Risk Of Pediatric Acute Lymphoblastic Leukemia Research Articles

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.

ARID5B, IKZF1, GATA3, CEBPE, and CDKN2A germline polymorphisms and predisposition to childhood acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most frequent type of pediatric cancer. Germline single nucleotide polymorphisms (SNPs), including ARID5B (rs10821936 T/C), IKZF1 (rs4132601 T/G), GATA3 (rs3824662 G/T), CEBPE (rs2239633 G/A), and CDKN2A (rs3731217 A/C) have been linked to pediatric ALL in different populations. Hitherto, no previous studies have tested the relationship between these SNPs and pediatric ALL in Gaza strip. Therefore, we investigated the association between these polymorphisms and the occurrence of childhood ALL in this part of Palestine. This case-control study recruited 100 healthy controls and 78 ALL patients. Allele-specific PCR (AS-PCR) technique was used for SNPs genotyping. Relevant statistical tests were used and the multifactor dimensionality reduction (MDR) approach was applied in the analysis of gene-gene interactions. Minor alleles of ARID5B rs10821936 T/C (p = 0.007) and IKZF1 rs4132601 T/G (p = 0.045) were significantly higher in ALL patients. The homozygous (TT) genotype of GATA3 rs3824662 G/T (p = 0.038), (CC) of ARID5B rs10821936 T/C (p = 0.008), and (AC and CC) genotypes of CDKN2A rs3731217 A/C (p < 0.0001) were significantly higher in ALL cases. On MDR analysis, the best model for ALL risk was the five-factor model combination of the examined SNPs (CVC = 10/10; TBA = 0.632; p < 0.0001). This work demonstrates the association of ARID5B rs10821936 T/C, IKZF1 rs4132601 T/G, GATA3 rs3824662 G/T, and CDKN2A rs3731217 A/C polymorphisms with increased risk of pediatric ALL among a patient cohort from Gaza Strip. Further studies with a larger sample size are needed in order to confirm these findings and test the value of these SNPs in prognosis and treatment sensitivity.

Abstract 4516: Rare high-penetrance and common low-penetrance variants associated with risk of pediatric acute lymphoblastic leukemia

Abstract Leveraging existing genetic data for survivors of pediatric acute lymphoblastic leukemia (ALL) from the St. Jude Lifetime Cohort Study (SJLIFE) and Childhood Cancer Survivor Study (CCSS; the CCSS original cohort data was downloaded from dbGaP, phs001327.v2), genetic variants across the full allelic spectrum were analyzed for their associations with ALL risk. A total of 2,695 ALL cases with whole-genome or whole-exome sequencing were available for rare variant analyses. Pathogenic/likely pathogenic (P/LP) variants in 60 genes associated with autosomal dominant cancer predisposition syndromes were characterized and classified with “PeCanPIE” - the Pediatric Cancer Variant Pathogenicity Information Exchange, a web- and cloud-based platform. We subsequently carried out an enrichment analysis of P/LP variants by comparing ALL survivors with a general population from the GnomAD database and found seven significant genes after adjustment for multiple testing (P&amp;lt; 8.3 × 10-4, i.e., 0.05/60) including: BRCA1 (odds ratio [OR]=4.06; 95% CI, 2.00-7.59; P=1.21 × 10-4), BRCA2 (OR=3.48; 95% CI, 1.82-6.15; P=1.50 × 10-4), CDKN2A (OR=22.30; 95% CI, 5.13-96.68; P=3.07 × 10-5), PALB2 (OR=5.12; 95% CI, 2.39-10.00, P=3.77 × 10-5), PAX5 (OR=44.58; 95% CI, 6.49-490.68; P=4.77 × 10-5), PTPN1 (OR=66.85; 95% CI, 11.96-670.57, P=1.63 × 10-7), and TP53 (OR=17.86; 95% CI, 6.12-50.36; P=3.43 × 10-7). Two of these genes have also been previously linked with pediatric ALL (CDKN2A and TP53). Repeating these analyses with 309 newly diagnosed patients from the Pediatric Cancer Genome Project, we observed similar results for five of these genes (BRCA1, BRCA2, CDKN2A, PALB2, and TP53). To further investigate common germline variants associated with ALL risk, we performed a genome-wide association analysis using 2,777 ALL cases and 6,255 controls (5,881 other pediatric cancer cases and 374 non-cancer controls) with whole-genome sequencing or imputed SNP-array data. In addition to replicating known associations at ARID5B, IKZF1, CDKN2A, BMI1, PIP4K2A, CCDC26 and CEPBE, we identified a novel variant (rs112425636, chr17:82324152:G:A; OR=1.65; 95% CI, 1.42-1.93; P=2.48 × 10-10) mapped to the intronic region of SECTM1 gene. Based on RNA sequencing data for 164 pediatric hematological cancer samples, we found that the expression of SECTM1 gene was significantly higher among patients with GG genotype than patients with AA or AG genotypes for rs112425636 (FPKM=1.34 vs. 0.71, P&amp;lt;0.01). Among the subset of 32 B-ALL samples, the magnitude of difference was larger (FPKM=1.90 vs. 0.70, P=0.017). In summary, we found statistical evidence for several cancer predisposition genes harboring rare high-penetrance variants and a novel common low-penetrance variant associated with risk of pediatric ALL. Our novel findings add new knowledge to the full allelic spectrum of genetic architecture of pediatric ALL susceptibility. Citation Format: Zhaoming Wang, Cheng Chen, Na Qin, Nan Song, Hui Wang, Gregory T. Armstrong, Kirsten K. Ness, Melissa M. Hudson, Jinghui Zhang, Leslie L. Robison, Cindy Im. Rare high-penetrance and common low-penetrance variants associated with risk of pediatric acute lymphoblastic leukemia. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4516.

