Differential methylation of cell‐free circulating DNA among patients with pancreatic cancer versus chronic pancreatitis

Abstract

BACKGROUND: Although patients with chronic pancreatitis (CP) have an increased risk of pancreatic cancer (PanCa), the timely detection of PanCa often is difficult, because the symptoms of CP and PanCa are very similar. Moreover, secondary inflammation may be identified in PanCa, further complicating diagnosis. To improve the survival of patients with PanCa, a reliable test to differentiate CP from PanCa is needed. In this article, the authors describe a methylation profile of cell-free plasma DNA that distinguished CP from PanCa with >90% accuracy. METHODS: Methylation in cell-free, plasma DNA was compared among 30 samples from patients with CP, 30 samples from patients with PanCa, and 30 samples from healthy controls (N) using a microarray-mediated methylation analysis of 56 fragments in each sample (MethDet56). Statistical analysis was done by using the Fisher exact test, a naive Bayes algorithm, and 25 rounds of 5-fold cross-validation. RESULTS: The MethDet56 methylation analysis technique identified 17 gene promoters as informative (8 for distinguishing N from CP and 14 for distinguishing CP from PanCa). It achieved 81.7% sensitivity and 78% specificity (P<.01) in the detection of CP (N vs CP) and 91.2% sensitivity and 90.8% specificity (P<.01) in the differential detection of PanCa (PanCa vs CP). CONCLUSIONS: The current data suggested that, among patients with pancreatic disease, the methylation profiles of inflammatory disease and cancer are different and open a new venue for the development of biomarkers for differential diagnosis. Further investigation of diagnostic biomarkers for pancreatic cancer based on methylation in cell-free, circulating DNA appears to be warranted.

Pancreatic Cancer Screening: Attempts and Possibilities

“…Circulating cell free DNA is also being investigated as a possible biomarker for screening, and one study successfully used methylation patterns in cell-free plasma DNA in differential detection of pancreatic cancer [37]. Glypican-1 circulating exosomes (GPC1 crExos) have also been identified as a possible mechanism to identify early pancreatic cancer.…”

Circulating DNA as a Biomarker for Early Detection of Cancer: A Brief Update with an Emphasis on Lung Cancer~!2010-06-09~!2010-08-03~!2010-09-06~!

“…It has been demonstrated that DNA methylation in the promoter region of tumor suppressor genes may be the underlying molecular mechanism responsible for this early event in carcinogenesis. Detection of epigenetic DNA methylation is promptly assessed by the circulating DNA technique, thereby opening up the possibility of using the methylated-based analysis of circulating DNA as a tool for early cancer detection [11,[13][14][15][16][17][18].…”

“…Liggett et al [19] reported a differential methylation status of cell-free circulating DNA among patients with pancreatic cancer and those with inflammatory disease alone. Moreover, a methylation profile of circulating plasma DNA in pancreatic cancer patients was reported by Melnikov et al These authors found that at least five genes were consistently predictive for plasma-based pancreatic cancer with reasonably high sensitivity and specificity outcomes in the developed composite biomarker [20].…”

“…Such studies have indicated a good correlation between restricted expression at the tissue level and the occurrence of detectable levels of candidate biomarkers in serum/plasma DNA. In this connection, the circulating methylated DNA approach has been applied as a biomarker in various forms of cancer, including pancreatic [19,20,24,25], ovarian [26][27][28][29], prostate carcinoma [30][31][32][33][34], hepatocellular carcinoma [35][36][37][38], esophageal adenocarcinoma [39,40], colorectal carcinoma [8,41,42], breast [3,[43][44][45], head and neck squamous cell carcinoma [46][47][48], non-Hodgkin lymphoma [49], and lung cancer [10,16,18,[50][51][52].…”

“…There are additional data in the literature showing that the circulating DNA in cancer patients mimics cancer-cell DNA. In fact, circulating tumor-derived nucleic acids in cancer patients may harbor tumor-specific genetic alterations and, in this way, could become an interesting target for the noninvasive examination of tumor DNA and ultimately might prove to be a suitable target for the development of diagnosis, prognosis, and follow-up cancer testing [7][8][9][10][11][12].…”