Allelic effects on KLHL17 expression underlie a pancreatic cancer genome-wide association signal at chr1p36.33.

Authors

Connelly KE, Hullin K, Abdolalizadeh E, Zhong J, Eiser D, O'Brien A, Collins I, Das S, 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. katelyn.connelly@nih.gov.
• 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.
• Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, MD, USA. amundadottirl@nih.gov.

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 chr1p36.33 (tagged by rs13303010) identified through a genome wide association study (GWAS). One of the fine-mapped SNPs, rs13303160 (OR = 1.23 (95% CI 1.15-1.32), P-value = 2.74×10^-9, LD r² = 0.93 with rs13303010 in 1000 G EUR samples) demonstrated allele-preferential gene regulatory activity in vitro and 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 with vimentin and nestin as candidate substrates for degradation in PDAC-derived cells. In silico differential gene expression analysis of high and low KLHL17 expressing GTEx pancreas samples suggested an association between lower KLHL17 levels (risk associated) and pro-inflammatory pathways. We hypothesize that KLHL17 may mitigate cell injury and inflammation by recruiting nestin and vimentin for ubiquitination and degradation thereby influencing PDAC risk.