Functional Characterization of Pancreatic Cancer GWAS Signal at PDX1 Promoter

Authors

• TA Christensen
• JW Hoskins
• DR Eiser
• E Char
• M Mobraki
• I Collins
• LT Amundadottir

Abstract

PanScan (Pancreatic Cancer Cohort Consortium), a genome-wide association study (GWAS) to identify common genetic variants associated with increased risk of pancreatic cancer, has been conducted over the past several years to improve detection and treatment of pancreatic cancer. A prominent signal at 13q12.2 was observed, which epigenomic fine mapping and experimental validation revealed to most likely be a functional SNP ~200bp upstream of PDX1. Using a doxycycline-inducible overexpression system, we found that increased PDX1 expression likely inhibits cell proliferation through upregulating apoptosis. We ran a gene set enrichment analysis of time-course RNA-seq data comparing cells with PDX1 overexpression to uninduced cells and found changes in several pathways linked to immune system activity, inflammation, diabetes, and other cancer-related or harmful outcomes. Finally, we used CRISPR to edit pancreatic cancer cells that were wild-type heterozygous (G/A) for the SNP of interest into multiple clones of both homozygous types (G/G and A/A), finding decreased PDX1 expression as well as other changes associated with increased copies of the risk SNP (A).

Scientific Focus Area: Cancer Biology

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