Abstract
Genome-wide hypomethylation and CpG island hypermethylation play a role in human cancer. We evaluated the utility of measuring epigenetic alterations in pancreatic and biliary fluids as molecular markers for pancreatobiliary cancers. As a surrogate of genome-wide hypomethylation, levels of LINE-1methylation were analyzed using bisulfite pyrosequencing. CpG island hypermethylation of tumor-associated genes was analyzed using MethyLight. Pancreatobiliary cancers exhibited significantly lower LINE-1 methylation levels in pancreatic and biliary fluids than did noncancerous pancreatobiliary disease. However, LINE-1 hypomethylation was more evident in pancreatic cancer tissues than in pancreatic fluids. CpG island hypermethylation of tumor-associated genes was detected at various frequencies, but it was not correlated with LINE-1 hypomethylation. Hypermethylation of the ubiquitin carboxylterminal esterase L1 (UCHL1) gene was cancer-specific and most frequently detected in pancreatic (67%) or biliary (70%) fluids from patients with pancreatobiliary cancer. As a single marker, hypermethylation of the UCHL1 gene in pancreatic and biliary fluids was most useful for the detection of pancreatic and pancreatobiliary cancer, respectively (100% specificity). Hypermethylation of the UCHL1 and RUNX3 genes in pancreatic and biliary fluids was the most useful combined marker for pancreatic (87% sensitivity and 100% specificity) and pancreatobiliary (97% sensitivity and 100% specificity) cancer. Treatment with a demethylating agent, 5-aza-2'-deoxycytidine, restored UCHL1 expression in pancreatobiliary cancer cell lines. The results suggest that hypermethylation of the UCHL1 gene plays a key role in the pathogenesis of pancreatobiliary cancers and that detection of hypermethylation of UCHL1 and RUNX3 in pancreatobiliary fluids is useful for the diagnosis of these malignancies.
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