Molecular analysis to detect pancreatic ductal adenocarcinoma in high-risk groups

Yan, Li and McFaul, Christopher and Howes, Nathan and Leslie, Jane and Lancaster, Gillian and Wong, Theresa and Threadgold, Jane and Evans, Jonathan and Gilmore, Ian and Smart, Howard and Lombard, Martin and Neoptolemos, John and Greenhalf, William (2005) Molecular analysis to detect pancreatic ductal adenocarcinoma in high-risk groups. Gastroenterology, 128 (7). pp. 2124-2130. ISSN 0016-5085

Abstract

Background & Aims: Screening of high-risk groups for pancreatic cancer has not been adopted because of concerns regarding specificity and sensitivity. Suitability of a combination of 3 novel molecular screening techniques was investigated. Methods: Pancreatic juice was extracted from 146 patients with pancreatic ductal adenocarcinoma, chronic pancreatitis, or biliary tract stones. p53 mutations were analyzed by using a modified yeast functional assay, K-ras status was analyzed using mutation-specific real-time PCR and the proportion of p16INK4a promoter methylation was estimated using comparative methylation-specific real-time PCR. Results: p53 mutations were detected in 20 of 48 (42%) cancer cases, none of 49 controls, and 2 of 49 (4%) patients with pancreatitis. K-ras mutations were detected in 31 of 57 (54%) cancer patients, 13 of 61 (21%) controls, and 23 of 67 (34%) patients with pancreatitis. Twenty-six of 42 (62%) cancer patients had promoter methylation levels > 12%, compared with 3 of 24 (13%) controls, and 2 of 26 (8%) with pancreatitis. Mutations in p53 or high-level p16INK4a promoter methylation occurred in 29 of 36 (80%) patients with cancer, 3 of 24 (13%) controls, and 3 of 22 (13%) with pancreatitis. Three patients (8%) of 36 with cancer; 14 of 24 (58%) controls, and 13 of 22 (59%) patients with pancreatitis had no marker. The gallstone disease patients had a high rate of positive K-ras mutations, possibly reflecting the fact that they were not disease free. Conclusions: Combination molecular analysis increased the discrimination between patients with malignant and benign disease. This level of discrimination would allow patients in high-risk groups to be stratified from negligible risk to over 50% probability of an early cancer.