Proteomics Identifies Circulating TIMP-1 as a Prognostic Biomarker for Diffuse Large B-Cell Lymphoma

Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, although disease stratification using in-depth plasma proteomics has not been performed to date. By measuring more than 1000 proteins in the plasma of 147 DLBCL patients using data-independent acquisition mass spectrometry and antibody array, DLBCL patients were classified into four proteomic subtypes (PS-I-IV). Patients with the PS-IV subtype and worst prognosis had increased levels of proteins involved in inflammation, including a high expression of metalloproteinase inhibitor-1 (TIMP-1) that was associated with poor survival across two validation cohorts (n = 180). Notably, the combination of TIMP-1 with the international prognostic index (IPI) identified 64.00% to 88.24% of relapsed and 65.00% to 80.49% of deceased patients in the discovery and two validation cohorts, which represents a 24.00% to 41.67% and 20.00% to 31.70% improvement compared to the IPI score alone, respectively. Taken together, we demonstrate that DLBCL heterogeneity is reflected in the plasma proteome and that TIMP-1, together with the IPI, could improve the prognostic stratification of patients. [Display omitted] •Proteomic platform combining DIA-MS and antibody array quantifies 1000+ plasma proteins.•Plasma proteome classifies DLBCL into four subtypes with different prognosis.•High TIMP-1 level shint poor prognosis, could complement IPI score for risk stratification. The in-depth proteomic platform quantifies more than 1000 proteins and classifies the DLBCL patients into four subtypes with distinct prognosis. Among signature proteins of PS-IV subtype with the worst prognosis, TIMP-1 was identified to be associated with poor prognosis and validated in two independent cohorts, which may help improve the prognostic ability of the IPI score for R-CHOP treatment.