Abstract B059: Blood proteomic profiles and pancreatic ductal adenocarcinoma risk – A Mendelian randomization and observational analysis

Abstract Background: Blood proteomic biomarkers hold promises for early detection and etiologic insights into pancreatic ductal adenocarcinoma (PDAC). We investigated the associations between genetically predicted plasma protein levels and PDAC risk using Mendelian randomization (MR) and confirmed MR identified PDAC-associated proteins in two prospective cohorts. Methods: We conducted a proteome-wide MR study of PDAC using summary statistics of cis-acting protein quantitative trait loci (pQTL) as instruments. Instruments were selected from genome-wide association studies of plasma protein levels conducted in UK Biobank (UKB, n=34,557; 2923 proteins) and deCODE (n=35,559; 4719 proteins). For each protein, we selected genome-wide significant cis-pQTLs (P<5.0×10-8 located within +-1Mb of the gene encoding of the protein, which were then applied to summary statistics from a large PDAC GWAS meta-analysis of PanScan1–3, PanC4 and FinnGen cohorts (10,244 cases, 360,535 controls of European ancestry). To assess the robustness of MR findings, we conducted colocalization to evaluate whether the same causal variant underlines both protein levels and PDAC risk. Finally, we validated the top MR-identified proteomic-PDAC associations using Cox proportional hazard models within UKB (50,068 cancer-free mostly white participants, 122 incident cases) and Atherosclerosis Risk in Communities Study (ARIC) (9476 cancer-free white and black participants, 88 incident cases) cohorts. The results were combined using fixed-effect meta-analysis. Results: The proteome-wide MR identified 44 proteins significantly associated with PDAC risk after Bonferroni correction (P<2.7×10-5 in UKB or P<3.0×10-5 in deCODE). Among these, 17 proteins were cross-validated in both datasets. Of the 44, eight proteins were previously identified, including ABO, CTRB1, B4GALT1, REG1A, FUT3, AMY2A, AMY2B, and NCF1 (odds ratio [OR] ranged 0.80–1.27 per standard deviation increment in UKB). The remaining 36 proteins were newly identified; 10 of these were validated in both cohorts, including MST1, ATRN, LEFTY2, ATXN3, SAT2, ACP6, PCSK7, CKMT1A, RTN4R, and ITIH1 (OR ranged 0.80–1.39 in UKB). Colocalization analyses supported shared genetic signals for 10 proteins (ABO, CTRB1, AMY2B, GRP, PSCA, PACS2, ZFYVE19, MST1, KRT18, and SDCCAG8) with posterior probability (PPH4) >0.70 in either UKB or deCODE. In prospective analyses, higher plasma levels of ABO (hazard ratio [HR]=1.21; 95% confidence interval [CI]=1.05–1.39) and ITIH3 (HR=1.19; 95% CI=1.03–1.37) were associated with incident PDAC risk in the meta-analysis of UKB and ARIC. Conclusions: Our proteome-wide MR identified multiple genetically predicted plasma proteins associated with PDAC risk. Among these, associations for ABO and ITIH3 were further validated using measured plasma protein levels in two prospective cohorts. These proteins highlight promising candidates for future investigations as biomarkers for early detection or targets for PDAC prevention. Citation Format: Ting Zhang, Devika Godbole, Ziqiao Wang, Xiaoyu Wang, Jia Liu, Chirayu Mohindroo, Shilpa Katta, Shengchao A. Li, Jiahui Wang, the PanScan and PanC4 Consortium, Brian M. Wolpin, Harvey A. Risch, Laufey T. Amundadottir, Alison P. Klein, Vernon A. Burk, Nilanjan Chatterjee, Kai Yu, Elizabeth A. Platz, Diptavo Dutta, Haoyu Zhang, Rachael Z. Stolzenberg-Solomon. Blood proteomic profiles and pancreatic ductal adenocarcinoma risk – A Mendelian randomization and observational analysis [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85(18_Suppl_3):Abstract nr B059.