A proteomics approach to identify predictive blood biomarkers for pleural mesothelioma in prospective cohorts.

BACKGROUND: Pleural mesothelioma (PM) is a rare, asbestos-linked cancer with a long asymptomatic latency, delaying diagnosis and limiting treatment options. Identifying blood‐based biomarkers that signal disease before symptoms onset could improve surveillance of at‐risk individuals. METHODS: In our work, we conducted a prospective proteomic study of pre-diagnostic serum from 21 PM cases (< 5 years before diagnosis) and 21 asbestos‐exposed controls in the EPIC cohort using SWATH‐MS, followed by ELISA validation. Findings were tested in an independent MoMar cohort of 32 pre‐diagnostic plasma samples (< 1 year before diagnosis) and 32 matched controls. RESULTS: SWATH-MS identified 12 differentially expressed proteins (nominal p < 0.05, fold change > 1.3 or < 0.75). Transferrin and complement C4A were elevated, while beta‐2‐microglobulin and dermcidin were reduced in pre‐diagnostic cases. ELISA confirmed a borderline significant rise in beta‐2‐microglobulin within two years of diagnosis in EPIC. Calretinin and mesothelin were also detected in both cohorts, with the five‐marker panel achieving an AUC of 0.91 (p = 0.001) in MoMar but not reaching significance in EPIC (AUC = 0.88, p = 0.17). CONCLUSIONS: Integrating novel proteomic biomarker candidates with established markers enhances early PM detection in high-risk populations. Larger, multi‐cohort validation is warranted to refine this biomarker panel for clinical surveillance. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10238-026-02058-x.