ABSTRACT: Over one million individuals are identified with pancreatic cysts every year. IPMNs and MCNs, are pre-cursors to pancreatic cancer, and offer the opportunity for the early detection, or even prevention, of pancreatic cancer. In contrast, serous cystadenomas or pseudocysts, are benign. Currently tools are inadequate to fully delineate these lesions prior to surgical resection, with up to 68% of the operations performed on patients with a pancreatic cyst ultimately found to be unnecessary. Guidelines recommend lifelong surveillance for IPMNs, however this is based on the lowest level of scientific evidence. Furthermore, no data exists on the molecular progression of IPMNs and MCNs in situ. We developed a Comprehensive Cyst (CompCyst) EUS companion test which combines clinical, radiological, genetic and protein marker data. In an initial evaluation of 862 surgically resected pancreatic cysts, the CompCyst test had a superior performance for identifying cysts which required surgery, needed surveillance, or were benign, compared with the current routine evaluation. The Aims of the proposed project are to: Aim 1: Evaluate the genetic and clinical natural history of pancreatic cysts in a prospective international study. Aim 2: Evaluation and optimization of approaches for the management of pancreatic cysts. Aim 3: Develop a Second-Generation CompCyst test (CompCyst2). The overarching goal of Project 3 is to develop a clinically relevant tool which will be incorporated into clinical practice and will improve outcomes for patients with pancreatic cysts, specifically avoiding unnecessary surveillance or surgical resection.