Risk Of Childhood Acute Lymphoblastic Leukemia Research Articles

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.

Evaluating the Role of Birth Weight and Gestational Age on Acute Lymphoblastic Leukemia Risk Among Those of Hispanic Ethnicity

High birth weight is an established risk factor for childhood acute lymphoblastic leukemia (ALL), especially in children younger than 5 years of age at diagnosis. The goal of this study was to explore the association between being born large for gestational age and the risk for ALL by race/ethnicity to determine if the role of this risk factor differed by these characteristics. The authors compared birth certificate data of 575 children diagnosed with ALL who were younger than 5 years and included in the Texas Cancer Registry, Texas Department of Health, between the years 1995 and 2003 with 11,379 controls matched by birth year. Stratified odds ratios were calculated for risk of ALL by birth weight for gestational age, categorized in 3 groups, small, appropriate, and large for gestational age (SGA, AGA, and LGA, respectively), for each race/ethnicity group. The risk of developing ALL was higher among Hispanics who were LGA (odds ratio [OR] = 1.90, 95% confidence interval [CI]: 1.34–2.68) compared with LGA non-Hispanic whites (OR = 1.27, 95% CI: 0.87–1.86) after adjusting for infant gender, year of birth, maternal age, birth order, and presence of Down syndrome. However, the difference was not statistically significant. These results suggest that there may be differences in the association between higher growth in utero and risk of childhood ALL among Hispanics versus non-Hispanic whites.

Abstract LB-194: Cesarean delivery and risk of childhood leukemia: findings from the Childhood Leukemia International Consortium (CLIC)

Abstract Introduction: Recent meta-analyses have reported modest but significant associations between birth by cesarean delivery (CD) and subsequent risk of immune-related disorders. An association of CD with childhood leukemia has not been established, although two recent case-control studies showed an increased risk of acute lymphoblastic leukemia (ALL) among young children born by CD, and elective CD (E-CD) in particular. Methods: We pooled data from 12 case-control studies in the Childhood Leukemia International Consortium. We analyzed CD overall and according to indications that likely resulted in E-CD (multiple birth and previous CD). Odds ratios (OR) and 95% confidence intervals (CIs) for risk of ALL and acute myeloid leukemia (AML) were estimated using multivariable logistic regression, adjusting for child's birth weight, sex, age, ethnicity, parental education, maternal age, and study center. Results: Delivery method was known for 8017 ALL cases, 659 AML cases, and 21273 controls. Among three studies with information on indication for CD, data were available for 3677 ALL cases, 114 AML cases, and 3929 controls. The association between CD and ALL (pooled OR: 1.06 [95% CI: 0.99, 1.14]) was not statistically significant, whereas birth by E-CD was associated with an increased risk of ALL (pooled OR: 1.27 [95% CI: 1.06, 1.52]). Subgroup analysis by immunophenotype revealed an association between E-CD and B-ALL (pooled OR: 1.28 [95% CI: 1.04, 1.57]), but not T-ALL. Pooled ORs for AML were 1.02 (95% CI: 0.82, 1.27) for overall CD and 1.39 (95% CI: 0.76, 2.53) for E-CD. Conclusions: Findings derived from a pooled analysis of data from several countries suggest a higher risk of childhood ALL following E-CD. More comprehensive assessment of the indications for E-CD in consortia studies will allow investigators to further explore the potential for confounding by indication. If this association is causal, maladaptive immune activation due to lack of stress response before birth and differential colonization of the microbiome in children born by E-CD should be considered as potential mechanisms. Risk of childhood leukemia associated with cesarean delivery overall and elective cesarean deliveryCesarean delivery (all indications)Pre-labor elective cesarean deliveryNumber of studiesExposed controlsExposed casesOR (95% CI)Number of studiesExposed controlsExposed casesOR (95% CI)Overall12340419241.06 (0.99, 1.14)32513081.27 (1.06, 1.52)ALL12340417491.06 (0.99, 1.14)32512901.27 (1.06, 1.52)AML824781221.02 (0.82, 1.27)1126161.39 (0.76, 2.53)ImmunophenotypeB-cell9313212201.07 (0.99, 1.16)22241961.28 (1.04, 1.57)T-cell931321300.95 (0.77, 1.18)2224241.18 (0.75, 1.88)Age012251561.08 (0.73, 1.60)36102.89 (0.93, 8.89)1-512221212261.05 (0.96, 1.15)31711921.22 (0.98, 1.53)6-10126693481.09 (0.93, 1.28)350591.34 (0.90, 2.01)11-14112721190.97 (0.74, 1.26)324291.25 (0.70, 2.24)Year of birth1970-1979464551.06 (0.70, 1.60)29111.13 (0.46, 2.80)1980-198997235351.01 (0.88, 1.15)31021221.30 (0.99, 1.72)1990-19991215296671.06 (0.95, 1.19)362741.32 (0.92, 1.90)2000-2009810524741.14 (0.98, 1.33)173781.14 (0.78, 1.65)2010-2013336181.93 (0.57, 6.51)1551.81 (0.16, 20.4)Gestational ageEarly preterm11126451.19 (0.67, 2.11)3650.58 (0.10, 3.24)Late preterm112581281.13 (0.84, 1.52)313151.56 (0.61, 3.98)Early term116943481.11 (0.93, 1.32)364851.27 (0.87, 1.86)Full term1113196331.01 (0.90, 1.14)31001311.31 (0.99, 1.72)Late term105482571.02 (0.86, 1.22)3760.95 (0.31, 2.90) Citation Format: Erin Marcotte, Thomas Thomopoulos, Jacqueline Clavel, John Dockerty, Sameera Ezzat, Stephen S. Francis, Claire Infante-Rivard, Corrado Magnani, Catherine Metayer, Ana Maria Mora, Beth A. Mueller, Wafaa M. Rashed, Michael E. Scheurer, Joachim Schuz, Catharina Wesseling, Alkistis Skalkidou, Eleni Petridou, Logan Spector. Cesarean delivery and risk of childhood leukemia: findings from the Childhood Leukemia International Consortium (CLIC). [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 LB-194. doi:10.1158/1538-7445.AM2015-LB-194

