The prediction of high-dose methotrexate (HD-MTX) toxicity is a key issue in the individualization of treatment in childhood acute lymphoblastic leukemia (ALL). Our aim was to evaluate the influence of MTX pathway polymorphisms on HD-MTX treatment outcome in children with ALL. In total, 167 children with ALLwere genotyped for methylenetetrahydrofolate dehydrogenase (MTHFD1) 1958G)A, methylenetetrahydrofolate reductase (MTHFR) 677C)T and 1298A)C, and thymidylate synthase (TYMS) 2R)3R polymorphisms. MTHFD1 1958A allele significantly reduced odds of hepatotoxicity (adjusted P=0.009), while TYMS 3Rallele significantly reduced odds of leukocytopenia and thrombocytopenia (adjusted P=0.005 and adjusted P=0.002, respectively). MTHFR polymorphisms didnot influence HD-MTX-related toxicity, but a significant effect of MTHFR 677C)T-TYMS 2R)3R and MTHFD1 1958G)A-MTHFR 677C)T interactions on HD-MTX-related toxicity was observed. None of the investigated polymorphisms influenced survival. Our study suggests an important role of polymorphisms andgene-gene interactions within folate pathway in HD-MTX-related toxicity in childhood ALL.
COBISS.SI-ID: 29379801
Purpose: Patients treated for childhood acute lymphoblastic leukemia (ALL) areconsidered to be at increased risk of developing second neoplasm. The aim of our study was to identify DNA repair polymorphisms contributing to the risk of second neoplasm in clinically well-characterized Slovenian patients treated for childhood ALL. Methods: Pediatric patients diagnosed with ALL between 1971 and 2001 were included in the study. According to the identified clinical risk factors for second neoplasm, a matched set of cases with second neoplasm and controls was selected and genotyped for 11 DNA repair polymorphisms. Results: Among 359 pediatric patients with ALL, 20 second neoplasms were observed. The dose of radiotherapy (P = 0.011), administration of epipodophyllotoxins (P = 0.006), and the dose of anthracyclines (P ( 0.001)showed a significant association with the risk of second neoplasm. Amonggenetic factors, we observed a significant association of NBN 1197G allele with increased risk of second neoplasms (RR = 4.36; 95 % CI: 1.19-15.98; P = 0.026), while the risk was decreased in carriers of XRCC3-316Gallele compared with patients with wild-type genotype (RR = 0.20; 95 % CI: 0.04-0.99; P = 0.049). Conclusions: Our results suggest an important role of NBN 1197A)G and XRCC3-316A)G polymorphisms in the development of second neoplasm in patients treated for childhood ALL.
COBISS.SI-ID: 30003929
Background: Papillon-Lefèvre syndrome (PLS) is a rare autosomal recessive disorder characterized by palmoplantar keratoderma together with a severe formof generalized aggressive periodontitis and associated with mutations in cathepsin C gene (CTSC). Objective: To investigate the clinical and mutationalcharacteristics of 6 PLS patients from 4 unrelated Slovenian families. Methods:CTSC mutational and functional analyses were performed. Results: In all patients, a novel homozygous substitution, c.-55C)A, in the CTSC 5Ž-untranslated region (UTR) was detected on genomic DNA level and confirmed by mRNA analysis, resulting in the almost complete loss of CTSC mRNAexpression and CTSC activity. In silico analysis revealed the potential ofthe mutation to disrupt putative transcription factor binding sites (TFBSs) for AP-2 and Sp families of transcription factors. Conclusion: Identification of a novel CTSC 5Ž-UTR mutation together with a severe reduction of CTSC mRNA expression and virtually nonexistent CTSC activity was suggestive of a novel mechanism of TFBS dysfunction associated with PLS.
COBISS.SI-ID: 583596