PHARMACOGENETICS AND CELL BIOLOGY OF PEDIATRIC ACUTE LYMPHOBLASTIC LEUKEMIA
Csányiné Dr. Sági Judit
Molecular Medicine
Dr. Enyedi Péter
2022-05-17 13:30:00
Basis of Human Molecular Genetics and Gene Diagnostics
Dr. Szalai Csaba
Félné Dr. Semsei Ágnes
Dr. Rónai Zsolt
Dr. Szelid Zsolt
Dr. Fekete György
Dr. Szabó Léna
Dr. Horváth Orsolya
Risk-based treatment has improved survival from childhood malignancies by about 80%. However, acute and late side effects and treatment failure continue to impair quality of life and survival. This work investigated the role of inherited SNPs and novel mutations in the development of side effects and relapse in patient populations with acute lymphoblastic leukemia (ALL) or osteosarcoma (OSC).
For the retrospective studies, samples and patient data were obtained partly from the Hungarian Pediatric Oncohematology Biobank and partly from European collaborations. Our objective was to investigate the correlations between the phenotypes studied (cardiotoxicity, neurotoxicity and central nervous system (CNS) relapse) and the germline SNPs present in the relevant genes (drug-metabolizing enzymes and transporters). In addition, acquired mutations in genes relevant for the development of relapse in a group of patients with T-ALL were also searched for.
In patients with ALL and OSC, ABCC2 rs3740066, NQO1 rs1043470, and SLC22A6 rs6591722 were associated with worse linear ejection fraction (linEF) in the acute phase of treatment and 5-10 years after diagnosis. In the ALL group, CYP3A4 rs3735451, CYP3A5 rs776746 and NQO1 rs1043470 were associated with changes in linEF values between different points of therapy. ABCB1 rs1045642 was associated with the occurrence of toxic seizures. However, ABCB1 rs1128503 and rs2032582 were inversely associated with toxic seizure and CNS relapse in the overall patient cohort: they were associated with higher toxicity and lower risk of CNS relapse and vice versa. The presence of the CYP3A4 rs3735451 and CYP3A5 rs4646450, rs776746 SNPs were associated with worse overall (OS) and event-free survival (EFS) in the acute encephalopathy (AE), acute toxic encephalopathy (ATE) and CNS relapse cohorts, respectively. NT5C2 inactivating mutations were associated with early T-ALL relapse but did not affect survival.
In the future, if these SNPs and mutations are found suitable for screening in clinical practice after validation, our results may contribute to improving the safety and efficacy of drugs and may reveal new drug targets for precision treatment of pediatric malignancies.
