will become public information. Therefore, do not include proprietary/confidential information. DO NOT EXCEED THE SPACE PROVIDED.Pancreatic cancer is an almost uniformly fatal disease that will strike -33,000 families in the United Statesthis year. It has been estimated that 5-10% of these cancers have a familial basis. A better understanding ofthe genetic basis for the familial aggregation of pancreatic cancer will form a foundation for counselingpatients and their families, a basis for the rational application of new tests to detect this disease earlier, andmay lead to gene-specific therapies. This project builds on progress made and collaborations establishedduring the last funding period of this Gl SPORE in which we demonstrated: a) that individuals with a strongfamily history of pancreatic cancer have a significantly increased risk of developing pancreatic cancer, b) thatthese at-risk individuals can be screened by endoscopic ultrasound for early neoplasia, c) that this earlyneoplasia has a distinct phenotype, d) that germ-line mutations in BRCA2 and other members of the Fanconianemia pathway are associated with an increased risk of developing pancreatic cancer, and e) that cancerswith these mutations are selectively sensitive to gene-specific therapies. We now propose to: 1) define thepatterns of clustering of pancreatic and non-pancreatic cancers in families and to use these data to develop arisk prediction tool (PancPRO) for clinical use, 2) perform a case-control genome wide association study onfamilial pancreatic cancer kindreds of Ashkenazi Jewish descent, and 3) determine the gene(s) responsiblefor the familial clustering of pancreatic cancer. The studies proposed here directly address a researchpriority identified in the NCI Pancreatic Cancer Program Review Group (PRG) - 'Identify genetic factors,environmental factors, and gene-environment interactions that contribute to pancreatic cancer development.'The studies proposed will utilize tissues and families from the Cores (Core 2 and Core 3) to translate geneticdiscoveries made in Project 1B and 3C to patient care and they will provide a scientific basis for the selectionof patients.
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