• Asian Pacific Journal of Cancer Prevention
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• v.15 no.15
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• pp.6211-6217
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• 2014

Previous genome-wide association studies (GWAS) have implicated several single nucleotide polymorphisms (SNPs) in the AT-rich interactive domain 5B (ARID5B) gene with childhood acute lymphoblastic leukemia (ALL). However, replicated studies reported some inconsistent results in different populations. Using meta-analysis, we here aimed to clarify the nature of the genetic risks contributed by the two polymorphisms (rs10994982, rs7089424) for developing childhood ALL. Through searches of PubMed, EMBASE, and manually searching relevant references, a total of 14 articles with 16 independent studies were included. Odds ratios (ORs) with 95% confidence intervals (95%CI) were calculated to assess the associations. Both SNPs rs10994982 and rs7089424 showed significant associations with childhood ALL risk in all genetic models after Bonferroni correction. Furthermore, subtype analyses of B-lineage ALL provided strong evidence that SNP rs10994982 is highly associated with the risk of developing B-hyperdiploid ALL. These results indicate that SNPs rs10994982 and rs7089424 are indeed significantly associated with increased risk of childhood ALL.

• Asian Pacific Journal of Cancer Prevention
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• v.16 no.11
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• pp.4727-4732
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• 2015

Background: Folylpolyglutamate synthetase (FPGS), an important enzyme in the folate metabolic pathway, plays a central role in intracellular accumulation of folate and antifolate in several mammalian cell types. Loss of FPGS activity results in decreased cellular levels of antifolates and consequently to polyglutamatable antifolates in acute lymphoblastic leukemia (ALL). Materials and Methods: During May 1997 and December 2003, 134 children diagnosed with ALL were recruited from one hospital in Thailand. We performed a mutation analysis in the coding regions of the FPGS gene and the association between single nucleotide polymorphisms (SNPs) within FPGS in a case-control sample of childhood ALL patients. Mutation screening was conducted by polymerase chain reaction-single strand conformation polymorphism (PCR-SSCP) and subsequently with direct sequencing (n=72). Association analysis between common FPGS variants and ALL risk was done in 98 childhood ALL cases and 95 healthy volunteers recruited as controls. Results: Seven SNPs in the FPGS coding region were identified by mutation analysis, 3 of which (IVS13+55C>T, g.1297T>G, and g.1508C>T) were recognized as novel SNPs. Association analysis revealed 3 of 6 SNPs to confer significant increase in ALL risk these being rs7039798 (p=0.014, OR=2.14), rs1544105 (p=0.010, OR= 2.24), and rs10106 (p=0.026, OR=1.99). Conclusions: These findings suggested that common genetic polymorphisms in the FPGS coding region including rs7039789, rs1544105, and rs10106 are significantly associated with increased ALL risk in Thai children.

• Clinical and Experimental Pediatrics
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• v.50 no.7
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• pp.601-605
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• 2007

The cure rate of acute lymphoblastic leukemia (ALL) in children dramatically improved over past 5 decades from zero to about 80%. The main cause of improvement is owing to the development of chemotherapy by multicenter clinical trial of large study groups with the understanding of leukemia biology. Recently, pediatric ALL protocols were applied to the treatment of adolescent and even adult ALL patients. For nearly 30 years, clinical factors have been used to risk-stratify therapy for children with ALL, so that the most intensive therapies are reserved for those patients at the highest risk of relapse. The risk groups of ALL are divided as standard- (low- plus intermediate-), high- and very high-risk group according to the prognostic factors, and treatment results improved by this risk based treatment. The factors used to risk-stratify therapy include age, gender, presenting leukocyte count, immunophenotype, cytogenetic aberrations including ploidy and translocations, and initial response after 1 to 2 weeks of therapy. But treatment efficacy is the most important determinant and can abolish the clinical significance of most, if at all, prognostic factors. Today, in the era of intensive, multiagent regimens, there is increasing evidence that we have reached the limits of prognostic significance of currently applied clinical risk factors in childhood ALL. As the cure rate of ALL is about 80%, introducing new prognostic factors such as new molecular prognostic markers, new methods of assessment about minimal residual disease, and pharmacogenetic study, with the development of stem cell transplantation and molecular targeted therapy are needed to cure residual 20% of childhood ALL patients without short and long term complications.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.7
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• pp.3461-3464
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• 2012

