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Polymorphisms in the ABCB1 gene and effect on outcome and toxicity in childhood acute lymphoblastic leukemia.

ABSTRACT: The membrane transporter P-glycoprotein, encoded by the ABCB1 gene, influences the pharmacokinetics of anti-cancer drugs. We hypothesized that variants of ABCB1 affect outcome and toxicity in childhood acute lymphoblastic leukemia (ALL). We studied 522 Danish children with ALL, 93% of all those eligible. Risk of relapse was increased 2.9-fold for patients with the 1199GA variant versus 1199GG (P=0.001), and reduced 61% and 40%, respectively, for patients with the 3435CT or 3435TT variants versus 3435CC (overall P=0.02). The degree of bone marrow toxicity during doxorubicin, vincristine and prednisolone induction therapy was more prominent in patients with 3435TT variant versus 3435CT/3435CC (P=0.01/P<0.0001). We observed more liver toxicity after high-dose methotrexate in patients with 3435CC variant versus 3435CT/TT (P=0.03). In conclusion, there is a statistically significant association between ABCB1 polymorphisms, efficacy and toxicity in the treatment of ALL, and ABCB1 1199G>A may be a new possible predictive marker for outcome in childhood ALL.

SUBMITTER: Gregers J

PROVIDER: S-EPMC4762905 | biostudies-other | 2015 Aug

REPOSITORIES: biostudies-other

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Polymorphisms in the ABCB1 gene and effect on outcome and toxicity in childhood acute lymphoblastic leukemia.

Gregers J J Gréen H H Christensen I J IJ Dalhoff K K Schroeder H H Carlsen N N Rosthoej S S Lausen B B Schmiegelow K K Peterson C C

The pharmacogenomics journal 20150113 4

The membrane transporter P-glycoprotein, encoded by the ABCB1 gene, influences the pharmacokinetics of anti-cancer drugs. We hypothesized that variants of ABCB1 affect outcome and toxicity in childhood acute lymphoblastic leukemia (ALL). We studied 522 Danish children with ALL, 93% of all those eligible. Risk of relapse was increased 2.9-fold for patients with the 1199GA variant versus 1199GG (P=0.001), and reduced 61% and 40%, respectively, for patients with the 3435CT or 3435TT variants versus ...[more]

PMID: 25582575

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Project description:The present study aimed to investigate the association between aberrant DNA methylation of the promoter region of the ephrin type-B receptor 4 (EPHB4) gene and the development of childhood acute lymphoblastic leukemia (ALL). Bisulfite sequencing polymerase chain reaction (BSP) was performed to determine the methylation density of cytosine-guanine pair islands in the promoter region of EPHB4, in bone marrow samples from 40 children with ALL. The mRNA and protein expression levels of EPHB4 were detected using reverse transcription-quantitative polymerase chain reaction and western blot analysis. A total of 10 children with idiopathic thrombocytopenic purpura (ITP) were recruited as controls. The results revealed that the average methylation density of the bone marrow samples from the patients with ALL was significantly higher, compared with the patients with ITP (P=0.046). The relative mRNA expression levels of EPHB4 in the patients with ITP (25.08±4.03) and the patients with ALL without methylation (12.33±2.16) were significantly higher, compared with that observed in the patients with ALL with methylation (6.48±2.73; P<0.01). Pearson analysis revealed a significant negative linear correlation between EPHB4 gene methylation and its expression levels (r=-0.957; P<0.01). Western blot analysis indicated that EPHB4 protein expression levels were low in the methylated ALL samples. An evaluation of the two-year disease-free survival (DFS) of the patients with ALL was performed, which revealed that the patients with unmethylated ALL exhibited a significantly higher two-year DFS rate, as compared with patients with methylated ALL (P=0.036). These results suggest that the methylation of the EPHB4 gene is prevalent in childhood ALL and may result in expressional inactivation, which consequently promotes ALL pathogenesis and is associated with an unfavorable prognosis. Therefore, the EPHB4 gene may function as a potential tumor suppressor in childhood ALL.

