Project Details
Projekt
Central diagnostics, genomics and biobanking
Subject Area
Hematology, Oncology
Term
from 2016 to 2021
Project identifier
Deutsche Forschungsgemeinschaft (DFG) - Project number 226262100
Chronic lymphocytic leukemia (CLL) is characterized by the frequent presence of recurrent chromosomal aberrations and gene mutations, indicating a significant level of genomic instability and heterogeneity in this disease. Besides genetic events, such as lesions in TP53, there seem to be additional mechanisms of treatment resistance, particularly towards novel substances like the small molecule (sm) inhibitors, which are not yet understood and are one particular focus of this CRU. As a core project of this CRU-286 it is one of our main tasks to provide central biobanking and molecular diagnostic services beyond the level of clinical routine, both of which ensure the availability of fully characterized CLL biomaterial to the research projects (RP) of this CRU. In the previous funding period we have established targeted next generation sequencing (NGS) as a standard tool available at the University Hospital Cologne. Combining NGS and classical cytogenetics in a clinically annotated subset of patients treated with chlorambucil-containing first-line chemoimmunotherapy, we were able to decipher complex aberrant karyotypes, POT1 and particularly KRAS mutations as important indicators of an unfavorable prognosis in CLL. In addition, we have collected first exome sequencing data in patients resistant to novel sm-inhibitors, which hint to significant dynamics in the longitudinal and inter-compartmental evolution of CLL. These findings have significantly shaped research projects included in the follow up proposal of this CRU. In the second funding period we aim to extend our genomic research activities with specific focus on the deciphering of clonal evolution in CLL and the performance of integrative analyses of genomic, transcriptomic (including splicing events) and particularly epigenetic alterations detected in patients prior to and after the development of resistance towards novel sm substances. We will further advance computational methodologies, which have successfully been implemented to follow phylogenetic clonal trajectories in small lung cell cancer and neuroblastoma, to the setting of CLL. These efforts will also be applicable to genetic data generated in various RPs of this CRU (e.g. in animal models or cell lines). Overall, CP2 offers a broad portfolio of diagnostic, genomic and computational methodologies, which will be irremissible to the successful completion of the research proposed in this CRU. Further, a comprehensive and particularly genetic workup of patients with relapsed/refractory disease after sm-inhibition will facilitate further research on personalized treatment strategies to finally overcome genetic mechanisms of drug resistance in CLL.
DFG Programme
Clinical Research Units