Methotrexate (MTX) is an important drug for the treatment of childhood acute lymphoblastic leukemia (ALL). However, related toxicity occurs in many organs which may cause interruption of treatment, morbidity, and mortality. Single nucleotide polymorphisms (SNPs) of dihydrofolate reductase (DHFR) and gamma glutamyl hydrolase (GGH) are known to alter their enzymatic activity and thus affect the metabolism of MTX and influence the effectiveness. Therefore, we hypothesized that genetic variations of DHFR and GGH genes may influence the risk of toxicity after high dose MTX. The study population comprised of 105 children with ALL who were treated according to the modified St Jude Total XV protocol. The patients received 2.5 or $5g/m^2$ of MTX for 5 doses during the consolidation phase. Genotyping of DHFR 829C>T and GGH-401C>T was performed using a polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The GGH-401CT and TT genotypes were associated with increased risk of leukopenia and thrombocytopenia after high dose MTX (OR 2.97, 95%CI; 1.24-7.13 and OR 4.02, 95%CI; 1.58-10.26). DHFR 829C>T was not associated with toxicity. In conclusion, the GGH-401CT and TT genotypes were found to increase the risk of severe leukopenia and thrombocytopenia after exposure to high dose MTX for childhood ALL therapy.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.2
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• pp.1127-1130
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• 2013

Background: The standard national protocol for treatment of acute lymphoblastic leukemia (ALL) in children was implemented in 2006. A systematic evaluation of the treatment outcome is needed. This study examined the relapse-free survival among childhood ALL cases treated with this protocol and related factors. Materials and Methods: A descriptive study was conducted in children aged between 0-15 years, newly diagnosed with ALL between March 2006 and March 2011 at Srinagarind Hospital, Department of Pediatrics, Faculty of Medicine, Khon Kaen University. The patients were treated on the basis of stratified risk as per the Thai national protocol. Data were compiled from the hospital records. The Kaplan-Meier method was used to describe relapse-free survival and the Cox proportional hazard model to investigate the associated factors. Results: Of the 103 children recruited, 86 (83.5%) achieved complete remission. The total follow-up time was 3132.5 person-months. Eighteen (20.9%) relapsed. The incidence density was 0.6 per 100 person-months (95%CI: 0.4, 0.9). The respective relapse-free rates at 1, 3 and 5 years were 93.0% (95%CI: 85.1, 96.8), 84.5% (95%CI: 74.0, 90.9) and 64.1% (95%CI: 45.6, 77.8). A factor associated with the relapse-free rate was age under 1 year (HR=6.0; 95%CI: 1.1, 33.8). Conclusions: The rate of being relapse-free in ALL children treated under the Thai national protocol at Srinagarind Hospital was better than with former protocols; however, it is still not as good as in developed countries. Further review of the treatment approach of ALL is needed.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.2
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• pp.877-877
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• 2016

• Child Health Nursing Research
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• v.25 no.1
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• pp.9-16
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• 2019

Purpose: Childhood leukemia is a serious trauma affecting both adolescents and their parents, who experience painful process. However, adolescents with leukemia and their parents also experience positive changes, which is referred to as posttraumatic growth. We examined posttraumatic growth, core beliefs, impact of event, and event-related rumination in adolescents within 5 years of a diagnosis of childhood leukemia and their parents. Methods: The participants were 68 adolescents with childhood leukemia (aged 13~18 years) and their parents, who were recruited from C university hospital in Korea from May to September 2016. The Posttraumatic Growth Inventory, Core Belief Inventory, Impact of Event Scale-Revised, and Event-related Rumination Inventory were completed by the adolescents and their parents. The mean scores and correlations between variables were investigated for both set of participants. Results: Parents showed significantly higher levels of posttraumatic growth, disruption of core beliefs, impact of event, and invasive rumination than adolescents. Disruption of core beliefs and deliberate rumination were positively correlated with posttraumatic growth in both groups. Conclusion: Nursing intervention programs that involve modifying core beliefs and inducing a positive thought can help adolescents with leukemia and their parents grow after traumatic events.

