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Pharmacogenetics of the Central Nervous System-Toxicity and Relapse Affecting the CNS in Pediatric Acute Lymphoblastic Leukemia

JC. Sági, A. Gézsi, B. Egyed, Z. Jakab, N. Benedek, A. Attarbaschi, S. Köhrer, J. Sipek, L. Winkowska, M. Zaliova, S. Anastasopoulou, BO. Wolthers, S. Ranta, C. Szalai, GT. Kovács, ÁF. Semsei, DJ. Erdélyi

. 2021 ; 13 (10) : . [pub] 20210512

Language English Country Switzerland

Document type Journal Article

Persistent link   https://www.medvik.cz/link/bmc21017777

Grant support
LM2018132 NCMG (Czech Republic)
not added St. Anna Kinderkrebsforschung (Austria)
UNKP-19-3-IV (JC Sagi) New National Excellence Program of the Ministry for Innovation and Technology (Hungary)
07/MGYH-MGYGYT/2018 Hungarian Paediatric Oncology Network (Hungary)
KP2017-0010, TJ2020-0082, TJ2019-0031 Swedish Childhood Cancer Fund (Sweden)
R150-A10181 Danish Cancer Society (Denmark)
not added Danish Childhood Cancer Fund (Denmark)
Grants No. PD109200 (ÁF Semsei), PD134449 (A Gézsi) and K115861 (DJ Erdélyi) National Research, Development and Innovation Office (NKFIH)
not added János Bolyai Research Scholarship of the Hungarian Academy of Sciences (A Gézsi)

Despite improving cure rates in childhood acute lymphoblastic leukemia (ALL), therapeutic side effects and relapse are ongoing challenges. These can also affect the central nervous system (CNS). Our aim was to identify germline gene polymorphisms that influence the risk of CNS events. Sixty single nucleotide polymorphisms (SNPs) in 20 genes were genotyped in a Hungarian non-matched ALL cohort of 36 cases with chemotherapy related acute toxic encephalopathy (ATE) and 544 controls. Five significant SNPs were further analyzed in an extended Austrian-Czech-NOPHO cohort (n = 107 cases, n = 211 controls) but none of the associations could be validated. Overall populations including all nations' matched cohorts for ATE (n = 426) with seizure subgroup (n = 133) and posterior reversible encephalopathy syndrome (PRES, n = 251) were analyzed, as well. We found that patients with ABCB1 rs1045642, rs1128503 or rs2032582 TT genotypes were more prone to have seizures but those with rs1045642 TT developed PRES less frequently. The same SNPs were also examined in relation to ALL relapse on a case-control matched cohort of 320 patients from all groups. Those with rs1128503 CC or rs2032582 GG genotypes showed higher incidence of CNS relapse. Our results suggest that blood-brain-barrier drug transporter gene-polymorphisms might have an inverse association with seizures and CNS relapse.

References provided by Crossref.org

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$a Despite improving cure rates in childhood acute lymphoblastic leukemia (ALL), therapeutic side effects and relapse are ongoing challenges. These can also affect the central nervous system (CNS). Our aim was to identify germline gene polymorphisms that influence the risk of CNS events. Sixty single nucleotide polymorphisms (SNPs) in 20 genes were genotyped in a Hungarian non-matched ALL cohort of 36 cases with chemotherapy related acute toxic encephalopathy (ATE) and 544 controls. Five significant SNPs were further analyzed in an extended Austrian-Czech-NOPHO cohort (n = 107 cases, n = 211 controls) but none of the associations could be validated. Overall populations including all nations' matched cohorts for ATE (n = 426) with seizure subgroup (n = 133) and posterior reversible encephalopathy syndrome (PRES, n = 251) were analyzed, as well. We found that patients with ABCB1 rs1045642, rs1128503 or rs2032582 TT genotypes were more prone to have seizures but those with rs1045642 TT developed PRES less frequently. The same SNPs were also examined in relation to ALL relapse on a case-control matched cohort of 320 patients from all groups. Those with rs1128503 CC or rs2032582 GG genotypes showed higher incidence of CNS relapse. Our results suggest that blood-brain-barrier drug transporter gene-polymorphisms might have an inverse association with seizures and CNS relapse.
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