Increased Risk Of Acute Lymphoblastic Leukemia Research Articles

A noncoding regulatory variant in IKZF1 increases acute lymphoblastic leukemia risk in Hispanic/Latino children

Hispanic/Latino children have the highest risk of acute lymphoblastic leukemia (ALL) in the US compared to other racial/ethnic groups, yet the basis of this remains incompletely understood. Through genetic fine-mapping analyses, we identified a new independent childhood ALL risk signal near IKZF1 in self-reported Hispanic/Latino individuals, but not in non-Hispanic White individuals, with an effect size of ∼1.44 (95% confidence interval= 1.33-1.55) and a risk allele frequency of ∼18% in Hispanic/Latino populations and <0.5% in European populations. This risk allele was positively associated with Indigenous American ancestry, showed evidence of selection in human history, and was associated with reduced IKZF1 expression. We identified a putative causal variant in a downstream enhancer that is most active in pro-B cells and interacts with the IKZF1 promoter. This variant disrupts IKZF1 autoregulation at this enhancer and results in reduced enhancer activity in B cell progenitors. Our study reveals a genetic basis for the increased ALL risk in Hispanic/Latino children.

PIWIL1 gene polymorphism and pediatric acute lymphoblastic leukemia relapse susceptibility among Chinese children: a five-center case-control study.

PIWIL1 polymorphisms' role in pediatric acute lymphoblastic leukemia (ALL) relapse susceptibility remains undiscovered. A case-control designed and multiple logistic regression model was performed to evaluate the overall risk of pediatric ALL and five single-nucleotide polymorphisms (SNPs) of PIWIL1 gene (rs35997018 C>T, rs1106042 A>G, rs7957349 C>G, rs10773771 C>T, and rs10848087 A>G) in 785 cases and 1,323 controls, which were genotyped by TaqMan assay. The odds ratio (OR) and its 95% confidence interval (CI) were used to estimate the relationship. Stratified analysis was used to investigate the correlation of rs1106042 and rs10773771 genotypes and pediatric ALL relapse susceptibility in terms of age, sex, number of white blood cells (WBC), immunophenotyping, gene fusion type, karyotype, primitive/naïve lymphocytes, and minimal residual disease (MRD) in bone marrow. Finally, the haplotype analysis was performed to appraise the relationship between inferred haplotypes of PIWIL1 and pediatric ALL risk. Among the five analyzed SNPs, rs1106042 A>G was related to increased ALL risk, and rs10773771 C>T was related to decreased ALL risk. Compared to the GG genotype, the rs1106042 GA/AA had a deleterious effect on children of age <120 months, who were female and male, had high or average number of WBC, pro-B ALL, pre-B ALL, T-ALL, low- and middle-risk ALL, E2A-PBX fusion gene, non-gene fusion, abnormal diploid, high hyperdiploid, hypodiploid, and normal diploid. Moreover, rs1106042 A>G harmfully affected primitive/naïve lymphocytes and MRD on days 15-19, day 33, and week 12. On the contrary, rs10773771 TC/CC exhibited a protective effect on ALL children with the TEL-AML fusion gene. Haplotype analysis demonstrated that haplotypes CAGT, TACC, TACT, and TAGT were significantly associated with increased pediatric ALL relapse susceptibility. PIWIL1 rs1106042 A>G was related to increased ALL risk, and rs10773771 C>T was linked to decreased ALL risk in eastern Chinese children. Rs1106042 GA/AA may predict poor prognosis.

Maternal antibiotics exposure during pregnancy and the risk of acute lymphoblastic leukemia in childhood: a systematic review and meta-analysis.

