Improving the early detection of cancer has proven to be one of the most effective ways of reducing cancermortality. Most patients with pancreatic cancer do not develop symptoms until after the disease has spread toother organs. Accurate laboratory tests that could detect pancreatic cancer while it is still curable would be ofgreat benefit to patients. The opportunity to cure individuals at high-risk of developing pancreatic cancer issuggested by the results of recent screening studies showing that imaging the pancreas with endoscopicultrasound and CT, can detect and cure individuals who have precursors to invasive pancreatic cancer.Screening such individuals with imaging alone is costly and therefore not an optimal early detection strategy.Thus, there is a need for accurate molecular markers that indicate the presence of microscopic pancreaticneoplasia that is invisible to imaging as a way to better define pancreatic neoplasia risk and burden. Thisproject has identified several promising markers of pancreatic cancer including the serum protein marker MIC-1 and methylated DMA markers for pancreatic juice analysis. We have also begun evaluating the utility of usingmethylated DNA markers along with endoscopic ultrasound to screen individuals at high risk of developingpancreatic cancer. To build on these successes, we will utilize tissues of Core 2 and the CAPS (Cancer of thePancreas) screening trials to translate the discoveries of this project and Project 3C (formerly 2A) to patientcare, to provide a scientific basis for approaches taken in Projects 3A and Core 3, and to adopt newtechnology developed in Project 1A. To achieve our goal of improving the diagnosis of early pancreaticneoplasia we will investigate three rational marker approaches. First, we propose to use microarrays to identifya more specific panel of DNA methylation markers and test their ability to identify individuals with early invasivepancreatic cancer and its precursors. Thus, we propose for Specific Aim #1: To detect and characterize genesspecifically methylated in early-stage invasive pancreatic cancer and its precursors and to develop a diagnosticmarker panel for pancreatic fluid analysis. Second, the detection of cancer using molecular markers dependsas much on accurate assays as on the markers being assayed. A novel method has been developed forquantifying low-abundance mutations in secondary fluids termed 'BEAMing' (Beads, Emulsion, Amplificationand Magnetics). We will adapt the BEAMing method to detecting circulating DNA methylation alterations thatarise in invasive pancreatic cancer and its precursors. Thus, we propose for Aim #2: To develop methods todetect methylated DNA and evaluate their utility as indicators of early pancreatic cancer and its precursors.Third, we will continue to identify and evaluate promising serum protein markers of pancreatic cancer and willevaluate the utility of serum markers to identify pre-invasive disease neoplasia. Thus, we propose for Aim #3:To identify protein markers of early pancreatic cancer and its precursors.
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