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

Abstract

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.