Home paint exposures and risk of childhood acute lymphoblastic leukemia: findings from the Childhood Leukemia International Consortium.

It has been suggested that home paint exposure increases the risk of childhood acute lymphoblastic leukemia (ALL). We obtained individual level data from eight case-control studies participating in the Childhood Leukemia International Consortium. All studies had home paint exposure data (sometimes including lacquers and varnishes) for the pregnancy period with additional data for the 1-3-month period before conception in five, the year before conception in two, and the period after birth in four studies, respectively. Cytogenetic subtype data were available for some studies. Data were harmonized to a compatible format. Pooled analyses of individual data were undertaken using unconditional logistic regression. Based on 3,002 cases and 3,836 controls, the pooled odds ratio (OR) for home paint exposure in the 1-3 months before conception and risk of ALL was 1.54 [95% confidence interval (CI) 1.28, 1.85], while based on 1,160 cases and 1,641 controls for exposure in the year before conception, it was 1.00 (95% CI 0.86, 1.17). For exposure during pregnancy, using 4,382 cases and 5,747 controls, the pooled OR was 1.14 (95% CI 1.04, 1.25), and for exposure after birth, the OR was 1.22 (95% CI 1.07, 1.39), based on data from 1,962 cases and 2,973 controls. The risk was greater for certain cytogenetic subtypes and if someone other than the parents did the painting. Home paint exposure shortly before conception, during pregnancy, and/or after birth appeared to increase the risk of childhood ALL. It may be prudent to limit exposure during these periods.

The Association of Methylenetetrahydrofolate Reductase Genotypes with the Risk of Childhood Leukemia in Taiwan

BackgroundAcute lymphoblastic leukemia (ALL) is the most prevalent type of pediatric cancer, the causes of which are likely to involve an interaction between genetic and environmental factors. To evaluate the effects of the genotypic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) on childhood ALL risk in Taiwan, two well-known polymorphic genotypes of MTHFR, C677T (rs1801133) and A1298C (rs1801131), were analyzed to examine the extent of their associations with childhood ALL susceptibility and to discuss the MTHFR genotypic contribution to childhood ALL risk among different populations.Methodology/Principal FindingsIn total, 266 patients with childhood ALL and an equal number of non-cancer controls recruited were genotyped utilizing PCR-RFLP methodology. The MTHFR C677T genotype, but not the A1298C, was differently distributed between childhood ALL and control groups. The CT and TT of MTHFR C677T genotypes were significantly more frequently found in controls than in childhood ALL patients (odds ratios=0.60 and 0.48, 95% confidence intervals=0.42–0.87 and 0.24–0.97, respectively). As for gender, the boys carrying the MTHFR C677T CT or TT genotype conferred a lower odds ratio of 0.51 (95% confidence interval=0.32–0.81, P=0.0113) for childhood ALL. As for age, those equal to or greater than 3.5 years of age at onset of disease carrying the MTHFR C677T CT or TT genotype were of lower risk (odds ratio= 0.43 and 95% confidence interval=0.26–0.71, P=0.0016).ConclusionsOur results indicated that the MTHFR C677T T allele was a protective biomarker for childhood ALL in Taiwan, and the association was more significant in male patients and in patients 3.5 years of age or older at onset of disease.

Folate pathway gene polymorphisms, maternal folic acid use, and risk of childhood acute lymphoblastic leukemia.

