Blood-first public transcriptomics nominates UPP1 as a myeloid/monocyte-associated colorectal cancer blood-signal candidate

Colorectal cancer (CRC) remains a major cancer burden, and non-invasive molecular candidates remain relevant to screening-adjacent research. We asked whether public blood transcriptomes nominate UPP1 as a myeloid/monocyte-associated CRC blood-signal candidate. Candidate generation was exploratory: a staged screen of the same three blood-related datasets retained NACA, UPP1, and GLOD4, after which a pre-lock GSE203024 shortfall check led to UPP1 being fixed as primary before the controlled full analysis. UPP1 was CRC-high in GSE164191 whole blood, GSE47756 peripheral blood monocytes, and GSE203024 peripheral blood, with apparent descriptive AUCs of 0.706, 0.872, and 0.649, respectively. GSE203024 compared CRC with no-known-cancer controls, not healthy-only controls. Whole-transcriptome Benjamini-Hochberg FDR remained significant in all three datasets. The expression association remained after age/sex adjustment and in analyses restricted to participants aged at least 50 years; however, clinical metadata were incomplete and residual confounding remains possible. Marker-correlation audits indicated low heuristic composition-confounding risk but could not replace measured blood counts, flow cytometry, or formal deconvolution. GSE132465 and the independent GSE146771 study placed UPP1 mainly in myeloid-related compartments; neither supplied a healthy-versus-CRC blood single-cell comparison. The preserved in silico virtual-knockout and observational UPP1-high myeloid-state modules supported inflammatory and uridine/pyrimidine hypotheses without establishing causality. Because candidate selection and AUC estimation used overlapping retrospective datasets, the AUCs are subject to selection optimism and are not independent validation. No clinical threshold, sensitivity/specificity pair, diagnostic algorithm, or decision-curve analysis was derived. UPP1 is therefore a public-data candidate, not a validated diagnostic, prognostic, or mechanistic biomarker.