Proteome-wide Mendelian randomization identifies protein associations and therapeutic targets for B-cell malignancy

Area of Science:

• Genetics
• Oncology
• Pharmacology

Background:

• B-cell malignancies often relapse or become refractory to treatment, indicating a need for new therapeutic targets.
• High attrition rates in drug development hinder the identification of effective treatments.

Purpose of the Study:

• To prioritize candidate drug targets for B-cell malignancies using human genetics.
• To evaluate causal associations between circulating proteins and B-cell cancers.

Main Methods:

• Mendelian randomization analysis of 2923 proteins against 6 B-cell malignancies (22,922 cases, 388,978 controls).
• Integration of single-cell RNA sequencing, Bayesian colocalization, and clinical trial data.
• Development of an interactive R/Shiny application for results visualization.

Main Results:

• Identified 27 significant protein-disease associations, including TNFSF13 (APRIL) and TNFRS13B (TACI) in multiple myeloma, CD40 in Hodgkin lymphoma, and FAS in chronic lymphocytic leukemia.
• Prioritized 23 proteins as potential drug targets based on integrated genetic and molecular evidence.
• All findings are publicly accessible via an R/Shiny application.

Conclusions:

• Human genetics, particularly Mendelian randomization, is a powerful tool for guiding therapeutic discovery in B-cell neoplasia.
• The identified protein targets offer promising avenues for developing novel treatments for relapsed or refractory B-cell malignancies.