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Age- and Disease-Related Methylation of Multiple Genes in Nonneoplastic Duodenum and in Duodenal Juice

Departments of ¹ Pathology, ² Oncology, ³ Medicine, and ⁴ Surgery and ⁵ Division of Biostatistics, Johns Hopkins Medical Institutions, Baltimore, Maryland and ⁶ Fourth Department of Internal Medicine, Tokyo Medical University, Shinjuku, Tokyo, Japan

Requests for reprints: Michael Goggins, Department of Pathology, Johns Hopkins Medical Institutions, 632 Ross Building, 720 Rutland Avenue, Baltimore, MD 21205-2196. Phone: 410-955-3511; Fax: 410-614-0671; E-mail: mgoggins{at}jhmi.edu.

Purpose: Methylation of CpG islands contributes to gene silencing during cancer development, and although some methylation alterations are promising diagnostic markers of cancer, some CpG islands are also methylated in normal tissues. We have previously observed that some normally unmethylated CpG islands that undergo methylation in pancreatic cancers are normally methylated in the adjacent duodenum. Because duodenal methylation patterns are an important consideration when sampling pancreatic tissues for pancreatic cancer methylation alterations, we determined the DNA methylation patterns of 24 genes in the normal duodenum of patients with pancreatic disease and related these patterns to demographic factors.

Experimental Design: The nonneoplastic duodenal mucosa of 158 patients with pancreatic carcinoma and 41 patients with chronic pancreatitis was analyzed using methylation-specific PCR and combined bisulfite restriction analysis. Secretin-stimulated pancreatic/duodenal juice from 15 individuals undergoing endoscopic investigation for upper gastrointestinal disease was also analyzed.

Results: Low-level methylation was detectable by methylation-specific PCR in the nonneoplastic duodenum of many patients with pancreatic cancer and chronic pancreatitis as well as in the pancreaticoduodenal secretions of patients without pancreaticobiliary disease. For many genes, the prevalence of methylation increased with age and was more prevalent in patients with pancreatic cancer than in age-matched patients with chronic pancreatitis.

Our results indicate that strategies to detect pancreatic cancer using aberrantly methylated genes should rely on analysis of pure pancreatic juice rather than on pancreatic juice collected within the duodenal lumen. Patients who develop pancreatic cancer may have a greater propensity to methylate CpG islands than age-matched controls.

Key Words: duodenum • pancreatic carcinoma • chronic pancreatitis • duodenal juice • methylation • smoking • aging

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