Genotype Analysis of ABCC1, NCF4 and CBR3 Polymorphism and the Association With Childhood Acute Lymphoblastic Leukemia in Mexican Childhood Population

Background: The identification of genetic risk factors for Acute Lymphoblastic Leukemia (ALL), are increasingly urgent and necessary.Objective: The purpose of this study is to determine the association of the genetic polymorphisms ABCC1 rs3743527, NCF4 rs1883112 and CBR3 rs1056892 with ALL.Methods: DNA samples were obtained in 71 children with ALL (from 2 to 18 years) and in 71 controls without ALL, to determine the polymorphisms by real-time polymerase chain reaction (qPCR), using specific TaqMan probes in a StepOne® thermal cycler (Applied Biosystems, United States).Results: The results of the Odds Ratio analysis show that in the rs1883112 polymorphism of the NCF4 gene, the heterozygous allele has a risk effect for ALL (OR = 3.1870, CI = 1.8880–7.9383 and p = 0.0002), in turn the mutated genotype (AA) is associated with a protective effect (OR = 0.26, 0.1248 to 0.5434 and p = 0.0003). On the other hand, the CBR3 rs1056892 polymorphism shows a significant association of risk to ALL, in the presence of the HT genotype (OR = 2.77, IC = 1.3837 to 5.5651 and p = 0.004) and the mutated genotype of this polymorphism has a significant association with protection to ALL in the HM genotype (OR = 0.52, IC = 0.2639 to 1.0304 and p = 0.05). While the inheritance models of the polymorphisms let us see that of the rs1883112 polymorphism of the NCF4 polymorphism; the HT genotype of the codominant model shows a protective effect against ALL (OR = 0.4117, IC = 0.1718 to 0.9866 and p = 0.04), the recessive model shows us and confirms what we already saw in table number 3, being that there is an association with protective effect in the HM genotype (OR = 0.2604, IC = 0.1248 to 0.5434 and p = 0.0003). In the polymorphism rs1056892 of the CBR3 gene, a protection association was found in the heterozygous allele of the codominant model (OR = 0.3448, IC = 0.1375 to 0.8896 and p = 0.0274). In addition, the recessive inheritance model for the HM genotype shows a protective effect to ALL, (OR = 0.52, CI = 0.9919 to 3.8638 and p = 0.05).Conclusion: There is an evident impact of the NCF4 rs1883112 and CBR3 rs1056892 polymorphisms with an increased risk of susceptibility to ALL; Likewise, through the codominant inheritance model, the effect of the variation of the CBR3 rs1056892 gene as a protective factor against ALL was evaluated.

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Variants Around miR-451 Can Affect the Risk of Large-artery Atherosclerosis Stroke in Chinese

10.21203/rs.3.rs-450391/v1 ◽

2021 ◽

Author(s):

Jinyu Gu ◽

Wuzhuang Tang ◽

Chong Shen ◽

Zibao Li ◽

Jie Li ◽

...

Keyword(s):

Protective Effect ◽

Stroke Risk ◽

Additive Model ◽

Recessive Model ◽

Large Artery ◽

Non Coding Rna ◽

Disability Rate ◽

Increased Risk ◽

Codominant Model ◽

High Incidence Rate

Abstract Background: Ischemic stroke has high incidence rate, mortality rate and disability rate. Genetic factors have a significant impact on stroke risk. MicroRNAs are a class of small non-coding RNA. Intergenic variants can affect the regulation of microRNAs and modulate large-artery atherosclerosis stroke susceptibility. The low expression of miR-451 aggravated ischemic injury significantly.Methods: Functional intergenic variants near hsa-mir-451 were identified by bioinformatics analysis. We conducted a case-control study to explore the associations of selected variants with large-artery atherosclerosis stroke risk in Chinese.Results: The rs901975 (G>A) near hsa-mir-451 was identified as a functional SNP for stroke susceptibility. The protective effect of A allele was significant in codominant model (OR = 0.62, 95% CI = 0.44-0.89, P = 0.005), recessive model (OR = 0.65, 95% CI = 0.47-0.89, P = 0.006) and log-additive model (OR = 0.82, 95% CI = 0.71-0.96, P = 0.012). We also found the significant effect in participants over 65 years old, male, hypertensive and diabetic people. Moreover, hypertensive people genotyped as GG+GA had 2.84 - fold increased risk compared with those genotyped as AA without hypertension (P interaction = 0.036). In the MEGASTROKE Consortium, rs901975 A allele also had protective effect on LAA stroke in Europeans (OR = 0.937, 95% CI: 0.882-0.996, P = 0.036). Combined analysis of our study and MEGASTROKE showed consistent trend (OR = 0.920, 95% CI: 0.869-0.973, P = 0.004).Conclusions: Our study suggested that rs901975 near hsa-mir-451 might affect large-artery atherosclerosis stroke susceptibility in Chinese population.