New association between splicing factor-coding gene polymorphisms and the risk of acute lymphoblastic leukemia in southern Chinese children: A five-center case-control study.

The role of splicing factor-coding gene polymorphisms in pediatric acute lymphoblastic leukemia (ALL) susceptibility is still unclear. A case-control designed model was used to estimate the overall risk of pediatric ALL and five single nucleotide polymorphisms (SNPs) of splicing factor-coding genes in 808 cases and 1,340 controls, which were genotyped using a TaqMan assay. Stratified analysis was performed to explore the association of rs2233911 genotype and pediatric ALL susceptibility. The influence of splicing factor arginine/serine-rich 1 (SFRS1) polymorphisms on the sensitivity to different chemotherapeutic regimens based on minimal residual disease (MRD) levels was analyzed. The haplotype analysis was adopted to evaluate the association between inferred haplotypes of the splicing factor-coding genes and pediatric ALL risk. Among the five analyzed SNPs, SFRS1 rs2233911 AG/GG exhibited a significant association with increased pediatric ALL risk. The stratified analysis further identified the harmful effect of SFRS1 rs2233911 AG/GG in specific subgroups. Moreover, rs2233911 AG/GG had a protective effect on MRD in marrow of ≥0.01% 12 weeks of Chinese Children Cancer Group chemotherapeutics, but provided a harmful effect on MRD in the marrow of ≥0.01% at days 15-19 of the South China Children Leukemia Group chemotherapeutics. Haplotype analysis of these five SNPs yielded haplotypes ACGCC and ACGTC significantly correlating with increased pediatric ALL susceptibility. On the contrary, haplotypes GCATG and GTACC were linked with remarkably decreased pediatric ALL risk. SFRS1 gene polymorphism was associated with increased pediatric ALL risk and indicated that rs2233911 AG/GG might be a potential biomarker for choosing chemotherapeutics.

Genetic variants in m5C modification core genes are associated with the risk of Chinese pediatric acute lymphoblastic leukemia: A five-center case-control study.

To explore the functions of the polymorphisms in 5-methylcytosine (m5C) modification-related coding genes on the susceptibility of pediatric acute lymphoblastic leukemia (ALL). Case-control study and multinomial logistic regression analysis were performed to construct models to evaluate the susceptibility of pediatric ALL. The relationship between five functional SNPs in m5C modification-coding genes and pediatric ALL risk was analyzed. Genotyping of 808 cases and 1,340 healthy samples from South China was identified using a TaqMan assay; odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the relationship between the five selected SNPs and pediatric ALL susceptibility. Among the five analyzed SNPs, NOL1 rs3764909 and NSUN4 rs10252 variants significantly increased the susceptibility of pediatric ALL, while NSUN3 rs7653521, NSUN5 rs1880948, and NSUN6 rs3740102 variants were not associated with the risk of ALL. Stratification analyses demonstrated that NOL1 rs3764909 C>A exhibited a significant association with increased pediatric ALL risk in subgroups of common B ALL, pre-B ALL, T-cell ALL, low and middle risk, other gene fusion types, non-gene fusion, hypodiploid, normal diploid, primitive lymphocytes in marrow < 5% on week 12, and minimal residual disease (MRD) <0.01% on week 12 after induced therapy; NSUN4 rs10252 G>A was related to increased risk of ALL children in subgroups of age ≥ 120 months, normal white blood cell (WBC) number, middle risk, non-gene fusion, MRD ≥ 0.01 on days 15-19, and primitive lymphocytes in marrow < 5% on day 33 after induced therapy. Compared with the reference haplotype CAGTA, children who harbored haplotypes CCGTG and ACATA were remarkably related to increased ALL susceptibility. rs3764909 and rs10252 varieties of alleles were not associated with MRD levels after the selected chemotherapeutics. In conclusion, NOL1 rs3764909 and NSUN4 rs10252 variants were enhanced by pediatric ALL risk and were suggested to be potential biomarkers for pediatric ALL.

