Germ-Line Genetic Variations in TP53 and Risk for Pediatric Acute Lymphoblastic Leukemia.

Abstract The tumor suppressor p53 plays an essential role in the prevention of tumor development by its ability to respond to stress signals, resulting in the inhibition of cell growth, via cell-cycle arrest or induction of apoptosis. p53 also contributes to the repair of genotoxic DNA damages and is involved in cellular senescence. Previous studies have shown that both germ-line and somatic mutations in the TP53 gene, which encodes p53, can occur in a wide spectrum of cancers, including acute lymphoblastic leukemia, ALL. Recently, we characterized the common germ-line genetic variation across TP53 by extensive re-sequence analysis (http://snp500cancer.nci.nih.gov). Patients and Methods: We conducted a genetic association study in childhood ALL to investigate the possible contribution of common single nucleotide polymorphisms, SNPs, and the common haplotypes on which they reside. For TP53, we analyzed haplotype-tagging SNPs, which are estimated to capture greater than 95% of common haplotypes across the gene (IVS2+38C, Ex4+119 (R72P), IVS4-91, Ex6-34 (R213R), IVS6+62, IVS6-36 and 1846bp 3′ of STP). Cases of ALL (n = 513) were drawn from anonymized samples from the German co-operative therapy study (COALL-06-97) and 751 healthy anonymized blood donor controls collected from regional blood banks in Germany. Genotype analysis was performed by validated Taqman assays posted on the SNP500cancer website. Haplotypes were deduced by maximization-estimation analysis of unphased genotypes using PHASEv2.0.1 (http://www.stat.washington.edu/stephens/software.html). Results: The single locus analysis revealed an increased risk for ALL for four of the seven SNPs individually: C allele at IVS2+38C (304/982 in patients vs. 399/1476 in controls, OR 1.21 95% CI 1.01 – 1.45), G allele at IVS4-91 (150/988 vs. 168/1456, OR 1.37 95% CI 1.08 – 1.75), A allele at Ex6-34 (R213R) (164/996 vs. 178/1450, OR 1.41 95% CI 1.11 – 1.78) and T allele at 1846bp 3′ of STP (185/990 vs. 203/1420, OR 1.38 95% CI 1.10 – 1.72). Individuals homozygous AA at IVS6+62 (16/350 vs. 9/556, OR 2.82, 95% CI 1.16 – 6.99) or TT at 1846bp 3′ of STP (24/334 vs. 15/522 OR 2.50, 955 CI 1.24 – 5.09) showed further risk for disease. The non-synonymous coding SNP at Ex4+119 (R72P) did not show any association with ALL. The distribution of the inferred haplotypes differed significantly between cases and controls (global haplotype test p = 0.02). Children carrying the haplotype CCGAAGT have an increased risk for ALL (138/611 vs. 155/972, OR 1.42, 95% CI 1.09 −1.83) in reference to the most common haplotype GGAAGGC. Conclusions: Our data suggest that susceptibility to pediatric ALL could be associated with at least one copy of an “at risk” haplotype. The study results imply that germ-line genetic variation in TP53, a key tumor suppressor gene, could contribute to susceptibility to childhood ALL. Additional studies are required to confirm our findings and to characterize the functional elements in the at-risk haplotypes.

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HLA-DP genetic variation, proxies for early life immune modulation and childhood acute lymphoblastic leukemia risk

Blood ◽

10.1182/blood-2012-01-404723 ◽

2012 ◽

Vol 120 (15) ◽

pp. 3039-3047 ◽

Cited By ~ 14

Author(s):

Kevin Y. Urayama ◽

Anand P. Chokkalingam ◽

Catherine Metayer ◽

Xiaomei Ma ◽

Steve Selvin ◽

...