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Rs4846049 Polymorphism at the 3′-UTR of MTHFR Gene: Association with Susceptibility to Childhood Acute Lymphoblastic Leukemia

BioMed Research International ◽

10.1155/2019/4631091 ◽

2019 ◽

Vol 2019 ◽

pp. 1-12

Author(s):

Xiaolei Li ◽

Shunguo Zhang ◽

Feng Yu

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Mrna Expression ◽

Protective Factor ◽

Lymphoblastic Leukemia ◽

Childhood Acute Lymphoblastic Leukemia ◽

Allele Carrier ◽

Genotype Distribution ◽

Healthy Controls ◽

Mthfr Polymorphisms ◽

Increased Risk

Background. Accumulating evidence has suggested the polymorphisms of methylenetetrahydrofolate reductase (MTHFR) were associated with susceptibility to childhood acute lymphoblastic leukemia (ALL). However, the known conclusions of currently known polymorphic loci (677 C > T and 1298 A > C) remain controversial. This study was to investigate new genetic biomarkers for ALL by analyzing the MTHFR polymorphisms at the 3′-untranslated region, which is a location bound by miRNAs. Methods. Polymorphisms of rs4846049 (miR-555 binding) were assessed by PCR amplification and direct sequencing in 110 ALL patients and 105 healthy controls. The relative expression of MTHFR was detected by qRT-PCR. Results. Overall, genotype distribution or allele carrier frequencies were not significantly different between patients with ALL and healthy controls (P>0.05). Subgroup analysis results showed that T allele (OR = 0.134, 95% CI = 0.028–0.639; P=0.005) or genotypes with T allele (TT + GT) (OR = 0.133, 95% CI: 0.024–0.727; P=0.017) may be a protective factor for ALL susceptibility in patients with age >8 years. This conclusion was also true for the group only focusing on the precursor B-cell ALL patients. Furthermore, karyotype abnormality was more commonly observed in patients with the GG genotype (56.0%) compared to carriers of TT (0%) or GT (40.6%) genotypes, while c-myc break frequency was significantly higher in TT carriers (33%) than that of patients with GT (3.1%) or GG (0%) genotypes. PCR analysis showed patients carrying the GG genotype of rs4846049 exhibited the reduced mRNA expression of MTHFR. Conclusion. MTHFR rs4846049 polymorphism may be associated with increased risk of childhood with ALL and MTHFR mRNA expression.

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Faculty Opinions recommendation of A thymidylate synthase polymorphism is associated with increased risk for bone toxicity among children treated for acute lymphoblastic leukemia.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.727105440.793530142 ◽

2017 ◽

Author(s):

Kjeld Schmiegelow

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Thymidylate Synthase ◽

Lymphoblastic Leukemia ◽

Increased Risk

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Increased Levels of Adipocyte and Epidermal Fatty Acid-Binding Proteins in Acute Lymphoblastic Leukemia Survivors

Journal of Clinical Medicine ◽

10.3390/jcm10081567 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1567

Author(s):

Katarzyna Konończuk ◽

Eryk Latoch ◽

Beata Żelazowska-Rutkowska ◽

Maryna Krawczuk-Rybak ◽

Katarzyna Muszyńska-Rosłan

Keyword(s):

