Mechanistic Insights into Cancer Risk from the Circulating Proteome

Abstract Early, minimally invasive detection of cancer, ideally through biomarkers that also provide mechanistic insight, has the potential to substantially improve patient outcomes and reduce societal burden. To advance this goal, we examined associations between 7,523 circulating serum proteins and 13 cancer types in 5,376 older adults from the AGES cohort, including 1,235 individuals diagnosed with incident or prevalent cancers. The cancers analyzed spanned the digestive, genitourinary, respiratory, female reproductive systems, and skin. After adjusting for confounders and conducting sex-specific analyses, 526 proteins exhibited significant associations with cancer status. Additionally, 776 proteins were regulated by genetic cancer susceptibility loci, with 114 of these overlapping with cancer associations. Both sets were highly enriched for known cancer genes. Proteome-wide forward two-sample Mendelian randomization, leveraging 2,062 cis-acting pQTL instruments, identified 112 proteins with evidence of a causal influence on cancer risk. To place these findings in a broader biological context, we integrated them with genetic, tissue-specific expression, and tumor-specific datasets, thereby delineating the complex molecular landscape underlying cancer risk. This work illustrates the promise of serum proteomics for large-scale surveillance, early detection, and mechanistic insights into tumorigenesis. Competing Interest Statement J.L., L.L.J., N.F. and A.P.O. are employees and stockholders of Novartis. All other authors have nothing to disclose. Funding Statement Funding for V.E. was provided by the Icelandic Cancer Society.The National Institute on Aging (NIA) contracts N01-AG-12100 and HHSN271201200022C for V. G. financed the study. V. G. received funding from the NIA (1R01AG065596-01A1), and IHA received a grant from the Icelandic Parliament. T.M. acknowledges support from the Research Council of Norway (project number 312045), the European Union Horizon Europe (European Innovation Council) (grant agreement number 101115381), and the L. Meltzers Hoyskolefond. 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: This study was approved (approval number VSN-00-063) by the National Bioethics Committee in Iceland, which serves as the Icelandic Heart Association's institutional review board in accordance with the Helsinki Declaration, and by the US National Institutes of Health, National Institute on Aging Intramural Institutional Review Board, with all participants providing informed consent. 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 Footnotes ↵† Shared first authors This version of the manuscript has been revised to correct typographical errors in the main text, update the main text figures, transfer excess content to the Supplementary Information, and update and correct supplementary figures and tables. Additionally, a new section on proteome-wide forward MR analysis has been added, presenting many observations of interest. Data Availability Data generated in this study can be obtained from the authors upon reasonable request.