Many epidemiological studies have assessed the association between maternal antibiotic exposure during pregnancy and childhood acute lymphoblastic leukemia (ALL), while reaching inconsistent conclusions. In order to clarify the association, the publications in English that provided information about maternal antibiotic exposure during pregnancy and ALL risk in offspring in the PubMed, Embase, and Web of Science databases were systematically reviewed and we performed a meta-analysis using the random-effect models. Results of pooled analysis showed that maternal antibiotic intake during pregnancy is not associated with childhood ALL risk (pooled odds ratio 1.07, 95% confidence interval 0.98-1.18) without significant heterogeneity (I2 = 13.7%, P = 0.310). This finding was consistent across subgroups stratified by type of study design, measurement method, sample size, study quality, and pregnancy stage. Our findings suggest that maternal antibiotic consumption during pregnancy was not associated with ALL risk in progeny. Further investigations are needed to confirm the results and assess any risk differences of ALL by types of antibiotics.Conclusions: Our findings suggest that maternal antibiotics consumption during pregnancy was not associated with ALL risk in progeny. Further investigations are needed to confirm the results and assess any risk differences of ALL by types of antibiotics. What is Known: • It is not unusual for pregnant woman to receive antibiotics for local or systematic use during pregnancy. • The conclusions regarding the associations between maternal antibiotics use during pregnancy and childhood ALL risk were inconsistent. What is New: • Maternal antibiotics consumption during pregnancy was not associated with the increased ALL risk in offspring. • Further laboratory evidences are needed to confirm the results.

Genetic determinants of blood-cell traits influence susceptibility to childhood acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Despite overlap between genetic risk loci for ALL and hematologic traits, the etiological relevance of dysregulated blood-cell homeostasis remains unclear. We investigated this question in a genome-wide association study (GWAS) of childhood ALL (2,666 affected individuals, 60,272 control individuals) and a multi-trait GWAS of nine blood-cell indices in the UK Biobank. We identified 3,000 blood-cell-trait-associated (p < 5.0× 10-8) variants, explaining 4.0% to 23.9% of trait variation and including 115 loci associated with blood-cell ratios (LMR, lymphocyte-to-monocyte ratio; NLR, neutrophil-to-lymphocyte ratio; PLR, platelet-to-lymphocyte ratio). ALL susceptibility was genetically correlated with lymphocyte counts (rg = 0.088, p = 4.0× 10-4) and PLR (rg = -0.072, p = 0.0017). In Mendelian randomization analyses, genetically predicted increase in lymphocyte counts was associated with increased ALL risk (odds ratio [OR] = 1.16, p = 0.031) and strengthened after accounting for other cell types (OR = 1.43, p = 8.8× 10-4). We observed positive associations with increasing LMR (OR = 1.22, p = 0.0017) and inverse effects for NLR (OR = 0.67, p = 3.1× 10-4) and PLR (OR = 0.80, p = 0.002). Our study shows that a genetically induced shift toward higher lymphocyte counts, overall and in relation to monocytes, neutrophils, and platelets, confers an increased susceptibility to childhood ALL.

Outdoor artificial light at night, air pollution, and childhood acute lymphoblastic leukemia

BACKGROUND AND AIM: Acute lymphoblastic leukemia (ALL) is the most common form of cancer in children. An environmental exposure that has been previously associated with childhood ALL is air pollution but less is known about the association with artificial light at night (ALAN), another pervasive pollutant, particularly in urban areas. ALAN is believed to disrupt circadian rhythm and potentially lead to detrimental health outcomes. We sought to evaluate the risk of ALAN and air pollution in a large population-based case-control study of childhood ALL in California. METHODS: The California Linkage Study of Early-Onset Cancers is a large linkage study in the state of California. Childhood cancers identified in the California Cancer Registry are linked to birth records and 50 controls were randomly selected by year of birth. Between 2000-2015, a total of 2,782 cases and 139,100 controls were identified for this analysis. ALAN was assessed using the New World Atlas of Artificial Night Sky Brightness and PM2.5 with an ensemble-based air pollution model. Exposures were assigned to each participant’s geocoded residential addresses at birth. The associations between ALAN, PM2.5 and childhood leukemia were assessed using logistic regression from which odds ratios (OR) and 95% confidence intervals (95% CI) were calculated. RESULTS:After adjusting for known risk factors at birth (e.g. delivery by C-section), ALAN was associated with a 1.15 increased risk of childhood leukemia in Hispanic participants (95% CI 1.02-1.30) residing in the highest tertile of ALAN. There was an elevated risk of ALL among non-Hispanic White participants and PM2.5 (OR per 10 ug/m3 1.23, 95% CI 0.98-1.55) but not in Hispanic participants (OR per 10 ug/m3 1.04, 95% CI 0.90-1.21). CONCLUSIONS:ALAN was associated with increased ALL risk among Hispanic children. Further work is needed to understand the difference in risk of ALL associated with ALAN and air pollution among Hispanic and non-Hispanic children. KEYWORDS: light pollution, air pollution, cancer and cancer precursors, children's environmental health, epidemiology

History of Early Childhood Infections and Acute Lymphoblastic Leukemia Risk Among Children in a US Integrated Health-Care System.