Metabolic Syndrome ◽

Fatty Acid ◽

Acute Lymphoblastic Leukemia ◽

Binding Proteins ◽

Lymphoblastic Leukemia ◽

Fatty Acid Binding Proteins ◽

Fatty Acid Binding ◽

The Metabolic Syndrome ◽

Increased Risk ◽

Significant Difference

Childhood cancer survivors are highly exposed to the development of side effects after many years of cessation of anticancer treatment, including altered lipid metabolism that may result in an increased risk of overweight and metabolic syndrome. Adipocyte (A-FABP) and epidermal (E-FABP) fatty acid-binding proteins are expressed in adipocytes and are assumed to play an important role in the development of lipid disturbances leading to the onset of metabolic syndrome. The aim of this study was to investigate the association between serum A-FABP and E-FABP levels, overweight, and components of the metabolic syndrome in acute lymphoblastic leukemia survivors. Sixty-two acute lymphoblastic leukemia (ALL) survivors (34 females) were included in the study. The mean age at the time of the study was 12.41 ± 4.98 years (range 4.71–23.43). Serum levels of A-FABP and E-FABP were analyzed using a commercially available ELISA kit. The ALL survivors presented statistically higher A-FABP levels in comparison with the healthy controls (25.57 ± 14.46 vs. 15.13 ± 7.61 ng/mL, p < 0.001). The subjects with body mass index (BMI) above the normal range (18 overweight, 10 obese) had a greater level of A-FABP compared to the ALL group with normal BMI (32.02 ± 17.10 vs. 20.33 ± 9.24 ng/mL, p = 0.006). Of all participants, 53.23% had at least one risk factor of metabolic syndrome; in this group, only the A-FABP level showed a statistically significant difference compared to the healthy control group (30.63 ± 15.91 vs. 15.13 ± 7.61 ng/mL, p < 0.001). The subjects with two or more metabolic risk factors (16.13%) presented higher levels of both A-FABP (33.62 ± 17.16 vs. 15.13 ± 7.61 ng/mL, p = 0.001) and E-FABP (13.37 ± 3.62 vs. 10.12 ± 3.21 ng/mL, p = 0.021) compared to the controls. Univariable regression models showed significant associations between BMI and systolic blood pressure with the A-FABP level (coeff. 1.02 and 13.74, respectively; p < 0.05). In contrast, the E-FABP level was only affected by BMI (coeff. 0.48; p < 0.01). The findings reported herein suggest that the increased levels of A-FABP and E-FABP may be involved in the pathogenesis of overweight and the onset of metabolic syndrome in acute lymphoblastic leukemia. However, further longitudinal, prospective studies of fatty acid-binding proteins and their potential role in the pathogenesis of obesity and metabolic syndrome in ALL survivors remain to be performed.

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ALL-414: Obesity is Not Associated with an Increased Risk of Venous Thromboembolism in AYA Patients with Acute Lymphoblastic Leukemia

Clinical Lymphoma Myeloma & Leukemia ◽

10.1016/s2152-2650(21)01665-7 ◽

2021 ◽

Vol 21 ◽

pp. S276

Author(s):

Sandra Renee Jones ◽

Roshni Bharati Patel ◽

Mahvish Qureshi Rahim ◽

Sandra K. Althouse ◽

Sandeep Batra

Keyword(s):

Venous Thromboembolism ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Increased Risk

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Study of Some Biochemical Parameters in Iraqi Children with Acute Lymphoblastic Leukemia

Baghdad Science Journal ◽

10.21123/bsj.12.2.371-378 ◽

2015 ◽

Vol 12 (2) ◽

pp. 371-378

Author(s):