• Clinical and Experimental Pediatrics
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• v.54 no.3
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• pp.106-110
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• 2011

In pediatric patients with acute lymphoblastic leukemia (ALL), the Philadelphia chromosome translocation is uncommon, with a frequency of less than 5%. However, it is classified as a high or very high risk, and only 20-30% of Philadelphia chromosome-positive (Ph+) children with ALL are cured with chemotherapy alone. Allogeneic hematopoietic stem cell transplantation from a closely matched donor cures 60% of patients in first complete remission. Recent data suggest that chemotherapy plus tyrosine kinase inhibitors (TKIs) may be the initial treatment of choice for Ph+ ALL in children. However, longer observation is required to determine whether long-term outcome with intensive imatinib and chemotherapy is indeed equivalent to that with allogeneic related or alternative donor hematopoietic stem cell transplantation (HSCT). Reports on the use of second-generation TKIs in children with Ph+ ALL are limited. A few case reports have indicated the feasibility and clinical benefit of using dasatinib as salvage therapy enabling HSCT. However, more extensive data from clinical trials are needed to determine whether the administration of second-generation TKIs in children is comparable to that in adults. Because Ph+ ALL is rare in children, the question of whether HSCT could be a dispensable part of their therapy may not be answered for some time. An international multicenter study is needed to answer the question of whether imatinib plus chemotherapy could replace sibling allogeneic HSCT in children with Ph+ ALL.

• Asian Pacific Journal of Cancer Prevention
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• v.13 no.8
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• pp.3825-3827
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• 2012

FISH is one of the most sensitive molecular methods to detect genetic abnormalities with DNA probes. When cytogenetic studies are normal or insufficient, FISH may detect cryptic rearrangements, rare or slowly proliferative abnormal populations in non-mitotic cells. We cytogenetically evaluated 70 childhood ALL - 67.1% were found to have an abnormal karyotype. The 23 patients (32.9%) with a normal karyotype were analyzed by FISH applying two probes; TEL/AML1 and MYB which detect cryptic rearrangements of t(12;21)(p13;q22) and deletion of (6q) respectively, associated with a good prognosis. Out of 23 patients, one was positive for t(12;21)(p13;q22) (4.3%). None of our patients were positive for MYB del(6q). Two patients showed an extra signal for MYB on chromosomes other than 6 (8.6 %) indicating amplification or duplication. Findings were compared with the available literature. Our study clearly indicated the integrated FISH screening method to increase the abnormality detection rate in a narrow range. FISH is less useful for diagnostic study of patients with suspected del(6q) but it helps in detecting known cryptic rearrangements as well as identification of new abnormalities(translocation , duplication and amplification) at the gene level.

• Asian Pacific Journal of Cancer Prevention
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• v.17 no.8
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• pp.3989-3995
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• 2016

Background: Childhood acute lymphoblastic leukemia (ALL) is a heterogeneous genetic disease and its etiology remains poorly understood. Recent genome wide association and replication studies have highlighted specific polymorphisms contributing to childhood ALL predispositions mostly in European populations. It is unclear if these observations generalize to other populations with a lower incidence of ALL. The current case-control study evaluated variants in ARID5B (rs7089424, rs10821936), IKZF1 (rs4132601) and CEBPE (rs2239633) genes, which appear most significantly associated with risk of developing childhood B-lineage ALL. Materials and Methods: Using TaqMan assays, genotyping was conducted for 162 de novo B-lineage ALL cases and 150 unrelated healthy controls in India. Appropriate statistical methods were applied. Results: Genotypic and allelic frequencies differed significantly between cases and controls at IKZF1-rs4132601 (p=0.039, p=0.015) and ARID5B-rs10821936 (p=0.028, p=0.026). Both rs10821936 (p=0.019; OR 0.67; 95% CI=0.47-0.94) and rs4132601 (p=0.018; OR 0.67; 95%CI 0.48-0.94) were associated with reduced disease risk. Moreover, gender-analysis revealed male-specific risk associations for rs10821936 (p=0.041 CT+CC) and rs4132601 (p=0.005 G allele). Further, ARID5B-rs7089424 and CEBPE-rs2239633 showed a trend towards decreased disease risk but without significance (p=0.073; p=0.73). Conclusions: Our findings provide the first evidence that SNPs ARID5B-rs10821936 and IKZF1-rs4132601 are associated with decreased B-lineage ALL susceptibility in Indian children. Understanding the effects of these variants in different ethnic groups is crucial as they may confer different risk of ALL within different populations.