Several studies suggest that maternal folic acid supplementation before or during pregnancy protects against childhood acute lymphoblastic leukemia (ALL). We investigated associations between ALL risk and folate pathway gene polymorphisms, and their modification by maternal folic acid supplements, in a population-based case-control study (2003-2007). All Australian pediatric oncology centers provided cases; controls were recruited by national random digit dialing. Data from 392 cases and 535 controls were included. Seven folate pathway gene polymorphisms (MTHFR 677C>T, MTHFR 1298A>C, MTRR 66A>G, MTR 2756 A>G, MTR 5049 C>A, CBS 844 Ins68, and CBS 2199 T>C) were genotyped in children and their parents. Information on prepregnancy maternal folic acid supplement use was collected. ORs were estimated with unconditional logistic regression adjusted for frequency-matched variables and potential confounders. Case-parent trios were also analyzed. There was some evidence of a reduced risk of ALL among children who had, or whose father had, the MTRR 66GG genotype: ORs 0.60 [95% confidence interval (CI) 0.39-0.91] and 0.64 (95% CI, 0.40-1.03), respectively. The ORs for paternal MTHFR 677CT and TT genotypes were 1.41 (95% CI, 1.02-1.93) and 1.81 (95% CI, 1.06-3.07). ORs varied little by maternal folic acid supplementation. Some folate pathway gene polymorphisms in the child or a parent may influence ALL risk. While biologically plausible, underlying mechanisms for these associations need further elucidation. Folate pathway polymorphisms may be related to risk of childhood ALL, but larger studies are needed for conclusive results.

Highlights of This Issue

Bonn and colleagues investigated the effect of physical activity after a prostate cancer diagnosis in a large cohort. Statistically significantly lower overall mortality rates were found among men engaged in walking/bicycling ≥20 min/day, performing household work ≥1 h/day, or exercising ≥1 h/week, compared to less active men. Higher levels of physical activity were associated with reduced rates of overall and prostate cancer–specific mortality, further strengthening previous results indicating beneficial effects of physical activity on survival among men with prostate cancer.Fecal immunochemical testing (FIT) is one of the primary screening tests for colorectal cancer. Clarke and colleagues performed a meta-analysis to determine if uptake of FIT screening differs between men and women. Nineteen studies met the authors' inclusion criteria. Male FIT uptake was significantly lower than female uptake and this male/female difference persisted regardless of study design, screening organization, number of samples, age range, and setting. Further investigation is required to identify the factors that influence male nonparticipation in FIT screening.Milne and colleagues investigated associations between pediatric acute lymphoblastic leukemia (ALL) risk and folate pathway gene polymorphisms and their modification by maternal folic acid supplements. Seven folate pathway gene polymorphisms were genotyped in 392 pediatric ALL cases and pre-pregnancy maternal folic acid supplement use information was collected. The authors report some folate-pathway gene polymorphisms in the child or parent may influence ALL risk. Folate pathway polymorphisms may be related to risk of childhood ALL, but larger studies are needed for conclusive results.Schmit and colleagues searched for miRNA-related polymorphisms contributing to colorectal cancer etiology using the Axiom miRNA Target Site Genotyping Array containing 237,858 markers. The study included 596 cases from the Molecular Epidemiology of Colorectal Cancer study. The authors identified twenty-three markers with P values less than 5.0E–04 and replicated a previously published locus within the 3′-untranslated region of the insulin receptor gene INSR. This study demonstrates the potential for a miRNA-targeted genome-wide association study to identify candidate susceptibility loci and prioritize them for functional characterization.

Interaction Between IGF1 Polymorphisms and the Risk of Acute Lymphoblastic Leukemia in Chinese Children

Background/Aims: IGF1 is a key regulator in cell proliferation and apoptosis, and the 3' un-translated region (3'UTR) of the gene plays an important role in gene expression. For the first time, we explored the relationship between polymorphisms in the IGF1 3'UTR region and the risk of childhood acute lymphoblastic leukemia (ALL). Methods: Questionnaires were applied to collect epidemiological data. The genotypes of IGF1 polymorphisms were tested in a population of 744 ALL patients and 1088 cancer-free controls utilizing Taqman. Cell functional studies included real-time PCR, cell culture and transfection and luciferase assays. Results: We found that rs6214 homozygous AA genotype and rs6218 homozygous CC genotype were significantly associated with increased risk of childhood ALL. In addition, rs6218 CC genotype was associated with increased level of IGF1 mRNA in bone marrow, and the mutation in rs6218 led to aberrant binding capacity of hsa-miR-603 and hsa-miR-3941 in the 3'UTR of IGF1. Conclusion: Polymorphisms of rs6214 and rs6218 in the 3'UTR of IGF1 are associated with childhood ALL susceptibility, and the polymorphism of rs6218 is related with IGF1 expression at mRNA level.

CYP3A5 ∗ 3 genetic polymorphism is associated with childhood acute lymphoblastic leukemia risk: A meta-analysis.

