Laufey Amundadottir

Ph.D.

National Cancer Institution

Senior Investigator

PLCO (Learn more about this study)

PLCO-548

Sep 27, 2021

Pancreatic Cancer Genome Wide Association Study - PanScan

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal disease with limited diagnostic and treatment options. A small proportion the familial aggregation of pancreatic cancer is explained by hereditary cancer syndromes and inherited forms of pancreatitis, caused by rare high-risk inherited mutations. To identify common variants that influence risk of this cancer, we have performed Genome Wide Association Studies (GWAS) within the NCI Cohort Consortium (PanScan I, II and III) in collaboration with investigators from the Pancreatic Cancer Case Control Consortium (PanC4) and the PANcreatic Disease ReseArch (PANDoRA) consortium. With our most recent accomplishment, a joint meta-analysis of PanScan I, II, III and PanC4 GWAS data published in 2018, our combined work has led to the identification of 17 GWAS significant risk loci (20 independent signals) for pancreatic cancer in individuals of European ancestry. Due to the relative rarity of pancreatic cancer and the large number of cases required for well powered studies, few large genetic studies have been conducted. To date, we have GWAS genotyped and analyzed roughly 9,000 PDAC cases and 12,000 controls that have participated in PanScan I-III and PanC4 studies.

To further increase statistical power for pancreatic cancer gene mapping efforts, we propose to perform a new GWAS phase by genotyping: 1) an additional 10,135 cases and 4,205 control subjects of mostly European ancestry enrolled in PanScan and PanC4 studies (PanScan IV), and, 2) 2,000 pancreatic cancer cases and 2,000 control subjects from South Korea (KoreaPC).

This effort will almost triple the size of our GWAS set in European populations from the current set of roughly 9,000 to roughly 26,000 pancreatic cancer cases, including our previous PanScan I-III and PanC4 GWAS studies and the use of previously genotyped PDAC cases and controls from some of our participating studies as well as biobanks. To increase the number of control subject with GWAS genotype data, we would like to use GWAS genotype data from previously genotyped control samples from PLCO.

We therefore request data from newly diagnosed cases diagnosed with pancreatic ductal adenocarcinoma (PDAC) as well as 50,000 recently genotyped PLCO control subjects that do not have a diagnosis of any cancer. This includes: a) GWAS genotype data (GSA array data) and b) phenotype and other associated data (age, gender, cancer status, DNA source, smoking status, diabetes status, alcohol intake, family history of pancreatic cancer and adult BMI).

1. Conduct a new GWAS (PanScan IV) in populations of European ancestry to identify novel regions of the genome associated with pancreatic cancer. This will be accomplished by genotyping of ~10,000 pancreatic cancer cases and ~4,200 control subjects mostly of European ancestry drawn from cohort and case control studies that have participated in PanScan and PanC4, as well as novel studies. We also plan to include GWAS genotype data from ~50,000 controls subjects from PLCO as per this request. The results will be meta-analyzed with PanScan I-III, PanC4 and PANDoRA GWAS studies as well as data from various biobanks and previously genotyped cases and controls (26,000 cases and over 600,000 controls total in individuals of European ancestry.

2. Conduct a meta-analysis of GWAS data from all populations to identify regions of the genome associated with pancreatic cancer in of populations of both European and Asian ancestry. This will be accomplished by performing a meta-analysis of all available GWAS datasets (PanScan I-IV, PANDoRA, KOREA GWAS and others) to investigate the genetics of pancreatic cancer risk in of populations of both European and Asian ancestry.