Surrogate measures of infectious exposures have been consistently associated with lower childhood acute lymphoblastic leukemia (ALL) risk. However, recent reports have suggested that physician-diagnosed early-life infections increase ALL risk, thereby raising the possibility that stronger responses to infections might promote risk. We examined whether medically diagnosed infections were related to childhood ALL risk in an integrated health-care system in the United States. Cases of ALL (n=435) diagnosed between 1994-2014 among children aged 0-14 years, along with matched controls (n=2,170), were identified at Kaiser Permanente Northern California. Conditional logistic regression was used to estimate risk of ALL associated with history of infections during first year of life and across the lifetime (up to diagnosis). History of infection during first year of life was not associated with ALL risk (odds ratio (OR)=0.85, 95% confidence interval (CI): 0.60, 1.21). However, infections with at least 1 medication prescribed (i.e., more "severe" infections) were inversely associated with risk (OR=0.42, 95% CI: 0.20, 0.88). Similar associations were observed when the exposure window was expanded to include medication-prescribed infections throughout the subjects' lifetime (OR=0.52, 95% CI: 0.32, 0.85).

FOXO3 gene polymorphisms influence the risk of acute lymphoblastic leukemia in Chinese children.

Acute lymphoblastic leukemia (ALL) is the most frequently diagnosed cancer in children and single-nucleotide polymorphisms (SNPs) in certain genes influence risk of ALL. Although FOXO3 had been demonstrated to be involved leukemia, the role of FOXO3 polymorphisms was still not clear. In the present study, we explored the association of FOXO3 SNPs with ALL risk in Chinese children. We genotyped four polymorphisms (rs17069665 A>G, rs4945816 T>C, rs4946936 C>T, and rs9400241 A>C) of FOXO3 in 425 ALL cases and 1339 health controls. The associations were estimated by odds ratios (ORs) with their 95% confidence intervals (CIs). Further analyses were performed to explore associations of rs17069665 and rs9400241 with ALL susceptibility in terms of age, gender, immunophenotype, minimal residual disease (MRD), and other clinical characteristics. We found rs17069665 related to the increased ALL risk (OR = 1.76; 95% CI = 1.02-3.04), rs9400241 related to decreased ALL risk (OR = 0.80; 95% CI = 0.64-0.99). The effects of rs17069665 on ALL risk were more predominant in males and children < 10 years, and patients with lower rates of platelet or neutrophil. As for rs9400241, the effects were more predominant in children < 10 years, and in patients with pre B ALL, positive MRD, anemia, or hepatomegaly. In conclusion, FOXO3 gene polymorphisms influence the risk of ALL in children and might be a potential biomarker for ALL susceptibility.

IKZF1 genetic variants rs4132601 and rs11978267 and acute lymphoblastic leukemia risk in Tunisian children: a case-control study

BackgroundAssociations between IKZF1 gene variants and Acute Lymphoblastic Leukemia (ALL) was recently reported. We examined whether the common IKZF1 polymorphisms rs4132601 T/G and rs111978267 A/G are associated with ALL among a Tunisian pediatric cohort.MethodsThis case-control study involved 170 patients with ALL and 150 control subjects. SNP genotyping was performed by TaqMan® SNP Genotyping Assay.ResultsThe minor allele G of IKZF1 gene polymorphism rs4132601 T/G was significantly higher in ALL cases than in control subjects (P = 0.029), with 1.54-fold increased risk of ALL. The association of rs4132601 with ALL was seen under co-dominant (P = 0.009), recessive (P = 0.006), and additive (P = 0.027) genetic models, of which the co-dominant (P = 0.027) and recessive (P = 0.027) association remained significant after adjusting for covariates, and False Discovery Rate correction. In contrast, no association was noted for rs111978267 variant. Two-locus (rs4132601-rs11978267) IKZF1 haplotype analysis demonstrated association of GA (P = 0.053), with increased ALL risk [OR (95% CI) = 1.58 (1.00–2.51)], which remained significant after controlling for key covariates [aP = 0.046; aOR (95% CI) = 1.61 (1.01–2.57)].ConclusionWe demonstrated the association of IKZF1 polymorphism rs4132601 T/G with increased risk of ALL among Tunisian pediatric cohort, with altered phenotypic changes among ALL patients.