Several studies have investigated the association between CYP3A5 FNx01 3 genetic polymorphism and acute lymphoblastic leukemia (ALL) risk in children, but have yielded controversial results. Therefore, we performed a meta-analysis to evaluate synthetically the effect of CYP3A5 FNx01 3 polymorphism on the risk of ALL in children. Case-control studies investigating the relationship between CYP3A5 FNx01 3 genetic polymorphism and ALL risk in children were included. Odds ratios (ORs) with 95% confidence intervals (CIs) were calculated to assess the strength of association between CYP3A5 FNx01 3 polymorphism and ALL risk in children. Q-statistic test was used to evaluate the heterogeneity and publication bias was assessed through funnel plot. In total, five case-control studies with 1070 cases and 1125 controls were included in the meta-analysis. Based on the results of heterogeneity, fixed-effects or random-effects models were applied to estimate the pooled ORs. The pooled ORs (95% CIs) for CYP3A5 FNx01 3 heterozygous mutant, homozygous mutant, and (heterozygous + homozygous) mutant were 1.47 (0.97-2.21), 1.05 (0.62-1.79), and 1.67 (1.14-2.44) with P = 0.07, 0.86, and 0.009, respectively. In subgroup analysis, the Z values of CYP3A5 FNx01 3 (heterozygous + homozygous) mutant and children with ALL in Asian and Caucasian populations were 1.34 and 2.51 with P = 0.18 and 0.01, respectively. No significant publication bias was detected by funnel plot. The current meta-analysis showed that there was association between CYP3A5 FNx01 3 polymorphism and the altered risk of ALL in children, especially in Caucasian populations.

CD200 May be a Potential Target for Therapy in Standard Risk Childhood ALL

Multiagent therapies for children with acute lymphoblastic leukaemia (ALL) have resulted in impressive remission rates of around 90%. Unfortunately, relapse rates remain high and most children who relapse will not survive. Innovative antibody and chimeric antigen receptor (CAR) modified T-cell therapies have shown promising results in ALL. However, this is a heterogeneous disease and several groups have shown ALL evolves in a branching fashion. Moreover, some leukaemia stem cell (LSC) populations do not express antigens that are the targets of developing therapies such as CD19, CD20, and CD22. Consequently, these cells may be largely unaffected and could provide a reservoir of resistant cells, from which relapse may develop. The diversity of reported LSC populations may be a reason for treatment failure and improvements in therapy will require targeting of all cells that have the potential to initiate and maintain this disease. In an attempt to identify more appropriate therapeutic targets we conducted an extensive microarray screen of several LSC subpopulations and bulk leukaemia cells from a group of paediatric patients with favourable cytogenetic abnormalities. This screen identified a number of genes that were up-regulated in all LSC subpopulations compared to levels in normal haemopoietic cells. The up-regulated genes encode for cell surface antigens, including the type-1 membrane protein, CD200 and signalling pathways. Expression of CD200 was 12-fold higher in bulk ALL cells compared to normal BM cells (p=0.001). CD200 is a key immunosuppressive molecule that has been implicated as a poor prognostic factor in multiple myeloma and acute myeloid leukaemia. To validate the microarray results, we assessed expression of CD200 in 20 BCP-ALL cases (11 pre B, 9 c-ALL) by flow cytometry and in functional assays. Fifteen of these cases were classified as MRD low risk and had favourable cytogenetic abnormalities and 5 were classified as high risk by MRD and cytogenetic abnormalities. ALL cells were stained with antibodies against CD34, CD19 and CD200 and cells were sorted on the basis of expression/lack of expression of CD34/CD200. The functional ability of the sorted populations was assessed in NSG mice and serial transplantation experiments were performed to assess self-renewal capacity. Overall, the flow cytometric analyses confirmed the microarray data in that expression of CD200 was high in this patient cohort (60±6.6%) compared to normal BM (0.1%±0.04, p ≤ 0.001), regardless of cytogenetic abnormality or MRD risk status. In standard risk cases, BM engraftment was achieved with the CD34+/CD200+ (2-66% human leukaemia) and CD34-/CD200+ (10-26%) subpopulations only, using inocula of 4x104-107 cells. No engraftment was attained using similar numbers of CD200- cells, regardless of expression of CD34 or CD19 in this group. Interestingly, when cells from the 5 patients defined as high risk were inoculated, engraftment was achieved using all four sorted subpopulations. The levels of leukaemia engraftment in these cases ranged from 2-95% using 1x103-5x106 cells and levels were similar across all subpopulations in individual patient samples. Results from serial transplantation studies to date demonstrate the sorted subpopulations were capable of self-renewal. As with the primary transplants, all four subpopulations from high risk samples engrafted while this ability was restricted to CD200+ subpopulations in standard risk cases. FISH analyses have confirmed all the engrafting cells had an abnormal karyotype. These data provide further evidence that surface antigen immunophenotype is not a good predictor of function in paediatric ALL, particularly in high risk cases. However, in standard risk cases it may be possible to eliminate LSC by targeting CD200. Treating human chronic lymphocytic leukaemia cells with anti-CD200 antibodies has been shown to prevent engraftment in NSG mice. Our data suggests that investigation of the effects of anti-CD200 in standard risk childhood ALL are warranted. DisclosuresNo relevant conflicts of interest to declare.

