Connelly Katelyn E, Hullin Katherine, Abdolalizadeh Ehssan, Zhong Jun, Eiser Daina, O'Brien Aidan, Collins Irene, 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.
medRxiv. 2024 Sep 16:2024.09.16.24313748. doi: 10.1101/2024.09.16.24313748.
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 (r=0.93 in 1000G EUR samples, OR=1.23, value=2.74x10) demonstrated allele-preferential gene regulatory activity and allele-preferential binding of JunB and JunD and . Expression Quantitative Trait Locus (eQTL) analysis identified 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. 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.
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1p36.33（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（在1000G欧洲样本中r = 0.93，优势比[OR]=1.23，P值=2.74×10）显示出等位基因优先的基因调控活性以及JunB和JunD的等位基因优先结合。表达定量性状位点（eQTL）分析确定[具体基因未明确]为该信号潜在的靶基因。蛋白质组学分析确定KLHL17是源自PDAC的细胞中Cullin - E3泛素连接酶复合物的成员。对GTEx v8胰腺数据的差异基因表达分析表明，较低的KLHL17（与风险相关）与促炎途径之间存在关联。我们推测，KLHL17可能通过募集促炎蛋白进行泛素化和降解来减轻炎症，从而影响患PDAC的风险。
