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Pancreatic Cancer Genome-Wide Association Study (GWAS)

From the Cancer Genetic Markers of Susceptibility (CGEMS) Project

Within the framework of the NCI-sponsored Cohort Consortium, investigators from 12 prospective epidemiologic cohorts formed the Pancreatic Cancer Cohort Consortium in 2006. This study, also known as "PanScan", is funded by the National Cancer Institute (NCI) and involves conducting a genome-wide association study of common genetic variants to identify markers of susceptibility to pancreatic cancer. In 2007, the study expanded to include 8 case-controls studies. The study team includes scientists from the cohorts comprising the Consortium and NCI and from the PanC4 case-control studies.

The PanScan consortium has conducted two GWAS that have led to the discovery of four novel regions in the genome associated with risk for pancreatic adenocarcinoma. The first two scans were conducted in 12 cohort studies and 8 case-control studies.

Initially, we genotyped 523,345 single nucleotide polymorphisms in 1,528 incident cases and 1,594 controls from nested case-control studies of 12 cohorts plus 368 cases and 345 controls from one hospital-based case-control study. Taqman replication of SNPs from the three most promising regions in the initial scan, as determined by rank p-values, was done in 2,457 cases and 2,654 controls from eight case-control studies that were part of the PanC4 consortium. A combined analysis identified an association between a locus on 9q34 and pancreatic cancer, the single nucleotide polymorphism rs505922 (P= 5.37 x 10-8; multiplicative per-allele odds ratio (OR) 1.20; 95% CI 1.12-1.28), which maps to the first intron of the ABO blood group gene whose protein determines an individual's blood group (Amundadottir et al, Nature Genetics 2009, PMID: 19648918).

In PanScan 2, we conducted a combined analysis of 3,851 pancreatic cancer cases and 3,934 controls. These included 1896 cases and 1939 controls that were scanned in PanScan1 (above) and 1955 cases and 1995 controls that were newly scanned in PanScan2. The second GWAS did not include 502 cases and 659 controls that were part of the rapid replication. Three new regions were identified: chromosome 13q22.1 (rs9543325; P=3.27 x 10-11; per-allele odds ratio (OR) 1.26; 95% CI 1.18-1.35); chromosome 1q32.1 in the NR5A2 gene (rs3790844; P=2.45 x 10-10; per-allele OR 0.77; 95% CI 0.71-0.84); and chromosome 5p15.33 (rs401681 in the CLPTM1L and TERT region; P=3.66 x 10-7; per-allele OR 1.19; 95% CI 1.11-1.27). The first two regions have not been identified in GWAS of cancer to date but the last region has been reported to be associated with risk of other malignancies (Petersen et al, Nature Genetics 2010, PMID: 20101243).

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