High Resolution Melting Analysis for Evaluation of mir-612 (Rs12803915) Genetic Variant with Susceptibility to Pediatric Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia (ALL) is a highly heterogeneous malignancy that accounts for nearly 75% of leukemias in children. While the exact mechanism of ALL is not fully understood, some genetic variants have been implicated as associated with ALL susceptibility. The association between some genetic variants in miRNA genes and ALL risk has been described previously. A previous study suggested that mir-612 rs12803915 G> A may be associated with pediatric ALL risk. High-resolution melting (HRM) analysis is a reliable method that can be applied for polymorphism detection. This retrospective study was performed on 100 B-ALL patients (52 males and 48 females; age 4.6 ± 3.2 years) and 105 age- and sex-matched healthy controls (48 males and 57 females; age 5.1 ± 3 years). We used HRM to identify mir-612 rs12803915 genotypes. Sanger sequencing was applied to validate the HRM results. High resolution melting analysis was used to genotype the mir-612 rs12803915 polymorphism. We found no association between rs12803915 allele A and B-ALL risk in any inheritance models (p> 0.05). HRM is a suitable method to detect SNP rs12803915 in the mir-612 gene; however, we found no significant association between the rs12803915 polymorphism and ALL risk.

Methionine synthase A2756G polymorphism influences pediatric acute lymphoblastic leukemia risk: a meta-analysis.

Plenty of studies have investigated the effect of methionine synthase (MTR) A2756G polymorphism on risk of developing pediatric acute lymphoblastic leukemia (ALL), but the available results were inconsistent. Therefore, a meta-analysis was conducted to derive a more precise estimation of the association between MTR A2756G polymorphism and genetic susceptibility to pediatric ALL. The PubMed, Embase, Google Scholar, Web of Science, ScienceDirect, Wanfang Databases and China National Knowledge Infrastructure were systematically searched to identify all the previous published studies exploring the relationship between MTR A2756G polymorphism and pediatric ALL risk. Odds ratios (ORs) and 95% confidence intervals (CIs) were applied to evaluate the strength of association. Sensitivity analysis and publication bias were also systematically assessed. This meta-analysis finally included ten available studies with 3224 ALL cases and 4077 matched controls. The results showed that there was significant association between MTR A2756G polymorphism and risk of pediatric ALL in overall population (AG vs. AA: OR = 1.13, 95%CI = 1.02–1.26, P = 0.02; AG+GG vs. AA: OR = 1.13, 95%CI = 1.02–1.25, P = 0.01; G allele vs. A allele: OR = 1.10, 95%CI = 1.01–1.20, P = 0.03). In the stratification analyses by ethnicity, quality score and control source, significant association was found in Caucasians, population-based designed studies and studies assigned as high quality. In conclusion, this meta-analysis suggests that MTR A2756G polymorphism may influence the development risk of pediatric ALL in Caucasians. Future large scale and well-designed studies are required to validate our findings.

Abstract A51: Early-life infection delays B cell precursor leukemia onset in Eu-Ret mice via an IL-23-dependent depletion of leukemia-initiating cells

Abstract An influence of infection on the development of pediatric acute lymphoblastic leukemia (ALL) is supported by epidemiological studies that have uncovered associations between infection history and ALL risk. However, these studies have produced discordant results, with both reduced and increased risk having been reported, and a mechanistic explanation remains elusive. Back-tracking studies have demonstrated that the development of ALL depends upon the long-term survival and evolution of an abnormal leukemia-initiating cell (LIC) population that arises in utero. However, the occurrence of detectable LICs at birth is significantly greater than the incidence of leukemia, suggesting that events during the pre-leukemic phase may influence disease progression by altering the fate of these cells. In this study, we use the B cell precursor (BCP) leukemia-prone Emu-RET transgenic mouse to investigate whether infection exposure is capable of altering disease progression via changes in LIC survival. Epidemiological studies have associated low grade, sub-clinical infections with reduced ALL risk, while more severe infections are associated with increased risk. To mimic a sub-clinical infection, we exposed Emu-RET mice to an ActA-/- attenuated strain of Listeria monocytogenes (Lm) prior to leukemia onset. Infection resulted in a significant depletion of LICs in spleen and bone marrow (p&amp;lt;0.0001) and delayed disease onset by approximately fifty days (p&amp;lt;0.0001). The timing of infection has been identified as a critical variable in epidemiological studies assessing ALL risk. To evaluate whether timing was a factor in our model, we administered Lm to either neonatal (Day 6) or adult (Day 34) Emu-RET mice and measured LIC numbers. Only infections at the early time point were capable of depleting the LIC population (D6 depletion: p&amp;lt;0.0001; D34 depletion: p=0.4371 ). This time dependence was maintained when infection dose was normalized based on the weight of recipient mice. Importantly, given that no single infectious agent has been identified in the ALL epidemiological studies, we observed a similar age-dependent response pattern following nasal infection with live non-attenuated Murine gamma-herpesvirus (MHV)-68. An inherent deficit in IL-12p35 production in neonates leads to a skewing of the early-life immune system towards IL-23-driven Th17 responses in both mice and humans. Considering this age-related immune difference and reports of IL-23 as an anti-leukemic factor, we hypothesized that IL-23 and its downstream effectors mediate the infection-dependent LIC depletion. Using targeted blocking-antibodies, we found that both Lm and MHV-68 infection-associated depletion of LICs was entirely dependent on IL-12p40 (p&amp;lt;0.0001). IL-12p75 is not required for this depletion (p=0.889), confirming the role of IL-23 as a critical factor required for the early-life depletion of LICs. Overall, this study provides the first mechanistic explanation for the epidemiological link between early-life infections and reduced risk of pediatric ALL by demonstrating that low-grade infections administered during a brief neonatal period cause depletion of the in utero-derived LIC population. Citation Format: Mario Fidanza, Sheka Y. Aloyouni, Sehyun Cho, Alix E. Seif, Soren Gantt, Tobias R. Kollmann, Gregor SD Reid. Early-life infection delays B cell precursor leukemia onset in Eu-Ret mice via an IL-23-dependent depletion of leukemia-initiating cells. [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2016 Oct 20-23; Boston, MA. Philadelphia (PA): AACR; Cancer Immunol Res 2017;5(3 Suppl):Abstract nr A51.