Baghdad Science Journal

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

Biochemical Parameters ◽

Serum Proteins ◽

Lymphoblastic Leukemia ◽

White Blood Cells ◽

Total Serum ◽

Childhood All ◽

Marrow Cavity ◽

Increased Risk

Leukemia or cancer of the blood is the most common childhood cancer, Acute lymphoblastic leukemia (ALL), is the most common form of leukemia that occurs in children. It is characterized by the presence of too many immature white blood cells in the child’s blood and bone marrow, Acute lymphoblastic leukemia can occur in adults too, treatment is different for children. Children with ALL develop symptoms related to infiltration of blasts in the bone marrow, lymphoid system, and extramedullary sites, such as the central nervous system (CNS). Common constitutional indications consist of fatigue (50%), pallor (25%), fever (60%), and weight loss (26%). Infiltration of blast cells in the marrow cavity and periosteum often lead to bone pain (23%) and disturbance of normal hematopoiesis. Thrombocytopenia with platelet counts less than 100,000 are seen in approximately 75% of patients. About 40% of patients with childhood ALL present with hemoglobin levels less than 7 g/dL. Although leukocyte counts greater than 50,000/mm3 occur in 20% of cases, neutropenia defined as an absolute neutrophil count less than 500 is common at presentation and is associated with an increased risk of infection. The aim of this study was to investigate the differentiations in some biochemical parameters (Hb, PCV, total serum proteins Aspartate amino transferase(AST), Alanin amino transferase (ALT), and Malondialdehyde (MDA) in blood which can be conceder as a marker of ALL. Samples were collected from 50 patients (between 1-16 years old) diagnosed with ALL after one month treatment with induction therapy, compared with 30 control samples taken from healthy persons at the same age . The ALT and MDA showed a significant increase p < 0.001 and p

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Methotrexate-Induced Neurotoxicity and Leukoencephalopathy in Childhood Acute Lymphoblastic Leukemia

Journal of Clinical Oncology ◽

10.1200/jco.2013.53.0808 ◽

2014 ◽

Vol 32 (9) ◽

pp. 949-959 ◽

Cited By ~ 142

Author(s):

Deepa Bhojwani ◽

Noah D. Sabin ◽

Deqing Pei ◽

Jun J. Yang ◽

Raja B. Khan ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Multivariable Analysis ◽

Brain Magnetic Resonance Imaging ◽

Childhood Acute Lymphoblastic Leukemia ◽

Intrathecal Therapy ◽

High Dose ◽

Asymptomatic Patients ◽

A Genome ◽

Increased Risk

Purpose Methotrexate (MTX) can cause significant clinical neurotoxicity and asymptomatic leukoencephalopathy. We sought to identify clinical, pharmacokinetic, and genetic risk factors for these MTX-related toxicities during childhood acute lymphoblastic leukemia (ALL) therapy and provide data on safety of intrathecal and high-dose MTX rechallenge in patients with neurotoxicity. Patients and Methods Prospective brain magnetic resonance imaging was performed at four time points for 369 children with ALL treated in a contemporary study that included five courses of high-dose MTX and 13 to 25 doses of triple intrathecal therapy. Logistic regression modeling was used to evaluate clinical and pharmacokinetic factors, and a genome-wide association study (GWAS) was performed to identify germline polymorphisms for their association with neurotoxicities. Results Fourteen patients (3.8%) developed MTX-related clinical neurotoxicity. Of 13 patients rechallenged with intrathecal and/or high-dose MTX, 12 did not experience recurrence of neurotoxicity. Leukoencephalopathy was found in 73 (20.6%) of 355 asymptomatic patients and in all symptomatic patients and persisted in 74% of asymptomatic and 58% of symptomatic patients at the end of therapy. A high 42-hour plasma MTX to leucovorin ratio (measure of MTX exposure) was associated with increased risk of leukoencephalopathy in multivariable analysis (P = .038). GWAS revealed polymorphisms in genes enriched for neurodevelopmental pathways with plausible mechanistic roles in neurotoxicity. Conclusion MTX-related clinical neurotoxicity is transient, and most patients can receive subsequent MTX without recurrence of acute or subacute symptoms. All symptomatic patients and one in five asymptomatic patients develop leukoencephalopathy that can persist until the end of therapy. Polymorphisms in genes related to neurogenesis may contribute to susceptibility to MTX-related neurotoxicity.