Keyword(s):

Genetic Variation ◽

Acute Lymphoblastic Leukemia ◽

Immune Modulation ◽

Lymphoblastic Leukemia ◽

Human Leukocyte ◽

Potential Interaction ◽

Childhood Acute Lymphoblastic Leukemia ◽

Childhood All ◽

Increased Risk ◽

Ear Infections

Abstract The human leukocyte antigen (HLA) genes are candidate genetic susceptibility loci for childhood acute lymphoblastic leukemia (ALL). We examined the effect of HLA-DP genetic variation on risk and evaluated its potential interaction with 4 proxies for early immune modulation, including measures of infectious exposures in infancy (presence of older siblings, daycare attendance, ear infections) and breastfeeding. A total of 585 ALL cases and 848 controls were genotyped at the HLA-DPA1 and DPB1 loci. Because of potential heterogeneity in effect by race/ethnicity, we included only non-Hispanic white (47%) and Hispanic (53%) children and considered these 2 groups separately in the analysis. Logistic regression analyses showed an increased risk of ALL associated with HLA-DPB1*01:01 (odds ratio [OR] = 1.43, 95% CI, 1.01-2.04) with no heterogeneity by Hispanic ethnicity (P = .969). Analyses of DPB1 supertypes showed a marked childhood ALL association with DP1, particularly for high-hyperdiploid ALL (OR = 1.83; 95% CI, 1.20-2.78). Evidence of interaction was found between DP1 and older sibling (P = .036), and between DP1 and breastfeeding (P = .094), with both showing statistically significant DP1 associations within the lower exposure categories only. These findings support an immune mechanism in the etiology of childhood ALL involving the HLA-DPB1 gene in the context of an insufficiently modulated immune system.

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

Baghdad Science Journal ◽

10.21123/bsj.12.2.371-378 ◽

2015 ◽

Vol 12 (2) ◽

pp. 371-378

Author(s):

Baghdad Science Journal

Keyword(s):

Bone Marrow ◽

Acute Lymphoblastic Leukemia ◽

Biochemical Parameters ◽

Serum Proteins ◽

Lymphoblastic Leukemia ◽

White Blood Cells ◽

Total Serum ◽

Childhood All ◽

Marrow Cavity ◽

Increased Risk

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

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

BMC Medical Genetics ◽

10.1186/s12881-019-0900-1 ◽

2019 ◽

Vol 20 (1) ◽

Cited By ~ 1

Author(s):

Sana Mahjoub ◽

Vera Chayeb ◽

Hedia Zitouni ◽

Rabeb M. Ghali ◽

Haifa Regaieg ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Case Control Study ◽

Lymphoblastic Leukemia ◽

Case Control ◽

Snp Genotyping ◽

Control Subjects ◽

False Discovery ◽

Increased Risk ◽

The Common ◽

Control Study

Abstract Background Associations 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. Methods This case-control study involved 170 patients with ALL and 150 control subjects. SNP genotyping was performed by TaqMan® SNP Genotyping Assay. Results The 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)]. Conclusion We 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.

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Homozygous Deletion of the p16/MTS1 Gene in Pediatric Acute Lymphoblastic Leukemia Is Associated With Unfavorable Clinical Outcome

Blood ◽

10.1182/blood.v89.11.4161 ◽

1997 ◽

Vol 89 (11) ◽

pp. 4161-4166 ◽

Cited By ~ 77

Author(s):

Ursula R. Kees ◽

Paul R. Burton ◽

Changlong Lü ◽

David L. Baker

Keyword(s):