Metabolomics of neonatal blood spots reveal distinct phenotypes of pediatric acute lymphoblastic leukemia and potential effects of early-life nutrition.

Early-life exposures are believed to influence the incidence of pediatric acute lymphoblastic leukemia (ALL). Archived neonatal blood spots (NBS), collected within the first days of life, offer a means to investigate small molecules that reflect early-life exposures. Using untargeted metabolomics, we compared abundances of small-molecule features in extracts of NBS punches from 332 children that later developed ALL and 324 healthy controls. Subjects were stratified by early (1-5 y) and late (6-14 y) diagnosis. Mutually-exclusive sets of metabolic features - representing putative lipids and fatty acids - were associated with ALL, including 9 and 19 metabolites in the early- and late-diagnosis groups, respectively. In the late-diagnosis group, a prominent cluster of features with apparent 18:2 fatty-acid chains suggested that newborn exposure to the essential nutrient, linoleic acid, increased ALL risk. Interestingly, abundances of these putative 18:2 lipids were greater in infants who were fed formula rather than breast milk (colostrum) and increased with the mother's pre-pregnancy body mass index. These results suggest possible etiologic roles of newborn nutrition in late-diagnosis ALL.

The Contribution of MMP-8 Promoter Genotypes to Childhood Leukemia.

Accumulated evidence has supported the notion that matrix metalloproteinase (MMP) genotypes are associated with the susceptibility of many types of cancers. However, few reports have studied the contribution of MMP genotypes to either diagnostic or prognostic potential in non-solid tumors such as leukemia. In this study, we firstly investigated the contribution of a polymorphism in the promoter region of MMP-8 (-799C/T) and two non-synonymous polymorphisms (Val436Ala and Lys460Thr) to childhood leukemia. In this study, 266 patients with childhood acute lymphoblastic leukemia (ALL) and 266 non-cancer control patients were collected and the genomic DNA was isolated from their peripheral blood. MMP-8 -799C/T, Val436Ala and Lys460Thr polymorphic genotypes of each subject were determined by the typical polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The results showed that the three polymorphisms were not significantly associated with an increased risk of childhood ALL in the overall investigated population. Furthermore, when the analyses were stratified by age and gender, no significant association between these genotypes and increased ALL risk was found. Our findings suggest that the polymorphisms at MMP-8 -799C/T, Val436Ala and Lys460Thr may not play a major role in determining the personal susceptibility to childhood ALL in Taiwan.

Mutation Screening and Association Study of the Folylpolyglutamate Synthetase (FPGS) Gene with Susceptibility to Childhood Acute Lymphoblastic Leukemia

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). 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. 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). 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.

IKZF1 rs4132601 polymorphism and acute lymphoblastic leukemia susceptibility: a meta-analysis

Several studies have been conducted to examine the association between IKZF1 rs4132601 polymorphism and acute lymphoblastic leukemia (ALL) risk. However, the conclusions remain controversial. We therefore performed a meta-analysis. PubMed, Embase, Web of Science, Weipu and Chinese Biomedical Literature (CBM) databases were searched. Odds ratios (ORs) with 95% confidence intervals (CIs) were used to assess the strength of association. A total of 15 case–control studies with 8333 cases and 36 036 controls were included in this meta-analysis. The results suggested that rs4132601 was associated with an increased ALL risk. Significant associations were found among Caucasians and Hispanics but not among Asians. In subgroup analysis by age group, both adults and children showed increased ALL risk. In subgroup analysis by subtype of ALL, significantly increased risks were observed in B-cell ALL and B hyperdiploid ALL, but not in T-cell ALL. This study suggests that IKZF1 rs4132601polymorphism is a risk factor for ALL.

