MicroRNAs in plasma of pancreatic ductal adenocarcinoma patients as novel blood-based biomarkers of disease

Abstract

Development of minimally invasive biomarker assays for early detection and effective clinical management of pancreatic cancer is urgently needed to reduce high morbidity and mortality associated with this malignancy. We hypothesized that if aberrantly expressing microRNAs (miRNA) in pancreatic adenocarcinoma tissues are detected in blood plasma, then plasma profiling of these miRNAs might serve as a minimally invasive early detection biomarker assay for this malignancy. By using a modified protocol to isolate and quantify plasma miRNAs from heparin-treated blood, we show that miRNA profiling in plasma can differentiate pancreatic adenocarcinoma patients from healthy controls. We have profiled four miRNAs, miR-21, miR-210, miR-155, and miR-196a, all implicated in the development of pancreatic cancer with either proven or predicted target genes involved in critical cancer-associated cellular pathways. Of these, miR-155 has recently been identified as a candidate biomarker of early pancreatic neoplasia, whereas elevated expression of miR196a has been shown to parallel progression of disease. The results revealed a sensitivity of 64% and a specificity of 89% with the analyses of plasma levels for this panel of four miRNAs. The area under the receiver operating characteristic curve were estimated at 0.82 and 0.78 without and with leave-one-out cross-validation scheme, respectively. These observations, although a "proof of principle" finding at this time, show the feasibility of developing plasma miRNA profiling as a sensitive and specific blood-based biomarker assay for pancreatic cancer that has the potential of translation to the clinic with additional improvements in the future.

Figures

Figure 1

The relative fold change of four miRNAs in the plasma of pancreatic adenocarcinoma patients and normal healthy controls. The horizontal line of pluses (+) represent the mean fold change for each miRNA. (a) miR-21, (b) miR-210, (c) miR-155, (d) miR-196a.

Figure 2

Receiver operating characteristic (ROC) curves of different sample sets analyzed for the plasma levels of the four individual miRNAs (a-d) and an identical sample set analyzed for the four miRNA individually and in combination as a composite panel (e).