Risk Factors ◽

Acute Lymphoblastic Leukemia ◽

Clinical Outcome ◽

Lymphoblastic Leukemia ◽

Homozygous Deletion ◽

Cell Phenotype ◽

P16 Gene ◽

Childhood All ◽

Risk Of Death ◽

Increased Risk

Abstract The p16 gene (MTS1, CDKN2, p16INK4A, CDKI) encoding an inhibitor of cyclin-dependent kinase 4 (cdk4) has been found to be deleted in various types of tumors, including leukemia, and is thought to code for a tumor suppressor gene. Our preliminary findings on eight pediatric patients with acute lymphoblastic leukemia (ALL) suggested that the survival of patients carrying a homozygous p16 gene deletion was significantly inferior to that of those without a deletion. The present study on 48 patients tested the hypothesis that the clinical outcome for pediatric ALL patients is correlated with the presence or absence of the p16 gene. Overall, nine of 48 children (18.3%) carried a homozygous p16 deletion. Such deletions were significantly more common (P = .003) among T-ALL patients (five of eight, 62.5%) than among precursor-B-ALL patients (four of 40, 10.0%). Of nine patients exhibiting p16 deletions, eight (88.9%) were classified as high-risk patients by the recognized prognostic factors of age, white blood cell count, and T-cell phenotype. The 4-year event-free survival in the study population as a whole was 72.7%. Without adjustment for other risk factors (univariate model), the presence of a homozygous p16 deletion was associated with a markedly increased probability of both relapse (P = .0003) and death (P = .002). These findings raise the question of whether the p16 deletion itself confers an increased risk of relapse after adjusting for the known risk factors. In this analysis, the estimated risk multiplier factor for relapse in patients carrying the p16 deletion was 14.0 (P = .0004) and for the risk of death 15.6 (P = .0008). We therefore conclude that the presence of a homozygous p16 deletion may well be an important risk factor for both relapse and death in childhood ALL, and that its prognostic effect is not a consequence of confounding by other factors already known to influence outcome in this disease.

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Characterization of non-human primate antisera to acute lymphoblastic leukemia (ALL): evidence for unique antigen(s) on childhood ALL of "T" phenotype

Blood ◽

10.1182/blood.v61.1.66.66 ◽

1983 ◽

Vol 61 (1) ◽

pp. 66-70

Author(s):

T Mohanakumar ◽

TW Coffey ◽

MP Vaughn ◽

EC Russell ◽

D Conrad

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Cell Phenotype ◽

Membrane Component ◽

Childhood All ◽

Antigen Present ◽

The Common ◽

Blood Elements ◽

Human Primate

Abstract A non-human primate antiserum was prepared to acute lymphoblastic leukemia of T-cell phenotype (T-ALL) and, after absorptions with normal blood elements, reacted by immunofluorescence and microcytotoxicity to all the T-ALL tested. In addition, the antiserum reacted with cells from about 70% of the common ALL studied and immunoprecipitated the common ALL antigen of 100,000 daltons. However, when the anti-T-ALL serum was absorbed with with lymphoblasts from common ALL, it failed to react with common ALL lymphoblasts, yet reacted significantly with cells from patients with T-ALL phenotype and defined a 100,000-dalton membrane component not found on common ALL lymphoblasts. In addition, sequential immunoprecipitation of 125I-labeled T-ALL membranes by anti- common-ALL serum followed by anti-T-ALL serum detected the T-ALL membrane component of 100,000 daltons that was not found on common ALL. Thus, our results demonstrate the presence of of a unique human T-ALL antigen present on all T-ALL distinct from the common ALL antigen.

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Genomic Variants Associated with Childhood Acute Lymphoblastic Leukemia

Blood ◽

10.1182/blood.v116.21.sci-11.sci-11 ◽

2010 ◽

Vol 116 (21) ◽

pp. SCI-11-SCI-11

Author(s):

Mary V. Relling

Keyword(s):

Genetic Variation ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Drug Clearance ◽

