Unveiling Circulating Targets in Pancreatic Cancer: Insights from Proteogenomic Evidence and Clinical Cohorts

Pancreatic cancer (PC), lacking biomarkers and effective therapeutics, remains highly lethal. Data regarding the correlations of PC risk and the individual plasma proteome known for minimally cancer biomarkers, are scarce. Here, we measure 1,345 human plasma proteins via Proteome-Wide Association Studies, presenting 78 proteins are prominently related to PC risk, including 4 proteins (ROR1, FN1, APOA5, ABO) exhibit the strongest causal association identified via Mendelian Randomization and Colocalization. Our two independent cohorts further demonstrate FN1 and ABO are highly expressed in blood or tumors from patients with PC compared to specimens from healthy individuals or para-tumors. Moreover, patients with higher levels of FN1 and ABO in their blood or tumors have worse median survival than those with lower levels. Multiple drugs targeting FN1 are currently available or undergoing clinical testing, making FN1 a promisingly repurposed therapeutic target in addition to severing as a circulating prognostic indicator for PC. ### Competing Interest Statement The authors have declared no competing interest. ### Funding Statement This work was supported by grants from the National Natural Science Foundation of China (82372884 to H.S., 82372644 and 82002931 to F.Y., 81972257, 82273382, 81827807, 81972218, 82103409, 82272929, 82173116), the Shanghai Natural Science Foundation (23ZR1413600 to H.S.), the Scientific Research StartingFoundation of Affiliated Zhongshan Hospital of Fudan University (2023ZSQD03 to H.S.); the Scientific Research Starting Foundation of Fudan University (JIH1340033Y to H.S.); the program of Qingfeng Schloarship of Shanghai Medical School of Fudan University (DGF819014/062 to H.S.), the Shanghai Higher Education Talent Program (SSF828065 to H.S.); Shanghai ShenKang Hospital Development Centre Project (SHDC2020CR2017B), Program of Shanghai Academic/Technology Research Leader (23XD1400600), China Postdoctoral Science Foundation (2021M690037), Shanghai Sailing Program (21YF1407100), Science and Technology Planning Project of Yunnan Province (202305AF150148), Shanghai Municipal Health Commission (20224Y0307), CSCO Cancer Research Fund Project (Y-HR2022QN-0085) and Open Fund of Key Laboratory of Hepatoaplenic Surgery, Ministry of Education, Harbin(GPKF202302). The funding agencies had no role in the study design, data collection and analyses, decision to publish, or preparation of the manuscript. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee of Zhongshan Hospital, affiliated with Fudan University gave ethical approval for this work (B2023-342). I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes GWAS summary statistics of the UK Biobank were obtained from http://www.nealelab.is/uk-biobank. GWAS summary statistics of the FinnGen (R9 release) were obtained from https://finngen.fi/en. The human blood pQTLs in PWAS was obtained from http://nilanjanchatterjeelab.org/pwas/. This paper does not report the original code.