Identification of Plasma Protein Biomarkers and Drug Targets for Hematologic Malignancies by Proteome-wide Mendelian Randomization

Background: It has been reported that the proteome in blood was an important source for biomarker and therapeutic target discovery. However, up to now, few proteomes have been identified with the risk of hematologic malignancies.

Methods: Genome-wide association studies (GWASs) including 3,083 plasma proteins are based on data from 54,219 people in the UK Biobank Pharma Proteomics Project (UKB-PPP) and 35,559 individuals from Iceland (deCODE). Genetic correlations with 33 hematologic malignancies were derived from the FinnGen cohort and the UK Biobank Data. Further studies, including Bayesian colocalization, protein-protein interaction assessment, pathway enrichment analysis, and drug target evaluation, were performed to enhance knowledge and identify prospective therapeutic targets for 33 hematologic cancers.

Results: Our study indicated that 86 potential plasma proteins may have a substantial causal association with the incidence of 33 hematological tumors, such as BCL2, NFKB1, PARP1, and TNFRSF14. There are 18 proteins with strong evidence of genetic co-localization and 9 proteins with moderate support from colocalization analysis. Out of the 86 proteins, 51 have druggable targets, and 26 were identified as targets for current or prospective pharmaceuticals.

Conclusion: Our research revealed numerous significant proteins linked to the likelihood of hematologic malignancies. It may elucidate protein-mediated processes of hematological tumors and provide prospective treatment options for individuals with these conditions.