Childhood Acute Lymphoblastic Leukemia ◽

Pharmacokinetic Data ◽

Clinical Effects ◽

Childhood All ◽

Genome Wide ◽

A Genome

Abstract Abstract SCI-11 Genome-wide interrogations have a role in addressing both the etiology and the responsiveness of childhood acute lymphoblastic leukemia (ALL). Recent work by our own1 and other groups identified common polymorphisms in ARID5B, and to a lesser extent in IKZF1, as predisposing to the development of childhood ALL. Polymorphisms in these two genes can account for ∼ 40% of the population attributable risk of ALL, and differences in the frequency of the minor allele among different ancestral groups can account for a large portion of the differences in the incidence of ALL among different race groups. The association of these inherited polymorphisms with specific ALL subtypes (e.g. ARID5B with risk of hyperdiploid ALL) indicates that germline polymorphisms affect not only risk of ALL but may also affect or confound association analyses between germline variants and the probability of cure of ALL. The biological basis for the prognostic differences that exist among ALL subtypes remain largely unknown, and it is plausible that inherited polymorphisms may affect both susceptibility to subtypes of ALL as well as to drug responsiveness. Genome-wide analyses have also identified polymorphisms associated with eradication of MRD across multiple treatment protocols.2 Polymorphisms in IL15 indicate variants that likely affect the inherent pharmacodynamic responsiveness of ALL to drug-induced apoptosis. Approximately 20% of the polymorphisms associated with MRD were also associated with rapid drug clearance in the host, even though pharmacokinetic data were only available for 2 of the 4–8 medications used during induction. These findings lead us to suggest that perhaps half of the polymorphisms associated with eradication of ALL are related to effects on host drug clearance, and about half have penetrant effects on the inherent responsiveness of the ALL cells themselves. A genome-wide analysis for the determinants of clearance of one such drug, methotrexate, identified a strong effect of polymorphisms in the SLCO1B1 transporter.3 Genome-wide approaches have identified the importance of genes that decades of candidate gene approaches did not reveal, illustrating the utility of an agnostic approach to genotype-phenotype association studies in childhood ALL. 1. Treviño LR, Yang W, French D, et al. Germline genomic variations associated with childhood acute lymphoblastic leukemia. Nat Genet 41:1001–5, 2009. 2. Yang J, Cheng C, Yang W, et al. Genome-wide interrogation of germline genetic variation associated with treatment response in childhood acute lymphoblastic leukemia. JAMA 301:393–403, 2009. 3. Treviño LR, Shimasaki N, Yang W, et al. Germline genetic variation in an organic anion transporter polypeptide associated with methotrexate pharmacokinetics and clinical effects. J Clin Oncol 27:5972–8, 2009. Disclosures: Relling: St. Jude Children's Research Hospital: Employment, Patents & Royalties; Enzon Pharmaceuticals: Research Funding.

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Acute Lymphocytic Leukemia and Down Syndrome

Blood ◽

10.1182/blood.v118.21.sci-8.sci-8 ◽

2011 ◽

Vol 118 (21) ◽

pp. SCI-8-SCI-8

Author(s):

Shai Izraeli

Keyword(s):

Down Syndrome ◽

Conflicts Of Interest ◽

Lymphoblastic Leukemia ◽

Mtor Inhibitors ◽

Lymphocytic Leukemia ◽

Leukemic Cells ◽

Aberrant Expression ◽

Childhood All ◽

Increased Risk ◽

The Common

Abstract SCI-8 Children with Down syndrome are at a markedly increased risk for acute lymphoblastic leukemia (DS-ALL). These leukemias are exclusively of the B lymphoid precursor phenotype and occur in a similar age to “common” sporadic ALLs with the striking absence of infant ALL. Recent studies reveal that DS-ALLs are heterogeneous and differ from sporadic ALLs. Only about a fifth of DS-ALLs carry the common cytogenetic aberrations typical to childhood ALL. Genomic rearrangements leading to the expression of a cytokine receptor, CRLF2, are detected in 60% of DS-ALL in comparison with up to 10% of sporadic ALLs. CRLF2 heterodimerizes with Interleukin 7 receptor-α (IL7R) to form the receptor to thymic stromal lymphopoietin (TSLP). This receptor is usually present in macrophages, dendritic cells, and some T lymphocytes and participates in allergic and inflammatory processes. The aberrant expression of the TSLP receptor is DS-ALL (and sporadic ALL) is often associated with additional mutations that cause constitutive activation of the downstream JAK-STAT and mTOR growth signaling pathways. These are either lymphoid specific activating mutations of JAK2 or JAK1 or mutations in CRLF2 or IL7R that cause ligand-independent receptor dimerization. The role of the trisomy in selecting these somatic abnormalities is presently unknown. Clinically, the prognosis of DS-ALL is inferior to sporadic ALL mainly because of increased treatment toxicity. However, recent data suggest that the inferior outcome may also be related to the genetic properties of the leukemic cells and that excessive chemotherapy dose reduction may not be appropriate for these patients. Therefore increased vigilance for infectious complications and optimal supportive care are required during periods of intensive chemotherapy. The common activation of the TSLP signaling pathway in DS-ALLs suggests a future for targeted therapy with JAK and/or mTOR inhibitors. Importantly, research of DS-ALL has proven relevant for the general patient population with ALL, as somatic mutations in the TSLP pathway have been discovered in children and adults with sporadic ALL. A major research challenge is the elucidation of the roles of constitutional and somatic trisomy 21 in leukemogenesis. Disclosures: No relevant conflicts of interest to declare.

