Outline of Research
B-cell lymphomas are genetically heterogeneous and stratifiable into molecular subtypes with prognostic and therapeutic relevance. Current classifications focus mainly on tumor-derived somatic alterations, while the contribution of germline susceptibility remains largely unexplored. This project will examine the role of rare, damaging germline variants (in silico) in genes linked to inborn errors of immunity, DNA repair, and lymphoma drivers in the development and subtyping of B-cell lymphomas. Many patients harbor both somatic mutations and inherited variants in immunity or DNA repair pathways, but how these germline defects influence lymphomagenesis, disease biology, heterogeneity, and treatment response is poorly understood.
Research questions
Do rare, damaging germline variants in these pathways increase lymphoma susceptibility?
How do they interact with somatic mutations to shape disease biology and outcome?
Can they define biologically distinct subtypes with therapeutic implications?
What is their frequency and penetrance in the general population?
Objectives
Validate candidate variants identified in 366 B-cell lymphoma patients (paired germline-somatic data) using UK Biobank.
Assess prevalence of these variants in UK Biobank participants with lymphoma vs. matched controls.
Test whether germline variants stratify lymphomas into subtypes linked to treatment vulnerabilities (e.g., DNA repair defects, immune dysregulation).
Scientific rationale
By integrating UK Biobank data, we will define germline-driven subtypes of B-cell lymphoma and evaluate clinical relevance. Germline defects in DNA repair may identify patients suitable for PARP inhibitors or DNA damage-targeted therapies, while variants in immune-regulatory pathways may guide immunotherapy or novel treatments. This work will refine disease classification, improve risk stratification, and support personalized therapeutic strategies for lymphoma patients.