Abstract 1889: Proteomic profiling using high-dimensional multiplex platforms to identify prospective risk factors for lymphoid malignancies across multiple cohorts

Abstract Introduction: Circulating proteins play a central role in the development of lymphoid malignancies and the immune system’s response to these cancers. Methods: In this study, we measured 6, 412 unique proteins in prediagnostic plasma samples using the SomaScan 7K panel from a total of 4, 565 participants of a case-cohort study nested within the European Prospective Investigation into Cancer and Nutrition (EPIC)—484 who later developed a lymphoid malignancy (median follow-up 9 years) and 4, 081 who did not. We conducted subtype-specific analyses for non-Hodgkin lymphoma (NHL, n=348), chronic lymphocytic leukemia (CLL, n=80), multiple myeloma (MM, n=116), diffuse large B-cell lymphoma (DLBCL, n=80), follicular lymphoma (FL, n=51) and Hodgkin lymphoma (HL, n=20) using Prentice-weighted Cox regression with Benjamini-Hochberg correction for multiple testing. Results: We observed significantly altered plasma levels prior to NHL diagnosis for 147 unique proteins (161 aptamers), of which 131 were upregulated and 16 were downregulated. Increased plasma levels of members of several major immunomodulatory protein families, including the FC-receptor family and the semaphorin family, were associated with increased risk of NHL. Alongside established biomarkers such as sCD23 for CLL, CXCL13 for DLBCL, and sBCMA for MM, we identified potent novel markers, including FCMR and FDCSP for NHL. Time-stratified analyses revealed that a subset of these protein-lymphoma associations are evident over a decade before diagnosis, underscoring the protracted preclinical phase of lymphoid malignancies. Pathway analyses revealed dysregulation in immune modulation, epigenetic regulation, cytokine and chemokine signaling, B-cell receptor signaling, the NF-κB signaling pathway, alternative splicing and N-glycan biosynthesis. In total, 2136 out of 6412 proteins measured in our current study overlapped with those measured in a recent UK biobank study. The significant protein-cancer associations observed in our current analyses within EPIC showed high concordance in the UK biobank in terms of both FDR-adjusted significance (58%-82%) and the direction of the association (89%-92%), meaning positively or negatively associated with cancer risk. Conclusion: In conclusion, we identified hundreds of proteins associated with lymphoid malignancy risk, revealing a robust set of markers detectable many years prior to diagnosis, and advancing our understanding of lymphoid malignancy pathogenesis. Citation Format: Pieter Martijn Kolijn, Karl Smith-Byrne, Vivian Viallon, Matthew Lee, Keren Papier, Anton W. Langerak, Florentin Späth, Arjan Diepstra, Raul Zamora-Ros, Alessandra Macciotta, Amaia Aizpurua, Rosario Tumino, Ruth C. Travis, Elio Riboli, Marc J. Gunter, James McKay, Roel C. Vermeulen. Proteomic profiling using high-dimensional multiplex platforms to identify prospective risk factors for lymphoid malignancies across multiple cohorts [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 1889.