Genetic polymorphisms in candidate genes predict increased toxicity with methotrexate therapy in Lebanese children with acute lymphoblastic leukemia

2014 ◽  
pp. 1 ◽  
Author(s):  
Nathalie K. Zgheib ◽  
Maya Akra-Ismail ◽  
Carol Aridi ◽  
Rami Mahfouz ◽  
Miguel R. Abboud ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Candidate Genes ◽  
Genetic Polymorphisms ◽  
Lymphoblastic Leukemia ◽  
Methotrexate Therapy

MTHFR 677T-1298C haplotype in acute lymphoblastic leukemia: Impact on methotrexate therapy

2021 ◽  
pp. 107815522110171
Author(s):  
Rim Frikha ◽  
Moez Elloumi ◽  
Tarek Rebai ◽  
Hassen Kamoun
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Methylenetetrahydrofolate Reductase ◽  
Fragment Length Polymorphism ◽  
Lymphoblastic Leukemia ◽  
Allelic Frequency ◽  
Mthfr Gene ◽  
Methotrexate Therapy ◽  
Wild Type ◽  
Functional Variants ◽  
Toxicity Score

Introduction Functional variants of the Methylenetetrahydrofolate reductase ( MTHFR) gene, the C677T and A1298C, have largely investigated in pharmacogenomics of Methotrexate (MTX) in acute lymphoblastic leukemia (ALL), yet the conclusions are inconsistent. In addition; most of these studies do not analyze haplotypes. Here, we investigate the MTHFR 677/1298 genotypes and the 677-1298 haplotype and characterize the MTX response in Northern African ALL patients. Methods Genomic DNA was extracted from whole venous from a total of 28 patients with ALL. Genotyping were carried out with restriction fragment length polymorphism (RFLP). A toxicity score (TS) is calculated for each patient and correlate to the haplotype. Results The allelic frequency of MTHFR 677T-1298C haplotype was 10.7% in ALL patients. According to the toxicity’s score (TS) there was no significant differences between haplotype groups (p = 0.79): TS was higher with wild type of MTHFR (TS = 3.43; SEM ± 0.85) followed by combined genotype (677T-1298C) (TS = 2.67; SEM ± 0.88) and isolated variant (C677T or A1298C) (TS = 2.64; SEM ± 0.92). Conclusion Despite the limitation of this study; our results suggest that the MTHFR 677T-1298C haplotype is common in ALL and may be a promising HD-MTX chemotherapy-related adverse effects biomarker.

Folate pathway genetic polymorphisms modulate methotrexate-induced toxicity in childhood acute lymphoblastic leukemia

2019 ◽  
Vol 83 (4) ◽  
pp. 755-762 ◽  
Author(s):  
Al-Motassem Yousef ◽  
Rand Farhad ◽  
Daniah Alshamaseen ◽  
Abrar Alsheikh ◽  
Mohammed Zawiah ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Genetic Polymorphisms ◽  
Lymphoblastic Leukemia ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Folate Pathway

Biopterin and neurotransmitter amine metabolism in children with acute lymphoblastic leukemia receiving methotrexate therapy

1986 ◽  
Vol 108 (3) ◽  
pp. 470-474 ◽  
Author(s):  
C.R. Pinkerton ◽  
I. Smith ◽  
R.J. Leeming ◽  
G. Sarna ◽  
K. Hyland ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Lymphoblastic Leukemia ◽  
Methotrexate Therapy ◽  
Amine Metabolism

scholarly journals A PAI-1 (SERPINE1) polymorphism predicts osteonecrosis in children with acute lymphoblastic leukemia: a report from the Children's Oncology Group

Blood ◽  
2008 ◽  
Vol 111 (9) ◽  
pp. 4496-4499 ◽  
Author(s):  
Deborah French ◽  
Leo H. Hamilton ◽  
Leonard A. Mattano ◽  
Harland N. Sather ◽  
Meenakshi Devidas ◽  
...  
Keyword(s):  
Risk Factors ◽  
Genetic Variation ◽  
Acute Lymphoblastic Leukemia ◽  
Candidate Genes ◽  
Odds Ratio ◽  
Lymphoblastic Leukemia ◽  
Serum Levels ◽  
Oncology Group ◽  
Frequent Complication ◽  
Pai 1

