Genomic & transcriptomic profiling of post-transplant lymphoma

As part of her PhD research at KU Leuven, Ana-Lucía Rocha is investigating the molecular landscape of post-transplant lymphomas, a group of lymphoid malignancies that develop following solid organ or stem cell transplantation. Because transplant recipients require long-term immunosuppressive therapy to prevent graft rejection, they face an increased risk of lymphoma due to impaired immune surveillance.

At EHA 2026, findings were presented from a study analyzing tumor and germline samples from patients with post-transplant lymphoma. Using long-read sequencing of both tumor and healthy DNA, the team characterized the mutational profiles of these malignancies and identified marked differences between Epstein–Barr virus (EBV)-positive and EBV-negative cases. Notably, EBV-negative lymphomas exhibited a high tumor mutational burden and distinct mutational signatures, including evidence of defective DNA mismatch repair, suggesting mechanisms that may facilitate the accumulation of genetic alterations and drive lymphomagenesis.

The investigators also identified a mutational signature associated with prior exposure to azathioprine, an immunosuppressive agent historically used in some transplant recipients. This finding suggests that treatment-related DNA damage may contribute to the development of lymphoma in a subset of patients.

In addition, single-nucleus RNA sequencing revealed biological differences between early- and late-onset post-transplant lymphomas, defined by the interval between transplantation and lymphoma diagnosis. Whereas early-onset cases appeared relatively homogeneous, late-onset tumors displayed greater molecular diversity and distinct biological characteristics. 

Together, these findings provide novel insights into the pathogenesis of post-transplant lymphomas and may help inform future strategies for risk assessment, disease monitoring, and therapeutic intervention.