Search for early preclinical immune markers of B-cell lymphoproliferative disorders in biobank-based studies: A review

Introduction. Early diagnosis of malignant tumors, including those of lymphoid and hematopoietic tissues, is paramount for improving prognosis and survival outcomes. A key strategy for early detection involves the use of sensitive and specific biomarker-based screening tests. The identification of such biomarkers and the subsequent development of novel diagnostic assays can be achieved through the study of large-scale biorepositories.

Objective. To evaluate the feasibility of identifying early preclinical immune markers of B-cell lymphoproliferative disorders in retrospective studies drawing on data from global population-based biobanks.

Discussion. The most frequently identified early preclinical markers for non-Hodgkin lymphomas include sCD23, sCD27, sCD30, and CXCL13, along with several cytokines and their receptors, such as IL-10, TNF-α, sTNF-R2, and sIL-2Rα. In multiple myeloma, early preclinical markers comprise IL-10, MIP-1α, VEGF, and TGF-α. Notably, these biomarkers can be detected more than a decade prior to the clinical onset of B-cell lymphoproliferative disorders. Research into the association between these markers and cancer has been facilitated by population-based biobanks, which enable retrospective analysis following clinical diagnosis. Notable examples include the Janus Serum Bank (Norway), the PLCO biorepository (USA), the UK Biobank (United Kingdom), and repositories in Sweden and other countries.

Conclusions. Analysis of population-based biobank materials represents an effective tool for identifying associations between immune markers and cancer prognosis, thus facilitating the development of novel methods for early diagnosis. The proven success of global biorepositories demonstrates the potential for advancing biobanking infrastructure in Russia, as well as the need for fostering integration and collaboration with leading international institutions.

1. Bessmeltsev SS. Malignant lymphomas: history, prevalence, etiology and pathogenesis. Bulletin of Hematology. 2023;19(1):64–80 (In Russ.). EDN: IIWBEW

2. Ghaffari K, Hasan-Abad AM, Etedali M, Alizadeh S, Ghasemi A. Hematologic malignancies and an overview of emerging therapies for hematologic malignancies: a systematic review. Cancer Treatment and Research Communications. 2026;46:101074. https://doi.org/10.1016/j.ctarc.2025.101074

3. Prasanth BK, Alkhowaiter S, Sawarkar G, Dharshini BD, Baskaran AR. Unlocking early cancer detection: exploring biomarkers, circulating DNA, and innovative technological approaches. Cureus. 2023;15(12):e51090. https://doi.org/10.7759/cureus.51090

4. Meshkov AN, Pokrovskaya MS, Glotov AS, Ershova AI, Rodionova YuV, Drapkina OM. From idea to implementation: the development of biobanking in Russia. The Cardiovascular Therapy and Prevention journal’s top contributing institutions: National Association of Biobanks and Biobanking Specialists (NASBIO). Cardiovascular Therapy and Prevention. 2023;22(11):3864 (In Russ.). https://doi.org/10.15829/1728-8800-2023-3864

5. Langseth H, Gislefoss RE, Martinsen JI, Dillner J, Ursin G. Cohort profile: the Janus Serum bank cohort in Norway. International Journal of Epidemiology. 2017;46(2):403–4g. https://doi.org/10.1093/ije/dyw027

6. Gohagan JK, Prorok PC, Greenwald P, Kramer B. The PLCO Cancer Screening Trial: background, goals, organization, operations, results. Reviews on Recent Clinical Trials. 2015;(10):173–80. https://doi.org/10.2174/1574887110666150730123004

7. Hayes RB, Reding D, Kopp W, Subar AF, Bhat N, Rothman N, et al. Etiologic and early marker studies in the prostate, lung, colorectal and ovarian (PLCO) cancer screening trial. Controlled Clinical Trials. 2000;21(6 Suppl):349S–55S. https://doi.org/10.1016/s0197-2456(00)00101-x

8. Gohagan JK, Prorok PC, Hayes RB, Kramer BS. The Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial of the National Cancer Institute: history, organization, and status. Controlled Clinical Trials. 2000;21(6 Suppl):251S–72S. https://doi.org/10.1016/s0197-2456(00)00097-0

9. Hoyt M, Song Y, Gao S, O’Palka J, Zhang J. Prediagnostic BMI trajectories in relation to pancreatic cancer risk in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Obesity. 2022;30(11):2275–85. https://doi.org/10.1002/oby.23550

10. Späth F, Wennberg P, Johansson R, Weinehall L, Norberg M, Rosen A, et al. Cohort Profile: The Northern Sweden Health and Disease Study (NSHDS). International Journal of Epidemiology. 2025;54(1):dyaf004. https://doi.org/10.1093/ije/dyaf004

