Although the treatment of acute lymphoblastic leukemia (ALL) has improved significantly over recent decades, failure due to treatment-related toxicitiesand relapse of the disease still occur in about 20% of patients. This retrospective study included 308 pediatric ALL patients undergoing maintenance therapy and investigated the effects of genetic variants of enzymes involved in the 6-mercaptopurine (6-MP) metabolism and folate pathway on survival and relapse rates. The presence of at least one of the non-functional ITPA alleles (94C.A and/or IVS2+21A.C variant) was associated with longer event-free survival compared to patients with the wild-type ITPA genotype (p = 0.033). Furthermore, patients carrying at least one non-functional ITPA allele were shown to be at a lower risk of suffering early(p = 0.003) and/or bone marrow relapse (p = 0.017). In conclusion, the ITPA genotype may serve as a genetic marker for the improvement of risk stratification and therapy individualization for patients with ALL.
COBISS.SI-ID: 3742577
Thiopurine-related hematotoxicity in paediatric acute lymphoblastic leukemia (ALL) and inflammatory bowel diseases has been linked to genetically defined variability in thiopurine S-methyltransferase (TPMT) activity. While gene testing of TPMT is being clinically implemented, it is unclear if additional genetic variation influences TPMT activity with consequences for thiopurine-related toxicity. To examine this possibility, we performed a genome-wide association study (GWAS) of red blood cell TPMT activity in 844 Estonian individuals and 245 paediatric ALL-cases. Additionally, we correlated genome-wide genotypes to human hepatic TPMT activity in 123 samples. Only genetic variants mapping to chromosome 6, including TPMT gene region, were significantly associated with TPMT activity (P(5x10 -8) in each of the three GWAS and a joint meta-analysis of 1212 cases (top hit P=1.2x10 -72). This finding is consistent with TPMT genotype being the primary determinant of TPMT activity, reinforcing the rationale for genetic testing of TPMT alleles in routine clinical practice to individualize MP dosage. This article is protected by copyright. All rights reserved.
COBISS.SI-ID: 4231793
Adequate maintenance therapy for childhood acute lymphoblastic leukemia (ALL), with 6-mercaptopurine as an essential component, is necessary for retaining durable remission. Interruptions or discontinuations of the therapy due to drug-related toxicities, which can be life threatening, may result in an increased risk of relapse. In this retrospective study including 305 paediatric ALL patients undergoing maintenance therapy, we systematically investigated the individual and combined effects of genetic variants of folate pathway enzymes, as well as of polymorphisms in PACSIN2 and ITPA, on drug-induced toxicities by applying a multi-analytical approach including logistic regression (LR), classification and regression tree (CART) and generalized multifactor dimensionality reduction (GMDR). In addition to the TPMT genotype, confirmed to be a major determinant of drug related toxicities, we identified the PACSIN2 rs2413739TT genotype as being a significant risk factor for 6-MP-induced toxicity in wild-type TPMT patients. A gene-gene interaction between MTRR (rs1801394) and MTHFR (rs1801133) was detected by GMDR and proved to have an independent effect on the risk of stomatitis, as shown by LR analysis. To our knowledge, this is the first study showing PACSIN2 genotype association with hematological toxicity in ALL patients undergoing maintenance therapy.
COBISS.SI-ID: 4133233
Aim: In the present study, the influence of SAM on TPMT activity in vivo on human subjects was investigated. Subjects & methods: A total of 1017 donors from the Estonian Genome Center of the University of Tartu (Estonia) were genotyped for common TPMT variants, evaluated for TPMT activity, SAM levels, aset of 19 biochemical and ten hematological parameters and demographic data. Results: After adjustment in multiple regression models and correction for multiple testing, from the 43 factors that were tested, only TPMT genotype (p = 1 Ž 10-13) and SAM levels (p = 1 Ž 10-13) were found to significantly influence TPMT activity. The influence of SAM on TPMT activity was more pronounced in TPMT-heterozygous than wild-type individuals. Conclusion: SAM represents a potential pharmacometabolomic marker and therapeutic agent in TPMT-heterozygous subjects.
COBISS.SI-ID: 3742833
Treatment induced non traumatic osteonecrosis (ON) has been reported increasingly in children treated for acute lymphoblastic leukemia (ALL). Several risk factors for ON have been identified in childhood cancer patients; however, their diagnostic and prognostic power is limited and the etiology of the disease remains unclear. Therefore, a continuous effort is focused on the identification of additional ON risk factors. We performed a retrospective study of 313 childhood ALL patients to test the association between the ON occurrence in children receiving ALL therapy and common polymorphisms in potential target genes: Thiopurine S methyltransferase (TPMT; 460G)A, 719A)G), 5,10 methylenetetrahydrofolate reductase (MTHFR; 677C)T, 1298A)C), estrogen receptor alpha 1 (ESR1; XbaI) and collagen type I, 1 (COL1A1; Sp1). In the present cohort, higher age and more recently developed treatment protocols were independent risk factors for ON. In children )14.5 years old, TPMT genotype modulated the risk of ON. Additionally, in children (12.9 years old ESR1 genotypes were also implicated in the pathogenesis of ON. Besides greater age and more recent treatment protocols, genetic factors (polymorphisms in ESR1 and TPMT genes) were suggested to be implicated in the pathogenesis of ON and could be potentially used as genetic prognostic markers for ON.
COBISS.SI-ID: 4074609