Multi-Cohort High-Dimensional Proteomics Reveals Early Risk Markers for Lymphoid Cancer Subtypes

This study aims to investigate the early stages of lymphoid malignancy pathogenesis and identify novel pre-diagnostic proteomic markers for lymphoma. Using the SomaScan-7K platform, we analyzed 6,412 unique plasma proteins in a case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, comprising 4,565 participants (484 incident lymphoid malignancy cases, median follow-up 9 years). We identified over 500 unique protein-lymphoid malignancy associations. Enriched pathways included viral protein interactions, cytokine signaling, B-cell receptor signaling, and NF-κB activation, reflecting key mechanisms in lymphoma pathogenesis. Cross-cohort validation of the top 20 FDR-significant proteins revealed concordant nominal significance for 70%-95% of the associations in the UK Biobank (Olink) and ARIC (SomaScan) studies. Time-stratified analyses revealed that a subset of these protein-lymphoma associations is evident over a decade before diagnosis. These findings highlight the potential of circulating proteomic markers in risk stratification, early diagnosis, and targeted prevention strategies for lymphoid malignancies.