Mechanistic Insights into Cancer Risk from the Circulating Proteome

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.