Functional Analysis of Kinase-Activating Fusions in Ph-like Acute Lymphoblastic Leukemia

Introduction: Ph-like or BCR-ABL1-like B-progenitor acute lymphoblastic leukemia (ALL) is a high-risk subtype characterized by a gene expression profile similar to BCR-ABL1 ALL. The prevalence of Ph-like ALL rises from 10% in standard risk childhood ALL to over 25% in young adults. Next-generation sequencing of Ph-like ALL identified a variety of alterations involving kinase or cytokine receptor genes, including rearrangement, sequence mutation and copy number alterations. Chromosomal rearrangements in about one-third of Ph-like ALL cases create fusion genes of a variety of 5’ partners that involve ABL1-class genes (ABL1, ABL2, CSF1R and PDGFRB) or activate JAK family members (JAK2, TYK2, IL2RB) that are potentially amenable to treatment with ABL1-class or JAK-class tyrosine kinase inhibitors (TKIs). Notably, ABL2 (Abelson-related gene, ARG), a homolog of ABL1, has rarely been identified as a rearrangement partner in ALL. CSF1R (encoding the macrophage colony stimulating receptor) regulates the differentiation of macrophages, and is not normally expressed in lymphocytes. Likewise, rearrangements involving the JAK family member TYK2, the beta chain of the interleukin 2 cytokine receptor (IL2RB), and the neurotrophic tyrosine kinase receptor type 3 (NTRK3), have not been previously described in leukemia. The goals of this study were to assess the role of these kinase alterations in leukemogenesis, to determine the activation of signaling pathways, and to investigate the efficacy of TKIs.Methods: Kinase fusions were expressed in interleukin-3 dependent Ba/F3 cells, and co-expressed with the dominant negative isoform of IKAROS (IK6) in interleukin-7 dependent Arf-/- mouse pre-B cells. Xenograft models of 10 Ph-like ALL tumors - ETV6-ABL1, RANBP2-ABL1, PAG1-ABL2, RCSD1-ABL2, SSBP2-CSF1R, IGH-EPOR, ETV6-NTRK3, ATF7IP-JAK2, PAX5-JAK2 and ZEB2-PDGFRB - were generated by engrafting primary human leukemia cells into NOD-SCID IL2R gamma null (NSG) mice. Activation of kinase signaling was performed using phosphoflow cytometry analysis, and sensitivity to TKIs was assessed ex vivo and in vivo.Results: All kinase fusions (PAG1-ABL2, MYH9-IL2RB, ATF7IP-JAK2, ETV6-NTRK3 or MYB-TYK2) induced cytokine-independent proliferation of Ba/F3 cells. Mice transplanted with Arf-/- pre-B cells co-expressing IK6 and either RCSD1-ABL2 or SSBP2-CSF1R developed pre-B ALL (CD43+, B220+, CD19+, BP-1+ and IgM-) with a median latency of 36 and 40 days respectively, providing evidence that ABL2 and CSF1R fusions contribute to leukemogenesis.In human leukemic cells harvested from xenograft mice we observed distinct patterns of kinase signaling activation and TKI sensitivity for the different fusions. Xenograft cells expressing ABL1-class kinase fusions showed activation of STAT5 that was inhibited with imatinib or dasatinib. Phosphorylation of CRKL, a known target of ABL1 and ABL2, was only observed in cells expressing ABL1/2 fusions. Cells harboring ATF7IP-JAK2, PAX5-JAK2 or IGH-EPOR showed phosphorylation of STAT5 that was attenuated with the JAK2 inhibitor, ruxolitinib. In contrast, cells expressing ETV6-NTRK3 signaled through the MAPK pathway with constitutive pERK1/2 that was inhibited with the ALK-inhibitor, crizotinib. This TKI response profile was confirmed by cytotoxicity assays in xenograft cells, with ABL1-class fusions being sensitive to dasatinib (IC50 range 1-2nM), whilst cases harboring ATF7IP-JAK2 or EPOR rearrangement uniquely responded to ruxolitinib with IC50 values of 500nM and 850nM respectively. Interestingly, in human leukemic cells harboring the ETV6-NTRK3 fusion we observed selective inhibition with both crizotinib and the FLT3 inhibitor, lestaurtinib. Pre-clinical studies on three xenograft models of Ph-like ALL - ETV6-ABL1, RCSD1-ABL2 and SSBP2-CSF1R – showed significantly reduced leukemic burden in dasatinib treated mice (20mg/kg/day p.o) compared to vehicle treated mice.Conclusions: These data provide important insight on new targets of rearrangement in ALL and describe the first engineered mouse models of Ph-like B-ALL. Functional modeling of these alterations is essential to improve the clinical management of Ph-like ALL by identifying patients with specific genomic lesions at diagnosis and directing them to treatment with appropriate TKIs combined with chemotherapy, analogous to current treatment for BCR-ABL1 B-ALL. DisclosuresHunger:Bristol Myers Squibb: Consultancy.

Maternal supplementation with folic acid and other vitamins and risk of leukemia in offspring: a Childhood Leukemia International Consortium study.

