Pancreatic cancer is a devastating, highly lethal, but poorly understood cancer. Family history is an established risk factor for pancreatic cancer, and susceptibility gene discovery in high risk familial pancreatic cancer (FPC) is a valid objective. New technical developments make possible productive family based linkage analysis of cancer. We propose a multicenter, multidisciplinary Pancreatic Cancer Genetic Epidemiology (PACGENE) Consortium to identify susceptibility genes in high risk FPC pedigrees using cutting-edge genetic analysis methods. We hypothesize that (1) there are specific discoverable genotypes that greatly increase the risk of developing adenocarcinoma of the pancreas, and (2) some genotypes may manifest through tobacco exposure. To address these hypotheses, this project has assembled an experienced research team with expertise in genetic epidemiology, gene mapping, pancreatic cancer biology, cancer molecular genetics, and pathology/diagnosis of pancreatic cancer that will study high risk FPC pedigrees using state of the art linkage analysis techniques. The PACGENE Consortium will be composed of six experienced primary data collection centers, a statistical genetics Core, and a pathology/archival genotyping Core. Oversight of the whole will be provided by a Steering Committee with consultation from an External Advisory Committee.
Our specific aims are:
Aim 1 : To identify high risk pedigrees for genetic linkage analysis utilizing established pancreatic cancer family research resources. The six centers will screen 8,900 new cases over 5 years to accrue biospecimens, tumor tissue, and risk factor data (including smoking history) from available relevant family members of 75 FPC pedigrees suitable for genetic linkage studies (those containing 3 or more persons affected with pancreatic cancer and those providing expected lod scores of 0.3 or higher).
Aim 2 : To genotype informative individuals in high-risk FPC pedigrees with 400 evenly spaced markers (-10 centimorgan intervals) throughout the genome. Genotyping with genome-wide microsatellite markers will be done on an estimated 1,500 individuals in the 75 FPC families identified in Aim 1.
Aim 3 : To map a pancreatic cancer susceptibility gene(s) by genetic linkage analysis of the high-risk FPC pedigrees. We propose to use conventional parametric linkage strategies, but will also implement the latest methods that incorporate environmental covariates in the analyses. implications Through such efforts, the consortium will facilitate the development of a family-based gene-discovery research resource that will be positioned to characterize genetic risk of pancreatic cancer and to conduct future translational studies, including interventions targeted to high risk groups. The research described in this application is 100% relevant to pancreatic cancer.
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