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

Katelyn E. Connelly (), Katherine Hullin, Ehssan Abdolalizadeh, Jun Zhong, Daina Eiser, Aidan O’Brien, Irene Collins, Sudipto Das, Gerard Duncan, Stephen J. Chanock, Rachael Z. Stolzenberg-Solomon, Alison P. Klein, Brian M. Wolpin, Jason W. Hoskins, Thorkell Andresson, Jill P. Smith and Laufey T. Amundadottir ()
Additional contact information
Katelyn E. Connelly: National Cancer Institute
Katherine Hullin: National Cancer Institute
Ehssan Abdolalizadeh: National Cancer Institute
Jun Zhong: National Cancer Institute
Daina Eiser: National Cancer Institute
Aidan O’Brien: National Cancer Institute
Irene Collins: National Cancer Institute
Sudipto Das: Leidos Biomedical Research Inc
Gerard Duncan: Leidos Biomedical Research Inc
Stephen J. Chanock: National Cancer Institute
Rachael Z. Stolzenberg-Solomon: National Cancer Institute
Alison P. Klein: Johns Hopkins School of Medicine
Brian M. Wolpin: Dana-Farber Cancer Institute
Jason W. Hoskins: National Cancer Institute
Thorkell Andresson: Leidos Biomedical Research Inc
Jill P. Smith: Georgetown University
Laufey T. Amundadottir: National Cancer Institute

Nature Communications, 2025, vol. 16, issue 1, 1-18

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-59109-2

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