TSER polymorphism is not associated with risk of pediatric acute lymphoblastic leukemia

Accumulating studies have explored the effect of thymidylate synthase enhancer region (TSER) variation on risk of pediatric acute lymphoblastic leukemia (ALL) with controversial results. Therefore, this quantitative meta-analysis was performed to assess synthetically the association of TSER variation with susceptibility to develop pediatric ALL. The PubMed, ScienceDirect, Google Scholar, Wanfang Database, and China National Knowledge Infrastructure were systematically retrieved to obtain the published case-control studies about the relationship between TSER variation and pediatric ALL risk. The quality assessment of the included studies was preformed and relevant information was collected. Odds ratios (ORs) and 95% confidence intervals (CIs) were applied to evaluate the strength of association. This meta-analysis finally included 2681 children with ALL and 3854 matched controls from 11 investigations. The quantitative synthesis results found no significant association between TSER variation and susceptibility to pediatric ALL in overall comparisons under 5 genetic models (2R/3R vs 3R/3R: OR = 0.95, 95% CI = 0.84-1.07, P = 0.41; 2R/2R vs 3R/3R: OR = 0.99, 95% CI = 0.84-1.16, P = 0.90; 2R2R vs 3R/3R+2R/3R: OR = 1.05, 95% CI = 0.92-1.21, P = 0.45; 2R/3R+2R/2R vs 3R/3R: OR = 0.97, 95% CI = 0.87-1.09, P = 0.63; 2R vs 3R: OR = 1.03, 95% CI = 0.92-1.15, P = 0.61). Similarly, there was no significant association existed in the stratification analyses according to ethnicity, control source, and quality score. This meta-analysis shows that TSER variation is not related to the development risk of pediatric ALL.

ABCB1 Polymorphisms and Childhood Acute Lymphoblastic Leukemia Risk: A Meta-Analysis.

The association between ATP-binding cassette subfamily B member 1 (ABCB1) C3435T and C1236T polymorphisms and the risk for childhood acute lymphoblastic leukemia (ALL) is inconclusive. We conducted a meta-analysis of all published studies to determine the association of ABCB1 C3435T and C1236T polymorphisms and pediatric ALL risk. A systematic retrieval of relevant publications from the PubMed and Web of Science databases was performed. Data were calculated and statistical analysis was performed using STATA version 12.0 software. Metaanalysis results showed no significant association between C3435T polymorphism and pediatric ALL risk (TT vs. CC: odds ratio [OR] = 1.20, 95% confidence interval [CI] = 0.95-1.52; CT vs. CC: OR = 1.00, 95% CI = 0.82-1.23; the dominant model: OR = 1.07, 95% CI = 0.89-1.29; the recessive model: OR = 1.17, 95% CI = 0.84-1.62). Similarly, there was no association found for the C1236T polymorphism (TT vs. CC: OR = 1.18, 95% CI= 0.82-1.70; CT vs. CC: OR = 1.08, 95% CI = 0.80-1.45; the dominant model: OR = 1.10, 95% CI= 0.83-1.46; the recessive model: OR = 0.98, 95% CI = 0.61-1.58). Similar results were observed in the subgroup analyses on ethnicity and Hardy-Weinberg equilibrium. The present meta-analysis found no evidence for ABCB1 C3435T and C1236T polymorphisms as risk factors for pediatric ALL.