11. Kolijn PM, Hosnijeh FS, Späth F, Hengeveld PJ, Agathangelidis A, Saleh M, et al. High-risk subtypes of chronic lymphocytic leukemia are detectable as early as 16 years prior to diagnosis. Blood. 2022;139(10):1557–63. https://doi.org/10.1182/blood.2021012890

12. Kyle RA, Larson DR, Therneau TM, Dispenzieri A, Kumar S, Cerhan JR, et al. Long-term follow-up of monoclonal gammopathy of undetermined significance. The New England Journal of Medicine. 2018;378(3):241–9. https://doi.org/10.1056/NEJMoa1709974

13. Tahiru W, Santamaria AI, Hultdin J, Yi-Ying WW, Späth F. Progression patterns in monoclonal gammopathy of undetermined significance and multiple myeloma outcome: a cohort study in 42 patients. Experimental Hematology & Oncology. 2022;11(1):8. https://doi.org/10.1186/s40164-022-00259-0

14. Kolijn PM, Smith-Byrne K, Burk V, Viallon V, Lee M, Papier K. Multi-cohort high-dimensional proteomics reveals early risk markers for lymphoid cancer subtypes. Nature Communications. 2025;16(1):9517. https://doi.org/10.1038/s41467-025-64534-4

15. Rhee J, Birmann B, De Roos A, Epstein M, Martinez-Maza O, Breen E. Circulating immune markers and risks of non-Hodgkin lymphoma subtypes: A pooled analysis. International Journal of Cancer. 2023;152(5):865–78. https://doi.org/10.1002/ijc.34299

16. Purdue MP, Hofmann JN, Kemp TJ, Chaturvedi AK, Lan Q, Park JH, et al. A prospective study of 67 serum immune and inflammation markers and risk of non-Hodgkin lymphoma. Blood. 2013;122(6):951–7. https://doi.org/10.1182/blood-2013-01-481077

17. Landeira-Viñuela A, Arias-Hidalgo C, Juanes-Velasco P, Alcoceba M, Navarro-Bailón A, Pedreira C, et al. Unravelling soluble immune checkpoints in chronic lymphocytic leukemia: Physiological immunomodulators or immune dysfunction. Frontiers in Immunology. 2022;13:965905. https://doi.org//10.3389/fimmu.2022.965905

18. Purdue MP, Lan Q, Langseth H, Grimsrud TK, Hildesheim A, Rothman N. Prediagnostic serum sCD27 and sCD30 in serial samples and risks of non-Hodgkin lymphoma subtypes. International Journal of Cancer. 2020;146(12):3312–9. https://doi.org/10.1002/ijc.32684

19. Saberi Hosnijeh F, Kolijn PM, Casabonne D, Nieters A, Solans M, Naudin S, et al. Mediating effect of soluble B-cell activation immune markers on the association between anthropometric and lifestyle factors and lymphoma development. Scientific Reports. 2020;10(1):13814. https://doi.org/10.1038/s41598-020-70790-9

20. Späth F, Wibom C, Krop EJ, Johansson AS, Bergdahl IA, Vermeulen R, et al. Biomarker dynamics in b-cell lymphoma: a longitudinal prospective study of plasma samples up to 25 years before diagnosis. Cancer Research. 2017;77(6):1408–15. https://doi.org/10.1158/0008-5472.CAN-16-2345

21. Purdue MP, Lan Q, Bagni R, Hocking WG, Baris D, Reading DJ, et al. Prediagnostic serum levels of cytokines and other immune markers and risk of non-Hodgkin lymphoma. Cancer Research. 2011;71(14):4898–907. https://doi.org/10.1158/0008-5472.CAN-11-0165

22. Purdue MP, Lan Q, Martinez-Maza O, Oken MM, Hocking W, Huang WY, et al. A prospective study of serum soluble CD30 concentration and risk of non-Hodgkin lymphoma. Blood. 2009;114:2730–2. https://doi.org/10.1182/blood-2009-04-217521

23. Conroy SM, Maskarinec G, Morimoto Y, Franke AA, Cooney RV, Wilkens LR, et al. Non-Hodgkin lymphoma and circulating markers of inflammation and adiposity in a nested case-control study: the multiethnic cohort. Cancer Epidemiology, Biomarkers & Prevention. 2013;22(3):337–47. https://doi.org/10.1158/1055-9965.EPI-12-0947

24. Levin LI, Ramirez CM, Liao EL, Guo H, Kim BK, Marrogi AJ, et al. Longitudinal changes in immune activation serum biomarkers prior to diagnosis and risk of B-cell NHL subtypes. Cancer Epidemiology, Biomarkers & Prevention. 2023;32(2):233–41. https://doi.org/10.1158/1055-9965.EPI-22-0247

25. Nigam M, Mishra AP, Deb VK, Dimri DB, Tiwari V, Bungau SG, et al. Evaluation of the association of chronic inflammation and cancer: Insights and implications. Biomedicine & Pharmacotherapy. 2023;164:115015. https://doi.org/10.1016/j.biopha.2023.115015

