This re-submitted proposal seeks continued funding for the Pancreatic Cancer Genetic Epidemiology (PACGENE) Consortium, a multicenter, multidisciplinary team which has the goal to identify susceptibility genes for familial pancreatic cancer (FPC). The PACGENE Consortium has shown that coordinated case finding, family recruitment, and linkage analysis are productive: we have identified three novel regions, and are positioned to use the pedigree material to further gene discovery. The PACGENE Consortium comprises 7 data collection/analysis centers in the U.S. and Canada, 2 Cores (Data Management/Analysis and Pathology/Tissue Genotyping), and is guided by Steering and External Advisory Committees.
Our specific aims are:
AIM 1. To validate linkage findings for gene discovery with an extended, final sample of FPC families. We will: a) Develop a set of 63 new FPC pedigrees and follow up our existing cohort of FPC pedigrees to increase their informativeness;b) Perform a genomewide (~6008 single nucleotide polymorphism (SNP)) validation linkage analysis (genotyping will be sought at the Center for Inherited Disease Research (CIDR) at no cost to this grant);
AIM 2. To perform a familial case-control association study to validate SNP associations identified in other consortia studies. We will genotype 800 FPC probands and 800 unrelated family controls using a custom SNP marker panel identified by the PanScan genomewide association study of the Cohort Consortium, the Pancreatic Cancer Case-Control Consortium, and our own linkage analyses;
AIM 3. To identify the genes in candidate regions identified by linkage and association. We will: a) Fine map regions identified through linkage analyses (including chromosomes 2p, 2q, and 10q);b) Perform genomewide loss of heterozygosity allelotyping of microdissected early stage tumors (PanINs and IPMNs) from FPC probands (comparing tumor to normal), with a focus on regions of interest;c) Resequence the best candidate genes in the regions identified. Public Health Relevance: Over 37,000 new cases of pancreatic cancer will occur in the U.S. in 2007, almost all rapidly fatal. Our research will help identify the genes for FPC, furthering knowledge about the etiology of pancreatic cancer that should accelerate translation to care. Risk assessment will be improved, and identified FPC genes will lead to development of more effective strategies for early detection, prevention, and therapy.

Public Health Relevance

Over 37,000 new cases of pancreatic cancer will occur in the U.S. in 2007, almost all rapidly fatal. Our research will help identify the genes for familial pancreatic cancer (FPC), furthering knowledge about the cause(s) of pancreatic cancer that should accelerate translation to care. Risk assessment will be improved, and identified FPC genes will lead to development of more effective strategies for early detection, prevention, and therapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA097075-10
Application #
8259536
Study Section
Epidemiology of Cancer Study Section (EPIC)
Program Officer
Seminara, Daniela
Project Start
2002-08-01
Project End
2014-08-31
Budget Start
2012-09-01
Budget End
2014-08-31
Support Year
10
Fiscal Year
2012
Total Cost
$1,520,860
Indirect Cost
$219,164
Name
Mayo Clinic, Rochester
Department
Type
DUNS #
006471700
City
Rochester
State
MN
Country
United States
Zip Code
55905
Zhen, David B; Rabe, Kari G; Gallinger, Steven et al. (2015) BRCA1, BRCA2, PALB2, and CDKN2A mutations in familial pancreatic cancer: a PACGENE study. Genet Med 17:569-77
Wu, Lang; Goldstein, Alisa M; Yu, Kai et al. (2014) Variants associated with susceptibility to pancreatic cancer and melanoma do not reciprocally affect risk. Cancer Epidemiol Biomarkers Prev 23:1121-4
Cotterchio, Michelle; Lowcock, Elizabeth; Hudson, Thomas J et al. (2014) Association between allergies and risk of pancreatic cancer. Cancer Epidemiol Biomarkers Prev 23:469-80
Bosetti, C; Rosato, V; Li, D et al. (2014) Diabetes, antidiabetic medications, and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case-Control Consortium. Ann Oncol 25:2065-72
Grant, Robert C; Al-Sukhni, Wigdan; Borgida, Ayelet E et al. (2013) Exome sequencing identifies nonsegregating nonsense ATM and PALB2 variants in familial pancreatic cancer. Hum Genomics 7:11
Bosetti, C; Lucenteforte, E; Bracci, P M et al. (2013) Ulcer, gastric surgery and pancreatic cancer risk: an analysis from the International Pancreatic Cancer Case-Control Consortium (PanC4). Ann Oncol 24:2903-10
Anderson, Laura N; Cotterchio, Michelle; Knight, Julia A et al. (2013) Genetic variants in vitamin d pathway genes and risk of pancreas cancer; results from a population-based case-control study in ontario, Canada. PLoS One 8:e66768
Klein, Alison P; Lindström, Sara; Mendelsohn, Julie B et al. (2013) An absolute risk model to identify individuals at elevated risk for pancreatic cancer in the general population. PLoS One 8:e72311
Jang, Ji-Hyun; Cotterchio, Michelle; Borgida, Ayelet et al. (2013) Interaction of polymorphisms in mitotic regulator genes with cigarette smoking and pancreatic cancer risk. Mol Carcinog 52 Suppl 1:E103-9
Kanda, Mitsuro; Matthaei, Hanno; Wu, Jian et al. (2012) Presence of somatic mutations in most early-stage pancreatic intraepithelial neoplasia. Gastroenterology 142:730-733.e9

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