Polycyclic aromatic hydrocarbons in residential dust and risk of childhood acute lymphoblastic leukemia

Several polycyclic aromatic hydrocarbons (PAHs) are known or probable human carcinogens. We evaluated the relationship between PAH exposure and risk of childhood acute lymphoblastic leukemia (ALL) using concentrations in residential dust as an exposure indicator. We conducted a population-based case-control study (251 ALL cases, 306 birth-certificate controls) in Northern and Central California from 2001 to 2007. We collected residential dust using a high volume small surface sampler (HVS3) (n=185 cases, 212 controls) or by sampling from participants׳ household vacuum cleaners (n=66 cases, 94 controls). We evaluated log-transformed concentrations of 9 individual PAHs, the summed PAHs, and the summed PAHs weighted by their carcinogenic potency (the toxic equivalence). We calculated odds ratios (ORs) and 95% confidence intervals (CI) using logistic regression adjusting for demographic characteristics and duration between diagnosis/reference date and dust collection. Among participants with HVS3 dust, risk of ALL was not associated with increasing concentration of any PAHs based on OR perln(ng/g). Among participants with vacuum dust, we observed positive associations between ALL risk and increasing concentrations of benzo[a]pyrene (OR perln[ng/g]=1.42, 95% CI=0.95, 2.12), dibenzo[a,h]anthracene (OR=1.98, 95% CI=1.11, 3.55), benzo[k]fluoranthene (OR=1.71, 95% CI=0.91, 3.22), indeno[1,2,3-cd]pyrene (OR=1.81, 95% CI=1.04, 3.16), and the toxic equivalence (OR=2.35, 95% CI=1.18, 4.69). The increased ALL risk among participants with vacuum dust suggests that PAH exposure may increase the risk of childhood ALL; however, reasons for the different results based on HVS3 dust samples deserve further study.

Residential levels of polybrominated diphenyl ethers and risk of childhood acute lymphoblastic leukemia in California.

Background: House dust is a major source of exposure to polybrominated diphenyl ethers (PBDEs), which are found at high levels in U.S. homes.Methods: We studied 167 acute lymphoblastic leukemia (ALL) cases 0–7 years of age and 214 birth certificate controls matched on date of birth, sex, and race/ethnicity from the Northern California Childhood Leukemia Study. In 2001–2007, we sampled carpets in the room where the child spent the most time while awake; we used a high-volume small-surface sampler or we took dust from the home vacuum. We measured concentrations of 14 PBDE congeners including penta (28, 47, 99, 100, 153, 154), octa (183, 196, 197, 203), and decaBDEs (206–209). Odds ratios (ORs) were calculated using logistic regression, adjusting for demographics, income, year of dust collection, and sampling method.Results: BDE-47, BDE-99, and BDE-209 were found at the highest concentrations (medians, 1,173, 1,579, and 938 ng/g, respectively). Comparing the highest to lowest quartile, we found no association with ALL for summed pentaBDEs (OR = 0.7; 95% CI: 0.4, 1.3), octaBDEs (OR = 1.3; 95% CI: 0.7, 2.3), or decaBDEs (OR = 1.0; 95% CI: 0.6, 1.8). Comparing homes in the highest concentration (nanograms per gram) tertile to those with no detections, we observed significantly increased ALL risk for BDE-196 (OR = 2.1; 95% CI: 1.1, 3.8), BDE-203 (OR = 2.0; 95% CI: 1.1, 3.6), BDE-206 (OR = 2.1; 95% CI: 1.1, 3.9), and BDE-207 (OR = 2.0; 95% CI: 1.03, 3.8).Conclusion: We found no association with ALL for common PBDEs, but we observed positive associations for specific octa and nonaBDEs. Additional studies with repeated sampling and biological measures would be informative.Citation: Ward MH, Colt JS, Deziel NC, Whitehead TP, Reynolds P, Gunier RB, Nishioka M, Dahl GV, Rappaport SM, Buffler PA, Metayer C. 2014. Residential levels of polybrominated diphenyl ethers and risk of childhood acute lymphoblastic leukemia in California. Environ Health Perspect 122:1110–1116; http://dx.doi.org/10.1289/ehp.1307602

The role of KIR genes and their cognate HLA class I ligands in childhood acute lymphoblastic leukemia

AbstractKiller cell immunoglobulin-like receptors (KIRs), via interaction with their cognate HLA class I ligands, play a crucial role in the development and activity of natural killer cells. Following recent reports of KIR gene associations in childhood acute lymphoblastic leukemia (ALL), we present a more in-depth investigation of KIR genes and their cognate HLA ligands on childhood ALL risk. Genotyping of 16 KIR genes, along with HLA class I groups C1/C2 and Bw4 supertype ligands, was carried out in 212 childhood ALL cases and 231 healthy controls. Frequencies of KIR genes, KIR haplotypes, and combinations of KIR-HLA ligands were tested for disease association using logistic regression analyses. KIR A/A genotype frequency was significantly increased in cases (33.5%) compared with controls (24.2%) (odds ratio [OR] = 1.57; 95% confidence interval [CI], 1.04-2.39). Stratifying analysis by ethnicity, a significant difference in KIR genotype frequency was demonstrated in Hispanic cases (34.2%) compared with controls (21.9%) (OR = 1.86; 95% CI, 1.05-3.31). Homozygosity for the HLA-Bw4 allele was strongly associated with increased ALL risk exclusively in non-Hispanic white children (OR = 3.93; 95% CI, 1.44-12.64). Our findings suggest a role for KIR genes and their HLA ligands in childhood ALL etiology that may vary among ethnic groups.

