Connelly Katelyn E, Hullin Katherine, Abdolalizadeh Ehssan, Zhong Jun, Eiser Daina, O'Brien Aidan, Collins Irene, Das Sudipto, Duncan Gerard, Chanock Stephen J, Stolzenberg-Solomon Rachael Z, Klein Alison P, Wolpin Brian M, Hoskins Jason W, Andresson Thorkell, Smith Jill P, Amundadottir Laufey T
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.
Nat Commun. 2025 Apr 30;16(1):4055. doi: 10.1038/s41467-025-59109-2.
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, LD r = 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.
胰腺导管腺癌（PDAC）是美国癌症相关死亡的第三大主要原因。罕见和常见的种系变异均会导致患PDAC的风险。在此，我们对通过全基因组关联研究（GWAS）确定的位于1号染色体p36.33区域（由rs13303010标记）的常见PDAC风险信号进行精细定位并进行功能表征。其中一个精细定位的单核苷酸多态性（SNP），即rs13303160（优势比（OR）=1.23（95%置信区间1.15 - 1.32），P值 = 2.74×10，在1000基因组计划的欧洲裔样本中与rs13303010的连锁不平衡（LD）r = 0.93）在体外表现出等位基因优先的基因调控活性，并且在体外和体内均显示与JunB和JunD结合。表达定量性状位点（eQTL）分析确定KLHL17是该信号潜在的靶基因。蛋白质组学分析确定KLHL17是Cullin - E3泛素连接酶复合体的成员，波形蛋白和巢蛋白是PDAC来源细胞中可能被降解的底物。对高表达和低表达KLHL17的基因型 - 组织表达（GTEx）胰腺样本进行的计算机差异基因表达分析表明，较低的KLHL17水平（与风险相关）与促炎途径之间存在关联。我们推测，KLHL17可能通过募集波形蛋白和巢蛋白进行泛素化和降解，从而减轻细胞损伤和炎症，进而影响患PDAC的风险。