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Low incidence of second neoplasms among children diagnosed with acute lymphoblastic leukemia after 1983

Blood ◽

10.1182/blood.v99.12.4257 ◽

2002 ◽

Vol 99 (12) ◽

pp. 4257-4264 ◽

Cited By ~ 129

Author(s):

Smita Bhatia ◽

Harland N. Sather ◽

Olga B. Pabustan ◽

Michael E. Trigg ◽

Paul S. Gaynon ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Brain Tumors ◽

Myeloid Leukemia ◽

Lymphoblastic Leukemia ◽

Malignant Neoplasms ◽

Childhood All ◽

Second Neoplasms ◽

Increased Risk ◽

The Impact

Second malignant neoplasms are a serious complication after successful treatment of childhood acute lymphoblastic leukemia (ALL). With improvement in survival, it is important to assess the impact of contemporary risk-based therapies on second neoplasms in ALL survivors. A cohort of 8831 children diagnosed with ALL and enrolled on Children's Cancer Group therapeutic protocols between 1983 and 1995 were observed to determine the incidence of second neoplasms and associated risk factors. The median age at diagnosis of ALL was 4.7 years. The cohort had accrued 54 883 person-years of follow-up. Sixty-three patients developed second neoplasms, including solid, nonhematopoietic tumors (n = 39: brain tumors n = 19, other solid tumors n = 20), myeloid leukemia or myelodysplasia (n = 16), and lymphoma (n = 8). The cumulative incidence of any second neoplasm was 1.18% at 10 years (95% confidence interval, 0.8%-1.5%), representing a 7.2-fold increased risk compared with the general population. The risk was increased significantly for acute myeloid leukemia (standardized incidence ratio [SIR] 52.3), non-Hodgkin lymphoma (SIR 8.3), parotid gland tumors (SIR 33.4), thyroid cancer (SIR 13.3), brain tumors (SIR 10.1), and soft tissue sarcoma (SIR 9.1). Multivariate analysis revealed female sex (relative risk [RR] 1.8), radiation to the craniospinal axis (RR 1.6), and relapse of primary disease (RR 3.5) to be independently associated with increased risk of all second neoplasms. Risk of second neoplasms increased with radiation dose (1800 cGy RR 1.5; 2400 cGy RR 3.9). Actuarial survival at 10 years from diagnosis of second neoplasms was 39%. Follow-up of this large cohort that was treated with contemporary risk-based therapy showed that the incidence of second neoplasms remains low after diagnosis of childhood ALL.