Association of genetic variation in IKZF1, ARID5B, CDKN2A, and CEBPE with the risk of acute lymphoblastic leukemia in Tunisian children and their contribution to racial differences in leukemia incidence

ABSTRACTRecent genome-wide association studies (GWAS) focusing on pediatric acute lymphoblastic leukemia (ALL), the most common malignancy in children younger than 15 years old, have found evidence that single-nucleotide polymorphisms (SNPs) in IKZF1 (7p12.2), ARID5B (10q21.2), CDKN2A (9p21.3), and CEBPE (14q11.2) are strongly associated to the risk of developing pediatric ALL. These studies have been conducted in European and Thai populations, and it is unclear whether these observations generalize to other populations with a lower incidence of pediatric ALL. In order to explore the impact of these variants on pediatric ALL risk in the Tunisian population, we genotyped 58 cases of pediatric ALL and 150 controls for SNPs rs4132601 (7p12.2), rs7089424 (10q21.2), rs3731217 (9p21.3), and rs2239633 (14q11.2). Our results, which are consistent with findings in European populations, show that 3 SNPs, i.e., rs4132601 (P = .00116, odds ratio [OR] = 2.78, 95% confidence interval [CI] = [1.42, 5.87]), rs7089424 (P = .0022, OR = 0.49, 95% CI = [0.31, 0.79]), and rs2239633 (P = .0010, OR = 0.47, 95% CI = [0.29, 0.75]) are significantly associated with a higher risk of developing pediatric ALL (P < .05). Furthermore, we show differences in allele frequencies in SNPs between Tunisian and Caucasian and/or Thai populations (e.g., CEBPE, rs2239633; population attributable risk [PAR] ∼15-fold the PAR of Thai population). These differences, combined with differences in linkage disequilibrium structure between populations and differences in size between populations, may contribute to racial differences in pediatric ALL incidence.

A common genetic variation in CEBPE and acute lymphoblastic leukemia: a meta-analysis of the available evidence.

Acute lymphoblastic leukemia (ALL) has been studied intensively for decades, but the details of its etiology and underlying mechanisms have yet to be fully elucidated. It is now generally acknowledged that genetic factors contribute greatly to the development of this disease. The gene encoding CCAAT/enhancer-binding protein ε (CEBPE) is involved in the development of leukemia, and in particular the rs2239633 single nucleotide polymorphism (SNP) of CEBPE. The association between rs2239633 and risk of ALL has been well studied, but remains unclear. Therefore, a meta-analysis was performed in this study to establish a more precise estimation of that relationship. A comprehensive literature search of the PubMed electronic database was conducted, and relevant studies published up to February 20, 2015 were selected for analysis. The references of the retrieved articles were also screened. The extracted data were analyzed statistically, and pooled odds ratios with 95% confidence intervals were calculated using Review Manager (version 5.2) to estimate the association strength. Finally, eleven studies were included in the meta-analysis. The pooled analyses revealed that rs2239633 was associated with an increased risk of childhood ALL in Caucasians under any contrast models (P<0.01). However, this SNP did not affect the risk of ALL in adulthood among Caucasians, or in childhood among East Asians. In conclusion, these findings confirm that the CEBPE rs2239633 SNP could be considered a good marker of pediatric ALL risk in Caucasians, but not in East Asians; it is not a good marker of adult ALL risk in Caucasians.

Abstract 1877: Age at introduction to solids is associated with the odds ratio of pediatric acute lymphoblastic leukemia

Abstract Introduction: Breastfeeding for &amp;gt; 6 months is associated with protection from acute lymphoblastic leukemia (ALL) (OR 0.81 95% CI 0.72-0.91), the most common pediatric cancer in the United States. These data are based on any breastfeeding. There is little research concerning infant formula or solid food consumption patterns and risk of pediatric ALL. We previously identified greater duration of milk formula feeding and later age at introduction to solid foods as risk factors for ALL. The purpose of this study was to determine whether the increased OR of ALL was confined to children who began receiving solids after 4 or 6 months of age. Methods: 172 incident cases of ALL aged 0-14 years were recruited at Texas Children's Cancer Center (TCCC) and matched on sex, age at diagnosis/interview and ethnicity to 344 healthy population-based controls from Houston, San Antonio and Austin, Texas. Data were collected on sociodemographics, infant feeding patterns and known or hypothesized risk factors for ALL. Logistic regression was used to model the OR of ALL according to quartile of age at introduction of solids with the first/earliest quartile as the reference group. Results: In adjusted models, the OR of ALL among children in quartile 3 (7-9 months) was 3.43, 95% CI 1.66 - 7.09; for children in quartile 4 (≥ 10 months) the OR was 4.19, 95% CI 2.00 - 8.75. Each additional month of milk formula feeding was associated with a 7% increase in the OR of ALL (95% CI 1.02 - 1.12). The OR of ALL among non-Hispanic compared to Hispanic children was 1.76 (95% CI 1.10 - 2.84). Discussion: These results support our published findings that later introduction to solids is positively associated with ALL. Our finding of lower risk among Hispanic children contrasts with previous research indicating this group is at greater risk than non-Hispanics. Citation Format: Jeremy M. Schraw, Michael Scheurer, Michele R. Forman. Age at introduction to solids is associated with the odds ratio of pediatric acute lymphoblastic leukemia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1877. doi:10.1158/1538-7445.AM2015-1877