Maternal prenatal supplementation with folic acid and other vitamins has been inconsistently associated with a reduced risk of childhood acute lymphoblastic leukemia (ALL). Little is known regarding the association with acute myeloid leukemia (AML), a rarer subtype. We obtained original data on prenatal use of folic acid and vitamins from 12 case-control studies participating in the Childhood Leukemia International Consortium (enrollment period: 1980-2012), including 6,963 cases of ALL, 585 cases of AML, and 11,635 controls. Logistic regression was used to estimate pooled odds ratios (ORs) and 95% confidence intervals (CIs), adjusted for child's age, sex, ethnicity, parental education, and study center. Maternal supplements taken any time before conception or during pregnancy were associated with a reduced risk of childhood ALL; odds ratios were 0.85 (95% CI = 0.78-0.92) for vitamin use and 0.80 (0.71-0.89) for folic acid use. The reduced risk was more pronounced in children whose parents' education was below the highest category. The analyses for AML led to somewhat unstable estimates; ORs were 0.92 (0.75-1.14) and 0.68 (0.48-0.96) for prenatal vitamins and folic acid, respectively. There was no strong evidence that risks of either types of leukemia varied by period of supplementation (preconception, pregnancy, or trimester). Our results, based on the largest number of childhood leukemia cases to date, suggest that maternal prenatal use of vitamins and folic acid reduces the risk of both ALL and AML and that the observed association with ALL varied by parental education, a surrogate for lifestyle and sociodemographic characteristics.

A Task-Based Assessment of Parental Occupational Exposure to Organic Solvents and Other Compounds and Risk of Acute Lymphoblastic Leukemia in the Offspring

A Task-Based Assessment of Parental Occupational Exposure to Organic Solvents and Other Compounds and Risk of Acute Lymphoblastic Leukemia in the OffspringAbstract Number:2249 Catherine Metayer*, Ghislaine Scélo, Alice Y. Kang, Robert B. Gunier, Kyndaron Reinier, C. Suzanne Lea, Jeffrey S. Chang, Steve Selvin, Janice Kirsch, Monique Does, Patricia Quinlan, and S. Katharine Hammond Catherine Metayer* University of California, Berkeley, United States, E-mail Address: [email protected] Search for more papers by this author , Ghislaine Scélo International Agency for Research on Cancer, France, E-mail Address: [email protected] Search for more papers by this author , Alice Y. Kang University of California, Berkeley, United States, E-mail Address: [email protected] Search for more papers by this author , Robert B. Gunier University of California, Berkeley, United States, E-mail Address: [email protected] Search for more papers by this author , Kyndaron Reinier Cedars-Sinai Medical Center, United States, E-mail Address: [email protected] Search for more papers by this author , C. Suzanne Lea East Carolina University, United States, E-mail Address: [email protected] Search for more papers by this author , Jeffrey S. Chang National Institute of Cancer Research, Taiwan, E-mail Address: [email protected] Search for more papers by this author , Steve Selvin University of California, Berkeley, United States, E-mail Address: [email protected] Search for more papers by this author , Janice Kirsch Medical oncologist and hematologist, United States, E-mail Address: [email protected] Search for more papers by this author , Monique Does University of California, Berkeley, United States, E-mail Address: [email protected] Search for more papers by this author , Patricia Quinlan University of California, San Francisco, United States, E-mail Address: [email protected] Search for more papers by this author , and S. Katharine Hammond University of California, Berkeley, United States, E-mail Address: [email protected] Search for more papers by this author AbstractBackground: Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Studies examining paternal occupational exposures and risk of childhood ALL have mainly relied on job titles lacking specificity.Methods: We examined the relationship between the father’s workplace exposures before and after birth and risk of ALL in the offspring. Children with ALL (n=667) and controls (n=1,020) were enrolled in a population-based case-control study in California (2000-2008). We developed 19 task-based job modules (JMs) based on the prevalence of occupations in the study area and the probability of exposures to carcinogens. Expert assessment was then applied to estimate exposure to organic solvents and other compounds. Unconditional logistic regression models adjusted for socio-demographic factors were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs).Results: Of 1,634 fathers, 903 were assigned a JM and 643 (71%) completed the interview (55% Hispanic origin). Occupations were stable over time. Among children with non-Hispanic fathers, no associations were observed with any exposures evaluated. In contrast in children with Hispanic fathers, the OR for exposure to organic solvents was 1.48 (95% CI: 1.01-2.16). In multivariable analyses, the OR for chlorinated hydrocarbons was 2.28 (95% CI: 0.97- 5.37; n=31 exposed cases vs. 17 controls) and close to one for aromatic hydrocarbons, glycol ethers, and other hydrocarbon mixtures. Moderate elevated risks were seen with exposure to combustion exhausts, metals, paints, structural pesticides (data on agricultural pesticides are presented separately), and wood dust, although not statistically significant in univariate or multivariable models.Conclusion: Our data support associations between paternal occupational exposures to known carcinogens contained in organic solvents for children of Hispanic origins, specifically chlorinated hydrocarbons. Explanations for ethnic differences are under investigation.

