Multi-cohort high-dimensional proteomics reveals early risk markers for lymphoid cancer subtypes.
Kolijn PM., Smith-Byrne K., Burk V., Viallon V., Lee MA., Papier K., Wang Z., Langerak AW., Späth F., Diepstra A., Lill CM., Zamora-Ros R., Macciotta A., Aizpurua A., Tumino R., Chatterjee N., Travis RC., Gunter MJ., Platz EA., Riboli E., McKay J., Vermeulen RCH.
This study aims to investigate the early stages of lymphoid malignancy pathogenesis and identify pre-diagnostic proteomic markers for lymphoma. Using the SomaScan-7K platform, we analyze 6412 unique plasma proteins in a case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort, comprising 4565 participants (484 incident lymphoid malignancy cases, median follow-up 9 years). We identify over 500 unique protein-lymphoid malignancy associations. Enriched pathways include 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 reveals concordant nominal significance for 70%-95% of the associations in the UK Biobank (Olink) and ARIC (SomaScan) studies. Time-stratified analyses reveals 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.