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Thromboembolism Prophylaxis in Adult Patients with Acute Lymphoblastic Leukemia Treated in the GRAALL-2005 Study

Blood ◽

10.1182/blood.2020004919 ◽

2020 ◽

Author(s):

Corentin Orvain ◽

Marie Balsat ◽

Emmanuelle Tavernier ◽

Jean-Pierre Marolleau ◽

Thomas Pabst ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Fresh Frozen Plasma ◽

Adult Patients ◽

Bleeding Complications ◽

Thromboembolism Prophylaxis ◽

Prophylactic Measures ◽

Increased Risk ◽

Fresh Frozen ◽

Grade 3

Patients undergoing treatment for acute lymphoblastic leukemia (ALL) are at risk for thrombosis, in part due to the use of L-asparaginase (L-ASP). Antithrombin (AT) replacement has been suggested to prevent VTE and thus might increase exposure to ASP. We report herein the results of the prophylactic replacement strategy in the pediatric-inspired prospective GRAALL-2005 study. Between 2006 and 2014, 784 adult patients with newly diagnosed Philadelphia-negative ALL were included. The incidence rate of VTE was 16% with 69% of them occurring during induction therapy. Most patients received AT supplementation (87%). After excluding patients who did not receive L-ASP or developed thrombosis before L-ASP, AT supplementation did not have a significant impact on VTE (8% versus 14%, OR: 0.6, p=0.1). Fibrinogen concentrates administration was associated with an increased risk of VTE (17% versus 9%, OR 2.2, p=0.02) whereas transfusion of fresh-frozen plasma had no effect. Heparin prophylaxis was associated with an increased risk of VTE (13% versus 7%, OR 1.9, p=0.04). Prophylactic measures were not associated with an increased risk of grade 3-4 bleeding complications. The rate of VTE recurrence after L-ASP reintroduction was 3% (1/34). In ALL patients receiving L-ASP therapy, the use of fibrinogen concentrates may increase the risk of thrombosis and should be restricted to rare patients with hypofibrinogenemia-induced hemorrhage. Patients developed VTE despite extensive AT supplementation which advocates for additional prophylactic measures. While this large descriptive study was not powered to demonstrate the efficacy of these prophylactic measures, it provides important insight to guide future trial design. NCT00327678.

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Intensification With Intermediate-Dose Intravenous Methotrexate Is Effective Therapy for Children With Lower-Risk B-Precursor Acute Lymphoblastic Leukemia: A Pediatric Oncology Group Study

Journal of Clinical Oncology ◽

10.1200/jco.2000.18.6.1285 ◽

2000 ◽

Vol 18 (6) ◽

pp. 1285-1294 ◽

Cited By ~ 32

Author(s):

Donald H. Mahoney ◽

Jonathan J. Shuster ◽

Ruprecht Nitschke ◽

Stephen Lauer ◽

C. Philip Steuber ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lower Risk ◽

Lymphoblastic Leukemia ◽

Effective Therapy ◽

Remission Induction ◽

Intrathecal Therapy ◽

Continuation Therapy ◽

Increased Risk ◽

Significant Difference ◽

Prevention Of Relapse

PURPOSE: To determine whether early intensification with 12 courses of intravenous (IV) methotrexate (MTX) and IV mercaptopurine (MP) is superior to 12 courses of IV MTX alone for prevention of relapse in children with lower-risk B-lineage acute lymphoblastic leukemia (ALL). PATIENTS AND METHODS: Six hundred fifty-one eligible patients were entered onto the study. Vincristine, prednisone, and asparaginase were used for remission induction therapy. Patients were randomized to receive intensification with IV MTX 1,000 mg/m2 plus IV MP 1,000 mg/m2 (regimen A) or IV MTX 1,000 mg/m2 alone (regimen C). Twelve courses were administered at 2-week intervals. Triple intrathecal therapy was used for CNS prophylaxis. Continuation therapy included standard oral MP, weekly MTX, and triple intrathecal therapy every 12 weeks for 2 years. RESULTS: Six hundred forty-five patients (99.1%) achieved remission. Three hundred twenty-five were assigned to regimen A and 320 to regimen C. The estimated 4-year overall continuous complete remission for patients treated with regimen A is 82.1% (SE = 2.4%) and for regimen C is 82.2% (SE = 2.6%; P = .5). No significant difference in overall outcome was shown by sex or race. Serious grade 3/4 neurotoxicity, principally characterized by seizures, was observed in 7.6% of patients treated with either regimen. CONCLUSION: Intensification with 12 courses of IV MTX is an effective therapy for prevention of relapse in children with B-precursor ALL who are at lower risk for relapse but may be associated with an increased risk for neurotoxicity. Prolonged infusions of MP combined with IV MTX did not provide apparent advantage.

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