Parental Occupational Pesticide Exposure and Childhood Acute Lymphoblastic Leukemia

Parental Occupational Pesticide Exposure and Childhood Acute Lymphoblastic LeukemiaAbstract Number:2286 Robert Gunier*, Alice Kang, Katharine Hammond, Suzanne Lea, Patricia Quinlan, Kyndaron Reinier, Monique Does, and Catherine Metayer Robert Gunier* University of California, Berkeley, United States, E-mail Address: [email protected] Search for more papers by this author , Alice Kang University of California, Berkeley, United States, E-mail Address: [email protected] Search for more papers by this author , Katharine Hammond University of California, Berkeley, United States, E-mail Address: [email protected] Search for more papers by this author , Suzanne Lea East Carolina University, United States, E-mail Address: [email protected] Search for more papers by this author , Patricia Quinlan University of California, San Francisco Search for more papers by this author , Kyndaron Reinier Cedars-Sinai, United States Search for more papers by this author , Monique Does University of California, Berkeley, United States Search for more papers by this author , and Catherine Metayer University of California, Berkeley, United States Search for more papers by this author AbstractBackground: Most studies investigating the association between parental occupational pesticide exposure and childhood acute lymphoblastic leukemia (ALL) have relied on job titles.Methods: Children diagnosed with ALL (n=669) and age-, sex, race-matched controls (n=1,021) were enrolled in the California Childhood Leukemia Study (2000-2008). We assessed parental pre- and postnatal occupational pesticide exposure using job-title (JT) and corresponding occupational codes from the United States Bureau of Labor Statistics, as well as detailed task-based job modules (JM) and corresponding expert rating. We used unconditional logistic regression to calculate odds ratios (OR) and 95% confidence intervals (95% CI) for parental occupational pesticide exposure adjusting for child’s sex, age, ethnicity, and household income.Results: The overall specificity of occupational pesticide exposure using JT compared to JM was 94-95% and the sensitivity was 70-77% in both cases and controls. The use of JT to assess paternal postnatal occupational pesticide exposure and risk of ALL resulted in an OR=0.9 (95% CI: 0.6, 1.2); in contrast, the use of JM resulted in ORs equal to 1.5 (95% CI = 1.0, 2.2) and 1.7 (95% CI: 1.1, 2.5) for pre- and postnatal exposure, respectively. Risk of ALL was only elevated in children diagnosed at four years of age or younger, with an OR=2.2 (95% CI: 1.3, 3.9) for postnatal paternal exposure. Maternal occupational pesticide exposure was not associated with ALL during the prenatal or postnatal period. Risk estimates were nearly identical among Hispanic and non-Hispanic children, and were very similar using conditional logistic regression.Conclusions: We observed an increased risk of childhood ALL with paternal occupational pesticide exposure assessed using task-based JM, but not JT. In this study, the use of JT instead of JM resulted in exposure misclassification and underscores the importance of improved exposure assessment.

Maternal benzene exposure during pregnancy and risk of childhood acute lymphoblastic leukemia: a meta-analysis of epidemiologic studies.

BackgroundThe prevalence of childhood leukemia is increasing rapidly all over the world. However, studies on maternal benzene exposure during pregnancy and childhood acute lymphoblastic leukemia (ALL) have not been systematically assessed. Therefore, we performed a meta-analysis to investigate the association between maternal solvent, paint, petroleum exposure, and smoking during pregnancy and risk of childhood ALL.MethodsRelevant studies up to September 1st, 2013 were identified by searching the PubMed, EMBASE, Cochrane library and the Web of Science databases. The effects were pooled using either fixed or random effect models based on the heterogeneity of the studies.ResultsTwenty-eight case-control studies and one cohort study were included for analysis, with a total of 16,695 cases and 1,472,786 controls involved. Pooled odds ratio (OR) with 95% confidence interval (CI) for ALL was 1.25 (1.09, 1.45) for solvent, 1.23 (1.02, 1.47) for paint, 1.42 (1.10, 1.84) for petroleum exposure, and 0.99 (0.93, 1.06) for maternal smoking during pregnancy. No publication bias was found in this meta-analysis and consistent results were observed for subgroup and sensitivity analyses.ConclusionsChildhood ALL was associated with maternal solvent, paint, and petroleum exposure during pregnancy. No association was found between ALL and maternal smoking during pregnancy. Avoidance of maternal occupational and environmental benzene exposure during pregnancy could contribute to a decrease in the risk of childhood ALL.

Confirmation of childhood acute lymphoblastic leukemia variants, ARID5B and IKZF1, and interaction with parental environmental exposures.

Genome wide association studies (GWAS) have established association of ARID5B and IKZF1 variants with childhood acute lymphoblastic leukemia (ALL). Epidemiological studies suggest that environmental factors alone appear to make a relatively minor contribution to disease risk. The polygenic nature of childhood ALL predisposition together with the timing of environmental triggers may hold vital clues for disease etiology. This study presents results from an Australian GWAS of childhood ALL cases (n = 358) and population controls (n = 1192). Furthermore, we utilised family trio (n = 204) genotypes to extend our investigation to gene-environment interaction of significant loci with parental exposures before conception, and child’s sex and age. Thirteen SNPs achieved genome wide significance in the population based case/control analysis; ten annotated to ARID5B and three to IKZF1. The most significant SNPs in these regions were ARID5B rs4245595 (OR 1.63, CI 1.38–1.93, P = 2.13×10−9), and IKZF1 rs1110701 (OR 1.69, CI 1.42–2.02, p = 7.26×10−9). There was evidence of gene-environment interaction for risk genotype at IKZF1, whereby an apparently stronger genetic effect was observed if the mother took folic acid or if the father did not smoke prior to pregnancy (respective interaction P-values: 0.04, 0.05). There were no interactions of risk genotypes with age or sex (P-values >0.2). Our results evidence that interaction of genetic variants and environmental exposures may further alter risk of childhood ALL however, investigation in a larger population is required. If interaction of folic acid supplementation and IKZF1 variants holds, it may be useful to quantify folate levels prior to initiating use of folic acid supplements.