Analysis of a G1793A polymorphism of methylenetetrahydrofolate reductase gene in children with acute leukemia

Objective To investigate the distribution of methylenetetrahydrofolate reductase (MTHFR) gene G1793A genotype and allele frequency in children with acute leukemia (AL), and to analyze the association between MTHFR gene polymorphism and the risk of AL. Methods Bone marrow samples from 109 childhood patients with AL and peripheral blood samples from 120 control children were obtained to prepare complementary DNAs (cDNAs). The cDNAs were analyzed for MTHFR G1793A polymorphism by reverse transcriptase-polymerase chain reaction-denaturing gradient gel electrophoresis and sequencing. Results The frequencies of 1793 GG, GA and AA genotypes in MTHFR of the AL patients, acute lymphoblastic leukaemia(ALL) patients, acute myeloid leukaemia(AML) patients and the control children were 83.5%, 15.6%, 0.9%; 82.8%, 16.1%, 1.1%; 86.4%, 13.6%, 0% and 89.2%, 7.5%, 3.3%, respectively. While the A allele frequency of MTHFR G1793A in those group were 8.7%, 9.2%, 6.8% and 7.1%, respectively. However, no significant difference was observed in MTHFR G1793A genotypes or A allele frequency between the patients and controls (all P>0.05). The MTHFR 1793 GA+ AA genotype was linked with an increased risk of AL, ALL and AML (AL: OR=1.71, 95%CI: 0.77-3.80, P=0.19; ALL: OR=2.00, 95%CI: 0.85-4.49, P=0.12; AML: OR=1.36, 95%CI: 0.33-5.62, P=0.67), but no significant difference in our population(all P>0.05). The A allele frequency of MTHFR G1793A in the study was 7.9%, significantly different from those reported in Ashkenazi Jewish, African-American, Brazilian, Austrian, Iran and Harbin populations (all P<0.05). Conclusion MTHFR G1793A may be not a genetic susceptibility factor for pediatric AL, but may exhibit an ethnic difference. Key words: Methylenetetrahydrofolate reductase; Single nucleotide polymorphism; Acute leukemia; Child

Does cytochrome P450 1A1 MspI polymorphism increase acute lymphoblastic leukemia risk? Evidence from 2013 cases and 2903 controls

Previous studies indicated that cytochrome P450 1A1 (CYP1A1) MspI polymorphism might be a possible risk factor for several malignancies. Increasing investigations have been conducted on the association of CYP1A1 MspI polymorphisms with acute lymphoblastic leukemia (ALL). However, the results were controversial. The goal of the present study was to address this controversy by pooling and analyzing the published data. Therefore, quantitative meta-analyses evaluating the association of CYP1A1 MspI variation with ALL were performed and subgroup analyses on ethnicity, age groups and source of controls were further carried out. After a rigorous search in the Medline, EMBASE, OVID, ScienceDirect, and CNKI databases, all eligible studies for the period up to May 2012 were identified and screened according to the inclusion and exclusion criteria. Consequently, a total of fourteen case–control studies including 2013 cases and 2903 controls were selected for analysis. The overall data indicated a significant association of CYP1A1 MspI polymorphism with ALL risk (CC+TC vs TT: OR=1.33; 95%CI=1.05–1.69). In a subgroup analysis according to ethnicity, no associations were shown among Asians, Caucasians and Mixed ethnicity subgroups. In the subgroup analysis regarding age groups, increased risk was observed in the childhood ALL subgroup (C vs T: OR=1.23; 95%CI=1.04–1.45; CC+TC vs TT: OR=1.31; 95%CI=1.08–1.59). In the subgroup analysis stratified by source of controls, significant associations were observed in the population-based subgroup (CC+TC vs TT: OR=1.33; 95%CI=1.03–1.71). In conclusion, the results of the present study suggest that CYP1A1 MspI polymorphism might be a risk factor for ALL, particularly childhood ALL. Future well-designed high quality investigations with large sample sizes are required to elucidate the gene polymorphism–ALL relationship and gene–environment interactions.