Abstract As glucocorticoid use increased in acute lymphoblastic leukemia, osteonecrosis became an increasingly frequent complication. Besides increased age, host risk factors are poorly defined. We tested whether 12 polymorphisms were associated with osteonecrosis among patients 10 years and older treated on the CCG1882 protocol. Candidate genes (TYMS, MTHFR, ABCB1, BGLAP, ACP5, LRP5, ESR1, PAI-1, VDR, PTH, and PTHR) were chosen based on putative mechanisms underlying osteonecrosis risk. All children received dexamethasone, with doses varying by treatment arm. A PAI-1 polymorphism (rs6092) was associated with risk of osteonecrosis in univariate (P = .002; odds ratio = 2.79) and multivariate (P = .002; odds ratio = 2.89) analyses (adjusting for gender, age, and treatment arm). Overall, 21 of 78 (26.9%) children with PAI-1 GA/AA genotypes, versus 25 of 214 (11.7%) children with GG genotype, developed osteonecrosis. PAI-1 polymorphisms and PAI-1 serum levels have previously been associated with thrombosis. We conclude that PAI-1 genetic variation may contribute to risk of osteonecrosis.

Pharmacogenetics of Outcome in Children with Acute Lymphoblastic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 163-163 ◽  
Author(s):  
Jose Claudio Rocha ◽  
Cheng Cheng ◽  
Wei Liu ◽  
Shinji Kishi ◽  
Soma Das ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Genetic Polymorphisms ◽  
Cumulative Incidence ◽  
Failure Time ◽  
Lymphoblastic Leukemia ◽  
Classification And Regression Tree ◽  
Central Nervous System Relapse ◽  
Start Site ◽  
Genetic Characteristics ◽  
Expression Levels

Abstract The acquired genetic characteristics of acute lymphoblastic leukemia (ALL) blasts are often used to guide the intensity of therapy, whereas the germline host genetic characteristics of the patient generally have not been considered. Multiple common, functionally important polymorphisms affect genes whose products determine the pharmacokinetics and pharmacodynamics of antileukemic agents. It is not yet known how genetic polymorphisms may interact to affect the outcome of antileukemic therapy. Combining classification and regression tree with failure time analysis, we assessed whether 16 genetic polymorphisms, alone or in combination, predicted relapses in 246 children with ALL, 116 of whom were treated on the lower-risk (LR) and130 on the higher-risk (HR) arms of the St Jude protocol Total XIIIB. Genotyping was performed for the following polymorphic loci: CYP3A4*1B and CYP3A5*3; GSTP1 313A>G, GSTM1 and GSTT1 deletions; MDR1 exon 21 (2677G>T/A) and MDR1 exon 26 (3435C>T); MTHFR 677C>T and MTHFR 1298A>C; NR3C1 1088A>G; SLC19A1 80G>A; TPMT 238G>C, 460G>A and 719A>G; TYMS enhancer repeat; UGT1A1 promoter repeat polymorphism; VDR intron 8 G>A and VDR FokI (start-site) T>C. In all children with available RNA in their diagnostic ALL blasts, gene expression levels of prognostic genotypes were analyzed using the Affymetrix genechip array HG_U95Av2. Among the HR group, the glutathione S-transferase M1 (GSTM1) non-null genotype was associated with the risk of hematological relapse (5-year cumulative incidence, 17.1%±4.5% compared to 5.1%±2.9% for GSTM1 null genotype, p = 0.03), and among the non-null genotypes, the thymidylate synthetase (TYMS) 3/3 genotype was associated with a further increase in hematologic relapse risk (5-year cumulative incidence, 29.2%±9.5% compared to 10.9%±4.7% for TYMS 2/3 or 2/2 genotypes, p = 0.02). Increased expression levels of these two target genes (p < 0.0001 and p = 0.09, respectively) were consistent with resistance to the drugs interacting with these gene products. For central nervous system relapse, among the HR group, the vitamin D receptor (VDR) start site (p = 0.02) and intron 8 genotypes (p = 0.04) predisposed, whereas for LR patients the TYMS 3/3 genotype predisposed (p = 0.04). The genotypes associated with outcome have pharmacologic plausibility: e.g., high GST activity (GSTM1 non-null) could cause anticancer drug resistance; high TYMS activity (TYMS 3/3) would be less inhibited by antifolates. In conclusion, germline polymorphisms influence the outcome of antileukemic therapy, and therefore represent determinants of response that can be used to optimize therapy.

scholarly journals Genetic polymorphisms of NQO1, CYP1A1 and TPMT and susceptibility to acute lymphoblastic leukemia in a Tunisian population

2012 ◽  
Vol 40 (2) ◽  
pp. 1307-1314 ◽  
Author(s):  
Slah Ouerhani ◽  
Nouha Cherif ◽  
Ikbel Bahri ◽  
Ines Safra ◽  
Samia Menif ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Genetic Polymorphisms ◽  
Lymphoblastic Leukemia ◽  
Tunisian Population
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