and plasma K-ras mutations were identified as the only independent prognostic factor (odds ratio, 1.51; 95% confidence interval, 1.02 to 2.23).

CONCLUSION: Plasma K-ras analysis is a highly specific, low-sensitivity approach that has diagnostic and prognostic clinical implications in patients with pancreatic carcinoma.

The first two authors contributed equally to this study.

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