Clonal evolution and molecular ontogeny of relapsed peripheral T-cell lymphoma

• Applicant: Privatdozent Dr. Raphael Koch
• Subject Area: Hematology, Oncology
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 514061554

Peripheral T-cell lymphoma (PTCL) is a rare hematologic malignancy with poor prognosis. Standard chemotherapeutic treatment regimen are significantly challenged by high rates of primary resistant disease or early relapse with fatal outcome. For patients with relapsed PTCL, autologous or allogeneic stem cell transplantation can be considered for salvage therapy. However, treatment related mortality and relapse after stem cell transplantation still remains a major issue. Overall, the prognosis for relapsed PTCL is extremely poor. Importantly, the genetic background and molecular mechanisms of disease relapse have not been addressed thus far. Addressing this issue, we now strive to unravel the genetic background and molecular mechanisms of relapsed PTCL by comprehensive genetic profiling of a unique multi-center clinical cohort. For this effort, we are capitalizing on a multi-center, clinically annotated, longitudinal sample collection of primary PTCL at first diagnosis and relapse. Furthermore, we are taking advantage of a unique collection of peripheral blood stem cell products from patients with PTCL who underwent stem cell transplantation at our institution in Göttingen. This sample collection will allow to address the following specific research aims: Aim 1: Unravelling the clonal evolution and molecular basis of relapsed PTCL through a) identification of mutations and structural variants by WES and shallow WGS and b) complementary RNA-Seq for detection of gene fusions and characterization of gene expression profiles in longitudinal lymphoma samples of primary diagnosis and relapse. Aim 2: Deciphering the timing and cellular context of genetic alterations during PTCL-development through identification of somatic mutations in distinct hematopoietic compartments by targeted deep sequencing of FACS-sorted peripheral blood stem cell products. Aim 3: Functional data analysis for mechanistic concepts and therapeutic strategies for relapsed PTCL. The research effort will be embedded in a recently established European consortium for translational research in PTCL (EuroTCLym) and capitalize on established bioinformatics and data-analysis pipelines within our consortium and scientific network in Göttingen. For harmonized data distribution, the project will be embedded in the ICGC-ARGO project.

• DFG Programme: Research Grants