26. Epstein MM, Rosner B, Breen EC, Batista JL, Giovannucci EL, Magpantay L, et al. Pre-diagnosis plasma immune markers and risk of non-Hodgkin lymphoma in two prospective cohort studies. Haematologica. 2018;103(10):1679–87. https://doi.org/10.3324/haematol.2017.183236

27. Vendrame E, Hussain SK, Breen EC, Magpantay LI, Widney DP, Jacobson LP, et al. Serum levels of cytokines and biomarkers for inflammation and immune activation, and HIV-associated non-Hodgkin B-cell lymphoma risk. Cancer Epidemiology, Biomarkers & Prevention. 2014;23(2):343–9. https://doi.org/10.1158/1055-9965.epi-13-0714

28. Purdue MP, Lan Q, Kemp TJ, Hildesheim A, Weinstein SJ, Hofmann JN, et al. Elevated serum sCD23 and sCD30 up to two decades prior to diagnosis associated with increased risk of non-Hodgkin lymphoma. Leukemia. 2015;29(6):1429–31. https://doi.org/10.1038/leu.2015.2

29. Gu Y, Shore RE, Arslan AA, Koenig KL, Liu M, Ibrahim S, et al. Circulating cytokines and risk of B-cell non-Hodgkin lymphoma: a prospective study. Cancer Causes & Control. 2010;21(8):1323–33. https://doi.org/10.1007/s10552-010-9560-3

30. Chandan K, Gupta M, Sarwat M. Role of host and pathogen-derived microRNAs in immune regulation during infectious and inflammatory diseases. Frontiers in Immunology. 2020;10:3081. https://doi.org/10.3389/fimmu.2019.03081

31. Abu-Halima M, Keller A, Becker LS, Fischer U, Engel A, Ludwig N, et al. Dynamic and static circulating cancer microRNA biomarkers — a validation study. RNA Biology. 2023;20(1):1–9. https://doi.org/10.1080/15476286.2022.2154470

32. Mesaros O, Veres S, Onciul M, Matei E, Jimbu L, Neaga A, et al. Dysregulated microRNAs chronic lymphocytic leukemia. Cureus. 2024;16(9):e68770. https://doi.org/10.7759/cureus.68770

33. Kristinsson SY, Rognvaldsson S, Thorsteinsdottir S, Reed ER, Oskarsson JTT, Petursdottir I, et al. Screening for monoclonal gammopathy of undetermined significance: a population-based randomized clinical trial. First results from the Iceland screens, treats, or prevents multiple myeloma (iStopMM) study. Blood. 2021;138(Suppl 1):156. https://doi.org/10.1182/blood-2021-152333

34. Herdenberg S, Wibom C, Krop EJM, Langseth H, Vermeulen R, Harlid S, et al. Prediagnostic serum immune marker levels and multiple myeloma: a prospective longitudinal study using samples from the Janus serum Bank in Norway. Cancer Prevention & Research. 2025;18(7):383–91. https://doi.org/10.1158/1940-6207.CAPR-24-0501

35. Hofmann JN, Landgren O, Landy R, Kemp TJ, Santo L, McShane CM, et al. A prospective study of circulating chemokines and angiogenesis markers and risk of multiple myeloma and its precursor. JNCI Cancer Spectrum. 2019;4(2):pkz104. https://doi.org/10.1093/jncics/pkz104

36. Vermeulen R, Saberi Hosnijeh F, Bodinier B, Portengen L, Liquet B, Garrido-Manriquez J, et al. Pre-diagnostic blood immune markers, incidence and progression of B-cell lymphoma and multiple myeloma: univariate and functionally informed multivariate analyses. International Journal of Cancer. 2018;143(6):1335–47. https://doi.org/10.1002/ijc.31536

37. Li B, Xu J, Sun Y, Liu P, Yao Z. Early CRAB-like biomarker signatures reveal a preclinical susceptibility continuum for multiple myeloma. arXiv. 2025;arXiv:2512.15056. https://doi.org/10.48550/arXiv.2512.15056

38. Ucar MA, Tombak A, Akdeniz A, Dinçyürek HD, Şener M, Koyuncu MB, et al. Immune and inflammation markers as a predictor of overall survival in patients with hematologic malignancies: a retrospective cohort study. Medicina. 2025;61:1019. https://doi.org/10.3390/medicina61061019

39. Xu J, Li B, Yao Z, Liu P. Pre-diagnostic biomarkers show disease susceptibility continuum and enable early prediction of multiple myeloma. Blood. 2025;146(Suppl 1):2231. https://doi.org/10.1182/blood-2025-2231

40. Mandefro B, Addisu B, Kelem A, Workneh M, Adane T. The role of hematological biomarkers as diagnostic tool in pre-cancerous patients. Discover Oncology. 2026;17:567. https://doi.org/10.1007/s12672-026-04661-6