Genomic Profiling of Pediatric Malignant Haematopoietic and Lymphoid Diseases by Next-Generation Sequencing-based Methods and Bioinformatic Approaches
Bedics Gábor
Pathological Sciences
Dr. Matolcsy András
Patológiai és Kísérleti Rákkutató Intézet Digitális Szövettani Oktatóterem
2024-10-02 14:00:00
Experimental Oncology
Dr. Bödör Csaba
Dr. Alpár Donát
Dr. Bors András
Dr. Varga Gergely
Dr. Tordai Attila Árpád
Dr. Kocsmár Éva
Dr. Butz Henriett
My doctoral research focused on molecular genetic profiling using next-generation sequencingbased methods and bioinformatic approaches of certain pediatric malignant hematopoietic and
lymphoid diseases, such as pediatric acute lymphoblastic leukemia and histiocytic neoplasms.
We performed a comprehensive screening for disease-relevant CNAs in a cohort of Hungarian
patients diagnosed with pediatric B-ALL using digitalMLPA. The generated CNA profiles were
combined with cytogenetic data for risk assessment. We integrated IKZF1status
(IKZF1normal, IKZF1del and IKZF1plus) with cytogenetic classes, thus creating a cytogenetics
aware interpretation of IKZF1 imbalance for the first time, which substantially improved the
risk assessment for our patients by distinguishing three prognostic groups with significantly
different 5-year EFS. We also introduced a conceptually novel patient classification approach
called PersonALL, which assigns patients to prognostic subgroups based on highly
individualized cumulative scores reflecting the weighted impact of all relevant aberrations
detected in a particular patient. This newly developed prognostic classifier, which flexibly
considers all possible combinations of screened and potentially co-segregating genetic
alterations, provides a more refined, hence more personalized risk assessment for children with
B-ALL.
We discovered the first histiocytic neoplasm driven by a novel ROS1 gene fusion (GIT2::ROS1)
identified by comprehensive genomic profiling and validated by a range of different molecular
laboratory methods. Moreover, we reported the first evidence of efficacious ROS1-inhibitor
(entrectinib) treatment in the patient diagnosed with ROS1-translocated histiocytic neoplasm,
with significant improvement of clinical symptoms and achievement of a radiologically stable
disease. Although this association needs to be confirmed in additional cases, our finding raises
the possibility to expand the classification of histiocytic neoplasms with the novel ROS1 driver
alteration. Our study also clearly highlights the utility and clinical relevance of comprehensive
genomic profiling in the diagnostic workflow of histiocytic neoplasms.