A Novel Functional Polymorphism in the CCAAT/Enhancer Binding Protein (C/EBP), Epsilon (CEBPE) Gene Promoter Influences Acute Lymphoblastic Leukemia Risk Via Interaction with IKZF1

Purpose: We sought to identify and characterize the functional polymorphism in the CCAAT/enhancer binding protein (C/EBP), epsilon (CEBPE) gene, which is known to harbor a genetic risk modifier for childhood acute lymphoblastic leukemia (ALL).Background: Association between ALL risk and polymorphic variation at the CEBPE gene, a zinc-finger hematopoietic and apoptotic regulator expressed exclusively in myeloid cells, was established in a genome-wide association study and replicated in other populations. The actual functional genetic variation that actually contributes the leukemia risk is not known. The discovery and functional characterization of the functional variant may lead to risk stratification, prevention, and/or therapeutic modalities.Methods: Utilizing California Childhood Leukemia Study genome-wide SNP data from Hispanic subjects, we refine the genetic signal to a specific single nucleotide polymorphism (SNP) within the CEBPE gene promoter (rs2239635). This SNP was identified first using genetic imputation using 1000 Genomes data as a framework, and further validated in additional subjects using Taqman genotyping. Functional work to characterize the impact of the polymorphism was performed using prediction methods (database searches), chromatin immunoprecipitation assays from normal subjects heterozygous for rs2239635, and luciferase expression vectors carrying the SNP.Results: The minor allele of rs2239635 conferred a 1.87-fold increased risk of B-cell ALL (95% CI = 1.51-2.30; P = 6.2x10-9) and a 2.94-fold increased risk of high hyperdiploid B-cell ALL (95% CI = 2.12-4.06; P = 8.2x10-11), but only a 1.51-fold increased risk of non-hyperdiploid B-cell ALL (95% CI = 1.11-2.04; P = 8.8x10-3). Adjusting for rs2239635 attenuated all SNP associations in the region, including the original GWAS allele, strongly suggest that the GWAS signal in CCLS Hispanics is attributable to rs2239635. We also demonstrate, using published functional data and our own chromatin immunoprecipitation assays, that this SNP disrupts a canonical transcription factor binding site for Ikaros (IKZF1), an essential hematopoietic transcription factor. Using expression vectors, we found the polymorphic locus to have transcriptional repressive properties that are diminished in the presence of the ALL risk allele. Additionally, a heritable risk allele within IKZF1 interacts with rs2239635 in a multiplicative fashion (P = 0.02) in case-control association analyses.Discussion: In sum, evidence for a functional CEBPE polymorphism links two hematopoietic developmental transcriptional factors and highlights feedback control between them. The minor, risk-associated variant of CEBPE may alter the ability of IKZF1 to repress CEBPE expression in precursor B-cells, causing lineage confusion and enhanced pre-B cell leukemia risk. This risk primarily impacts risk of pediatric ALL that exhibits the high hyperdiploid phenotype. DisclosuresNo relevant conflicts of interest to declare.

Abstract A9: Uridine diphospho glucuronosyl-transferase 2B17 genotype and a risk of acute lymphoblastic leukemia and lymphoblastic lymphoma among Japanese children

Abstract Background: Using clinical samples and tumor cell lines, chromosomal aberrations and somatic mutations have been well explored in the field of pediatric oncology. However, genes susceptible to pediatric acute lymphoblastic leukemia (ALL) as well as lymphoblastic lymphoma (LBL) have not been delineated yet. Therefore, we examined copy number variations (CNVs) of genomic DNA by means of high-resolution comparative genomic hybridization (CGH) microarray to find significant susceptible genes to ALL and LBL. Methods: We investigated CNVs by array CGH in genomic DNA derived from a total of 58 children with ALL and LBL as case, and compared with control I (n=67): acute myeloid leukemia (AML)(n=10), other type of leukemia (n=4), non-LBL (n=7) and solid tumors such as neuroblastoma (n=46) as well as control II (N=301): adults patients with diabetic nephropathy and receiving dialysis (n=86), with neurological diseases (n=76) and with esophageal, gastric and colon cancers (n=72) plus control I (n=67). Normalization was performed using the Log2 signal ratio (sample DNA/control DNA) for individual 180K probes distributed throughout the whole genome. Control DNA was obtained from a single Japanese person. To compare data between two groups (e.g., ALL+LBL vs. control I or control II), an unpaired t test was used and subsequently corrected by the Benjamini-Hochberg false-discovery rate using GeneSpringGX v.11.5.1. Probes with a corrected p-value (=q-value) less than 0.05 and fold change greater than 1.8 or less than -1.8 were considered statistically significant. Significant gene was confirmed using real time polymerase chain reaction (PCR). Results: CNV of uridine diphospho glucuronosyltansferase 2B17 (UGT2B17) gene was statistically less deleted in children with ALL+LBL, compared with control I (q-value=5.51 x 10-12) and with control II (q-value=6.58 x 10-6). Presence or absence of UGT2B17 gene was reconfirmed by real time PCR. CNVs of other genes were similar in cases and controls. UGT2B17 glucuronidates several endogenous and exogenous compounds in particular steroid hormones as well as several pharmaceutical drugs such as anthraquinones and histone deacetylase inhibitor. As previously reported in some paper of adult solid tumors, CNV of UGT2B17 gene showed significant correlation to drug response. The frequency of CNV shows exceptional differences between populations from Africa, Europe, and Asia. Interindividual variability in UGT2B17 allele-frequency is accompanied by pronounced differences in gene expression characterized by more than 29 times higher mRNA levels in Caucasian compared with Japanese. Conclusion: These results suggest that homozygous or heterozygous gains of the UGT2B17 gene may be associated with a significant risk for pediatric ALL and LBL. Citation Format: Sae Ishimaru, Yuya Saito, Yuichi Yokokawa, Yuki Yuza, Takashi Kaneko, Mitsuyoshi Urashima. Uridine diphospho glucuronosyl-transferase 2B17 genotype and a risk of acute lymphoblastic leukemia and lymphoblastic lymphoma among Japanese children. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A9.

