Allelic effects on KLHL17 expression likely mediated by JunB/D underlie a PDAC GWAS signal at chr1p36.33.

Authors

Connelly KE, Hullin K, Abdolalizadeh E, Zhong J, Eiser D, O'Brien A, Collins I, Sudipto Das, Duncan G, Pancreatic Cancer Cohort Consortium, Pancreatic Cancer Case-Control Consortium, Chanock SJ, Stolzenberg-Solomon RZ, Klein AP, Wolpin BM, Hoskins JW, Andresson T, Smith JP, Amundadottir LT

Affiliations

• Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
• Protein Characterization Laboratory, Frederick National Laboratory for Cancer Research, Leidos Biomedical Research Inc., Frederick, MD, USA.
• Laboratory of Genomic Susceptibility, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
• Metabolic Epidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA.
• Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins School of Medicine, Baltimore, MD, USA.
• Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
• Department of Medicine, Georgetown University, Washington, USA.

Abstract

Pancreatic Ductal Adenocarcinoma (PDAC) is the third leading cause of cancer-related deaths in the U.S. Both rare and common germline variants contribute to PDAC risk. Here, we fine-map and functionally characterize a common PDAC risk signal at 1p36.33 (tagged by rs13303010) identified through a genome wide association study (GWAS). One of the fine-mapped SNPs, rs13303160 (r²=0.93 in 1000G EUR samples, OR=1.23, P value=2.74x10^-9) demonstrated allele-preferential gene regulatory activity in vitro and allele-preferential binding of JunB and JunD in vitro and in vivo. Expression Quantitative Trait Locus (eQTL) analysis identified KLHL17 as a likely target gene underlying the signal. Proteomic analysis identified KLHL17 as a member of the Cullin-E3 ubiquitin ligase complex in PDAC-derived cells. In silico differential gene expression analysis of the GTExv8 pancreas data suggested an association between lower KLHL17 (risk associated) and pro-inflammatory pathways. We hypothesize that KLHL17 may mitigate inflammation by recruiting pro-inflammatory proteins for ubiquitination and degradation thereby influencing PDAC risk.