Project description:Childhood acute lymphoblastic leukemia (ALL) is characterized by recurrent genetic aberrations. The identification of those abnormalities is clinically important because they are considered significant risk-stratifying markers.There are insufficient data of cytogenetic profiles in Saudi Arabian patients with childhood ALL leukemia. We have examined a cohort of 110 cases of ALL to determine the cytogenetic profiles and prevalence of FLT3 mutations and analysis of the more frequently observed abnormalities and its correlations to other biologic factors and patient outcomes and to compare our results with previously published results.Patients-We reviewed all cases from 2007 to 2016 with an established diagnosis of childhood ALL. Of the 110 patients, 98 were B-lineage ALL and 12 T-cell ALL. All the patients were treated by UKALL 2003 protocol and risk stratified according previously published criteria. Cytogenetic analysis-Chromosome banding analysis and fluorescence in situ hybridization were used to detect genetic aberrations. Analysis of FLT3 mutations-Bone marrow or blood samples were screened for FLT3 mutations (internal tandem duplications, and point mutations, D835) using polymerase chain reaction methods.Cytogenetic analysis showed chromosomal anomalies in 68 out of 102 cases with an overall incidence 66.7%. The most frequent chromosomal anomalies in ALL were hyperdiploidy, t(9;22), t(12;21), and MLL gene rearrangements. Our data are in accordance with those published previously and showed that FLT3 mutations are not common in patients with ALL (4.7%) and have no prognostic relevance in pediatric patients with ALL. On the contrary, t(9;22), MLL gene rearrangements and hypodiploidy were signs of a bad prognosis in childhood ALL with high rate of relapse and shorter overall survival compared with the standard-risk group (P = .031).The event-free survival was also found to be worse (P = .040).Our data are in accordance with those published previously, confirming the overall frequency of cytogenetic abnormalities and their prognostic relevance.

Project description:BACKGROUND:It has been shown that approximately half of survivors of childhood acute lymphoblastic leukemia (ALL) have symptomatic late effects (LE) that may be severe or life-threatening. The aim of our study was to assess the health status of childhood ALL survivors after over 10 years of follow-up and to assess its relationships with gene polymorphisms, numbers and types of LEs, as well as with intensity of chemotherapy and cranial radiotherapy (CRT). METHODS:We conducted a telephone survey in 125 ALL survivors (median time from completion of treatment was 12 years) and compared the results with those obtained in our previous study. Most of the patients were followed-up by local providers. RESULTS:The prevalence of LEs of approximately 50% was similar in both study groups. More than one LE was found in almost 25% of patients. Endocrine LEs were less frequent than in our previous study (44% vs 22%), probably due to underdiagnosis. The prevalence of hepatitis B/C decreased from 30%/50 to 18% (counted together), and prevalence of neurologic LEs decreased from 18 to 6%. The increase in the rate of second malignancies was not significant (2% vs. 3%). Sixty four percent of patients continued their education at the time of the study. Approximately 51% of ALL survivors who have completed their education by the time of the study had no permanent employment, including 4 mothers of infants and 3 persons qualified for a disability living allowance. These employment problems may have been due to cognitive impairment. The offspring of the ALL survivors included 11 children, all of them healthy. Further analysis showed higher prevalence of hepatitis in patients treated with CRT (p?=?0.0001). Genetic studies revealed higher prevalence of hepatitis in patients homozygous for the rs9939609A variant of the FTO gene compared with other patients (p?=?0.03). Moreover, wild-type rs1137101 polymorphism (Q223R) of the and leptin receptor gene was more frequent in patients with psychological LEs (p?=?0.03). CONCLUSIONS:The prevalence of LEs in ALL survivors is of key importance. The transition of childhood ALL survivors from pediatric to adult care should be urgently improved to maintain continued follow-up provide high-quality care. TRIAL REGISTRATION:Bioethics Committee of the Jagiellonian University approved the study protocol. Registration number: KBET/113/B/2006.

Dataset Information

Polymorphisms in the ABCB1 gene and effect on outcome and toxicity in childhood acute lymphoblastic leukemia.

Publications

Polymorphisms in the ABCB1 gene and effect on outcome and toxicity in childhood acute lymphoblastic leukemia.

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