Circulating Tumor DNA in Aggressive B-Cell Lymphomas: Tumor Cell Characterization and Disease Dynamics

B-cell lymphomas represent a heterogeneous group of malignancies, with diffuse large B-cell lymphoma (DLBCL) being the most common and aggressive subtype. Aggressive B-cell lymphomas may arise de novo, through transformation from indolent lymphomas such as marginal zone lymphoma (MZL), or in specific clinical contexts such as post-transplant lymphoproliferative disorders (PTLD) and relapsed/refractory DLBCL (R/R DLBCL). This thesis investigates the biological mechanisms underlying lymphoma progression and transformation, and evaluates the utility of circulating tumor DNA (ctDNA) as a biomarker across various aggressive B-cell lymphoma subtypes.
Clinical and molecular analyses identified risk factors for MZL transformation and revealed that transformed MZL frequently acquires features of germinal center B cells. Multi-omics approaches showed only subtle genomic and transcriptomic changes during transformation. Across subtypes, ctDNA emerged as a promising non-invasive biomarker for diagnosis, prognosis, and disease monitoring. In PTLD, ctDNA profiling revealed recurrent genetic alterations and closely reflected tumor characteristics and guide treatment decisions.
In R/R DLBCL, a high ctDNA tumor fraction was associated with poor prognosis. Persistent ctDNA mutations or copy number alterations provided complementary diagnostic value when combined with PET-CT, supporting their integrated use in assessing disease progression and guiding treatment decisions.
Together, these findings underscore ctDNA as a clinically informative biomarker across aggressive B-cell lymphoma subtypes, with potential to improve risk stratification and therapeutic guidance.