Paternal intake of folate and vitamins B6 and B12 before conception and risk of childhood acute lymphoblastic leukemia.

We investigated whether paternal dietary intake of folate before conception is associated with the risk of childhood acute lymphoblastic leukemia (ALL) in a nationwide case-control study. Data on dietary folate intake during the 6months before the child's conception were collected from 285 case fathers and 595 control fathers using a dietary questionnaire. Nutrient intake was quantified using a customized computer software package based on Australian food composition databases. Data on folate intake were analyzed using unconditional logistic regression, adjusting for study-matching variables, total energy, and potentially confounding variables. In a subset of 229 cases and 420 controls, data on vitamin B6 and vitamin B12 intake were also analyzed. No consistent associations were seen with paternal dietary intake of folate or vitamin B6. Higher levels of paternal dietary vitamin B12 were appeared to be associated with an increased risk of childhood ALL, with those in the highest tertile of consumption having an OR of 1.51 (0.97, 2.36). The use of supplements containing folate and vitamins B6 or B12 was rare. We did not find any biologically plausible evidence that paternal nutrition in the period leading up to conception was associated with childhood ALL. Our finding for vitamin B12 may be a chance finding, given the number of analyses performed, or be attributable to participation bias because parents with a tertiary education had the lowest level of B12 intake and tertiary education was more common among control than case parents.

CEBPE polymorphism confers an increased risk of childhood acute lymphoblastic leukemia: a meta-analysis of 11 case-control studies with 5,639 cases and 10,036 controls.

The association between CCAAT/enhancer binding protein-ε (CEBPE) rs2239633 polymorphism and acute lymphoblastic leukemia (ALL) risk has been reported, but results of previous studies remain controversial and ambiguous. To assess the association between CEBPE rs2239633 polymorphism and childhood ALL risk, a meta-analysis was performed. Based on comprehensive searches of the PubMed, Embase, Chinese National Knowledge Infrastructure (CNKI), and Chinese Biomedical Literature Database (CBM), we identified outcome data from all articles estimating the association between CEBPE rs2239633 polymorphism and childhood ALL risk. The pooled odds ratio (OR) with 95% confidence intervals (CIs) were calculated. A significant association between CEBPE rs2239633 polymorphism with childhood ALL was found (OR = 1.19, 95% CI 1.11-1.28, P < 0.01). Subgroup analysis stratified by ethnicity also suggested a significant association between this polymorphism and childhood ALL in the Caucasian subgroup (OR = 1.19, 95% CI 1.09-1.30, P < 0.01) and Hispanic subgroup (OR = 1.39, 95% CI 1.18-1.63, P < 0.01). No significant association was observed in the Asian subgroup (OR = 1.05, 95% CI 0.90-1.22, P = 0.53). The CEBPE rs2239633 polymorphism increased B cell ALL risk (OR = 1.29, 95% CI 1.15-1.44, P < 0.01) and B hyperdiploid ALL risk (OR = 1.84, 95% CI 1.40-2.43, P < 0.01). This meta-analysis demonstrated that the CEBPE rs2239633 polymorphism was significantly associated with childhood ALL risk.

Associations between AT-rich interactive domain 5B gene polymorphisms and risk of childhood acute lymphoblastic leukemia: a meta-analysis.

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

Glutathione-S-transferase polymorphism and acute lymphoblastic leukemia (ALL) in north Indian children: a case-control study and meta-analysis.

Various studies on association of glutathione S-transferase (GST) polymorphisms and childhood acute lymphoblastic leukemia (ALL) have yielded conflicting results. We examined this association among north Indian children and conducted an updated meta-analysis to overcome sample size-related limitations. GSTM1, GSTP1 and GSTT1 genotypes in 100 children with ALL and 300 healthy controls were compared. GSTT1 null mutation (odds ratio (OR) 2.54, 95% confidence interval (CI) 1.50-4.32) and GSTP1 homozygous mutation (OR 3.13, 95%CI 1.48-6.59) were found to increase the risk of childhood ALL, while GSTM1 did not alter the risk. Meta-analysis included 22, 10 and 20 studies examining the association of childhood ALL with GSTM1, GSTP1 and GSTT1 genotypes, respectively. Only GSTM1 genotype (OR 1.29, 95%CI 1.10-1.62) was associated with increased risk in the overall analysis. However, both GSTM1 (OR 1.54, 95%CI 1.12-2.10) and GSTT1 (OR 1.63, 95%CI 1.32-1.99) null genotypes were associated with increased risk in Asian subjects. The risk of developing childhood ALL was not associated with GSTP1 genotype.