The association between methylenetetrahydrofolate reductase C677 > T polymorphisms and risk of pediatric acute lymphoblastic leukemia in Asia.

The association between methylenetetrahydrofolate reductase (MTHFR) C677 > T polymorphisms and pediatric acute lymphoblastic leukemia (ALL) risk in Asia is controversial. The aim of this meta-analysis was to further assess the relationship between MTHFR C677 > T polymorphisms and pediatric ALL for Chinese children. Studies about the MTHFR C677 > T polymorphisms and pediatric ALL risk were searched in the Medline, PubMed, EMBASE, Wanfang and CNIK databases. The genotype of the case and control group were extracted and pooled by meta-analysis. The association between ALL risk and C677 > T polymorphisms was demonstrated by odds ratio (OR) and its 95% confidence interval (CI). Twelve articles were included in this study with 1803 ALL cases and 4146 controls. In recessive genetic model (TT vs. CC + CT), the OR was 0.37 (95%CI: 0.31-0.43); in dominant genetic model (TT + CT vs. CC) the OR was 0.94 (95%CI: 0.82-1.06); and in the homozygous model the OR was 0.84 (95%CI: 0.69-1.03). The results indicated that Asian children with TT genotype of MTHFR gene may have less risk of developing ALL.

Detection of trisomy 4 and 10 in Egyptian pediatric patients with acute lymphoblastic leukemia.

Improvement in cure rates for children with acute lymphoblastic leukemia (ALL) has focused attention on better methods of identifying patients with increased or decreased risk of treatment failure. Chromosome aberrations have a major role in pediatric ALL risk assessment. The aim of this work is to detect the frequency of trisomy 4 and 10 in Egyptian pediatric ALL patients and to analyze their possible prognostic significance. Forty newly diagnosed pediatric ALL patients were subjected to bone marrow aspirate morphological examination and immunophenotyping. Detection of copy number of chromosome 4 and 10 was done using Fluorescence In Situ Hybridization (FISH) technique using whole chromosome painting probes. Combined trisomy 4 and 10 was detected in 7 cases (17.5%), all of them were of B-ALL type. Single trisomy 4 or 10 was not detected in any case. Trisomy positive patients had a statistically significant lower total leucocytic count (p = 0.041), higher platelet count (p = 0.018), and lower blast percentage in peripheral blood (p = 0.016) at diagnosis. Combined trisomy 4 and 10 identifies a group of ALL patients that have good prognostic indicators. Screening of Egyptian pediatric ALL patients for trisomy 4 and 10 may help in "patients' stratification" aiming to develop a risk-adapted therapy in order to minimize therapy related morbidities particularly in children.

The Association of NAD(P)H:quinine Oxidoreductase Gene Polymorphisms With Pediatric Acute Lymphoblastic Leukemia

Objectives: Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. NAD(P)H:quinone oxidoreductase 1 (NQO1) is an enzyme that protects cells against mutagenicity of free radicals and toxic oxygen metabolites. C to T base substitution at nucleotides 609 and 465 of NQO1 cDNA, results in loss of enzyme activity. Low NQO1 activity may play a role in etiology of ALL. In the present study, we investigated the association between the NQO1 polymorphisms and increased risk of ALL in children. Methods: C609T and C465T polymorphisms of NQO1 were explored using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) assay in 100 pediatric ALL patients and 135 healthy controls. Results: Although C609T polymorphism is very common among the Iranian population, we found no association between this variant and increased risk for pediatric ALL [odds ratio (OR) = 0.95; 95% confidence interval (95% CI) = 0.55–1.64]. Interestingly the other polymorphic allele of NQO1 (C465T) was strongly associated with pediatric ALL (OR = 7.83; 95% CI= 3.27-18.75). Conclusion: These findings do not support the predisposing role of NQO1 C609T polymorphism for pediatric ALL. However, The C465T polymorphism was associated with increased risk of pediatric ALL. Further studies with larger sample including evaluating multiple gene– gene interactions seem necessary to validate the exact role of these mutations.

