This application for continuation of the Specialized Program of Research Excellence (SPORE) in Gastrointestinal Cancer at the Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins supports a highly interactive, multidisciplinary program. Four research projects, four cores, a career development and a research developmental program are proposed to extend our translational research in colorectal and pancreatic cancer. Project 1, Improving Pancreatic Cancer Risk Assessment: Clinical/Population Leader Dr. Alison Klein and Basic Science Leader Dr. Michael Goggins. Project 2, Neo-antigen Vaccines for Pancreatic Cancer and Colorectal Cancer. Basic Science Leaders Drs. Elizabeth Jaffee and Drew Pardoll and Clinical Leaders Drs. Daniel Laheru and Nilo Azad. Project 3, Diagnosis and Management of Pancreatic Cysts: Clinical Leader Dr. Anne Marie Lennon and Basic Science Leaders Drs. Ken Kinzler and Bert Vogelstein Project 4, Using TME genetics and immunobiology to drive combination immunotherapies. Basic Science Leader Dr. Elizabeth Jaffee and Clinical Leaders: Drs. Dung Le and Lei Zheng The cores support the research programs (Admin Core: Administration and Communication, Dr. Alison Klein; Core 1, Statistics/Bioinformatics, Drs. Elizabeth Sugar and Robert Scharpf: Core 2, Human Tissue Research and Logistics, Dr. Robert Anders; Core 3, Familial and Population Cancer Registries, Drs. Frank Giardiello and Alison Klein. The Career Development Program (Dr. Scott Kern) aids the emergence of new investigators and the Research Developmental Program (Dr. Bert Vogelstein) provides rapid funding of innovative directions