Thymidylate synthase polymorphisms and hematological cancer risk: a meta-analysis

Previous studies on the association of Thymidylate synthase (TYMS) polymorphisms with risk of hematological malignancies have produced conflicting results. The purpose of this meta-analysis was to define the effect of TYMS 5’-untranslated enhanced region (TSER) and 3’-untranslated region (TS3’-UTR) polymorphisms on the risk of hematological malignancies. Seventeen articles were identified as eligible in the case of TSER (2R > 3R) polymorphism (4511 cases and 6113 controls) and seven articles in the case of TS3’-UTR (1494del6) polymorphism (2721 cases and 3761 controls). The overall results suggested that either TSER or TS3’-UTR polymorphism was not associated with the risk of hematological malignancies. In stratified analyses, significantly decreased acute lymphoblastic leukemia (ALL) risk was found in adults (2R/3R vs. 2R/2R: odds ratio [OR] = 0.64, 95% confidence interval [CI]: 0.43–0.97), but increased ALL risk was observed in children (3R/3R vs. 2R/2R: OR = 1.46, 95% CI: 1.03–2.06). Increased non-Hodgkin lymphoma risk was found in the Caucasian population (2R/3R vs. 2R/2R: OR = 1.31, 95% CI: 1.10–1.56). Protective effects of the TS3’-UTR polymorphism (−6 bp/−6 bp) on hematological malignancies were found in a homozygote model and recessive model when the source of controls was stratified as hospital based. In conclusion, the TYMS TSER polymorphism may contribute to a susceptibility to risk of ALL in children and non-Hodgkin lymphoma in Caucasians, but protection from ALL risk in adults. The TS3’-UTR polymorphism (−6 bp/−6 bp) may have a protective effect in hematological malignancies.

Methylenetetrahydrofolate reductase gene polymorphisms and acute lymphoblastic leukemia risk: a meta-analysis based on 28 case–control studies

Methylenetetrahydrofolate reductase (MTHFR) is involved in DNA methylation and nucleotide synthesis. Accumulated evidence has demonstrated that C677T and A1298C polymorphisms of the MTHFR gene are associated with acute lymphoblastic leukemia (ALL) risk, but the results have been inconclusive. To determine a more precise estimation, we performed a meta-analysis of 28 studies with 4240 cases and 9289 controls. We found that the 677TT genotype showed a reduced risk of ALL compared with the 677CC genotype in the overall population (odds ratio [OR] 0.76, 95% confidence interval [CI] 0.61–0.92). The reduced risk was pronounced only among the Caucasian population (OR 0.68, 95% CI 0.51–0.90), not the Asian (OR 0.89, 95% CI 0.75–1.05). For the MTHFR A1298C polymorphism, no significant association with ALL susceptibility was observed in the pooled analyses. However, significantly increased ALL risk was found in childhood inthe comparison of 1298CA versus AA genotype. This study provides evidence that MTHFR polymorphisms may play animportant role in the development of ALL.

Candidate gene association analysis of acute lymphoblastic leukemia identifies new susceptibility locus at 11p15 ( LMO1 )

To determine the contribution of susceptibility loci in explaining the genetic basis of acute lymphoblastic leukemia (ALL), we genotyped 29 high-potential candidate genes with 672 tagged single-nucleotide polymorphisms (SNPs) in a sample (163 cases and 251 healthy controls) of Caucasian children. Fifty SNPs in 15 genes were significantly associated with ALL risk at the P < 0.05 level. After correction for multiple testing, rs442264 within the LIM domain only 1 (LMO1) gene at 11p15 remained significant [odds ratio (OR) = 1.90, P = 3 × 10(-5)]. In addition, a major haplotype within LMO1 comprising 14 SNPs with individual risk associations was found to significantly increase ALL risk (OR = 1.79, P = 0.0006). A stratified analysis on subtype indicated that risk associations of LMO1 variants are significant in children with precursor B-cell leukemia. These data show that genetic variants within LMO1 are associated with ALL and identify this gene as a strong candidate for precursor B-cell leukemogenesis.