Abstract 2649: Maternal and offspring folate metabolic genes and the risk of childhood acute lymphoblastic leukemia (ALL)

Abstract Introduction: Childhood ALL is the most common type of cancer in children. Although the survival rate is relatively high, there are significant clinical sequelae associated with treatment and little is known about the etiology of this condition. Family studies suggest a genetic component to ALL, and the peak incidence between 2 and 4 years of age indicates factors during pregnancy may influence risk. The folate metabolic pathway is a strong candidate for genetic epidemiologic studies due to its role in DNA synthesis and methylation. Objective: The purpose of this study was to conduct a case-parent triad analysis to assess both maternal and offspring genetic effects of the folate metabolic pathway on childhood ALL risk. Methods: We recruited pediatric ALL case-parent triads (n = 120) from Texas Children's Hospital. DNA samples were genotyped in the Human Genetics Center at The University of Texas School of Public Health using the Sequenom iPLEX MassARRAY for 80 tagSNPs in six folate metabolic pathway genes (MTHFR, MTRR, MTR, DHFR, BHMT, and TYMS). Log-linear modeling was used to examine the associations between ALL and both maternal and offspring genotypes. Results: After controlling for the false discovery rate (&amp;lt;0.10), there were 19 significant maternal effects in the following genes: BHMT (n = 3), MTR (n = 12), and TYMS (n = 4). For instance, maternal genotypes for BHMT rs558133 (RR = 0.51, 95% CI: 0.30-0.88, p = 0.008, q = 0.08), MTR rs2282369 (RR = 0.46, 95% CI: 0.26-0.79, p = 0.003, q = 0.08), and TYMS rs699517 (RR = 1.92, 95% CI: 1.17-3.17, p = 0.006, q = 0.08) were all associated with ALL. There were no significant offspring effects after controlling for the false discovery rate. Conclusions: This is one of the few studies conducted to evaluate maternal genetic effects in the context of pediatric ALL risk. Furthermore, we employed a family-based design (i.e., case-parent triad) that is robust to confounding due to population structure and allows for the evaluation of both maternal and offspring genotypes. These results provide additional evidence that the risk of pediatric ALL is influenced by variation within folate pathway genes and indicate that studies to explore these relationships further are warranted. We plan to extend these analyses to the evaluate folate pathway haplotypes, as well as other relevant genetic pathways (e.g., DNA repair). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2649. doi:1538-7445.AM2012-2649

Polymorphisms in folate-related genes: impact on risk of adult acute lymphoblastic leukemia rather than pediatric in Han Chinese

Folate metabolism plays an essential role in the processes of DNA synthesis and methylation. An aberrant folate metabolism caused by a genetic polymorphism may lead to genomic instability and affect the susceptibility to malignancies including acute lymphoblastic leukemia (ALL). This study was designed to explore the correlation between the polymorphisms in folate-related genes and the risk of ALL in Han Chinese. The DNA was isolated from 231 patients with pediatric ALL, 130 patients with adult ALL, and 367 healthy subjects (as controls). Polymorphisms were examined for RFC1 80G > A, DHFR 19 bp del/ins and 317A > G, SHMT1 1420C > T, MTHFR 677C > T and 1298A > C, MTR 2756A > G, MTRR 66A > G, TYMS 3R/2R, MTHFD1 1958G > A, and ABCG2 421G > T using real-time polymerase chain reaction (PCR) or PCR–restriction fragment length polymorphism (RFLP). The risk of adult ALL was increased by the RFC1 80AA variant (odds ratio [OR] = 2.09; 95% confidence interval [CI] 1.19–3.67) and MTRR 66GG variant (OR = 2.15; 95% CI 1.06–4.39) but reduced by the MTHFR 677TT variant (OR = 0.47; 95% CI 0.25–0.88), ABCG2 421GT variant (OR = 0.62; 95% CI 0.41–0.96), and ABCG2 421GT + TT variant (OR = 0.60; 95% CI 0.40–0.90). The increase in risk of adult ALL with the RFC1 80AA associated with the MTRR 66GG variant was even more significant (OR = 8.92; 95% CI 1.97–40.42). Furthermore, the MTHFR 677TT associated with the ABCG2 421GT + TT variant more significantly reduced the risk of adult ALL (OR = 0.32; 95% CI 0.12–0.85). However, all gene polymorphisms tested in this study failed to affect the pediatric ALL risk. Our study clearly demonstrates that polymorphisms in folate-related genes only modulate the susceptibility to adult ALL, but not to pediatric ALL, in Han Chinese.