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Characterization of non-human primate antisera to acute lymphoblastic leukemia (ALL): evidence for unique antigen(s) on childhood ALL of "T" phenotype

Blood ◽

10.1182/blood.v61.1.66.bloodjournal61166 ◽

1983 ◽

Vol 61 (1) ◽

pp. 66-70

Author(s):

T Mohanakumar ◽

TW Coffey ◽

MP Vaughn ◽

EC Russell ◽

D Conrad

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Cell Phenotype ◽

Membrane Component ◽

Childhood All ◽

Antigen Present ◽

The Common ◽

Blood Elements ◽

Human Primate

A non-human primate antiserum was prepared to acute lymphoblastic leukemia of T-cell phenotype (T-ALL) and, after absorptions with normal blood elements, reacted by immunofluorescence and microcytotoxicity to all the T-ALL tested. In addition, the antiserum reacted with cells from about 70% of the common ALL studied and immunoprecipitated the common ALL antigen of 100,000 daltons. However, when the anti-T-ALL serum was absorbed with with lymphoblasts from common ALL, it failed to react with common ALL lymphoblasts, yet reacted significantly with cells from patients with T-ALL phenotype and defined a 100,000-dalton membrane component not found on common ALL lymphoblasts. In addition, sequential immunoprecipitation of 125I-labeled T-ALL membranes by anti- common-ALL serum followed by anti-T-ALL serum detected the T-ALL membrane component of 100,000 daltons that was not found on common ALL. Thus, our results demonstrate the presence of of a unique human T-ALL antigen present on all T-ALL distinct from the common ALL antigen.

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Genetic Susceptibility Loci for Childhood Acute Lymphoblastic Leukemia Among Japanese

Blood ◽

10.1182/blood.v126.23.3731.3731 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3731-3731

Author(s):

Kevin Y Urayama ◽

Masatoshi Takagi ◽

Takahisa Kawaguchi ◽

Keitaro Matsuo ◽

Yoichi Tanaka ◽

...

Keyword(s):

Genetic Variation ◽

Acute Lymphoblastic Leukemia ◽

Lymphoblastic Leukemia ◽

Study Group ◽

Susceptibility Loci ◽

East Asians ◽

Childhood All ◽

Genome Wide

Abstract Scrutiny of the human genome through evaluation of common genetic variants has revealed hundreds of disease susceptibility loci. In childhood acute lymphoblastic leukemia (ALL), six regions that have replicated in several populations are now considered known susceptibility loci (ARID5B, IKZF1, CEBPE, CDKN2A, PIP4K2A, and GATA3), but their effects have yet to be fully confirmed in populations of non-European ancestry. Targeted validation attempts based on the same SNPs originally identified in European ancestral populations have been performed in East Asians, but findings have been inconsistent. This may be due to differences in linkage disequilibrium patterns, allele frequency, and/or magnitude of effect between Europeans and East Asians; thus a comprehensive characterization of genetic variation across the targeted genetic loci is required for an appropriate validation attempt in different populations. Using a large network of hospitals within the Tokyo Children's Cancer Study Group, saliva samples from previously diagnosed childhood ALL patients (aged 0-19 years) were collected between December 2012 and May 2015. Genome-wide single nucleotide polymorphism (SNP) genotyping was performed and resulted in the inclusion of a total of 570 ALL patients, with genetic data available for up to about 500,000 SNPs after quality control exclusions. Control genome-wide data were available for 2,712 previously genotyped samples from the Nagahama Study Group and Aichi Cancer Center Study, Japan. SNP imputation was performed on the combined case-control dataset using ShapeIT and Minimac3, and the 1000 Genomes Project Phase I Version 3 as the reference population. Tests of association between childhood ALL and all available SNP genotypes across the six genes (mentioned above) implicated in previous genome-wide association studies was performed using logistic regression and assuming a log-additive model of inheritance. Of the six genomic regions examined, SNPs within the IKZF1, ARID5B, and PIP4K2A genes showed a statistically significant association with childhood ALL risk after Bonferroni correction. SNPs with the strongest evidence of association for these three genes included rs7090445 (ARID5B, OR=1.75, P =3.7x10-17), rs12533431 (IKZF1, OR=1.43, P =4.3x10-5), and rs11013045 (PIP4K2A, OR=0.76, P =9.5x10-5). Further examination of these regions indicated a second independently associated locus within ARID5B. Furthermore, we observed that the same previously reported primary ALL susceptibility SNPs for IKZF1 (e.g. rs4132601, rs11978267) and PIP4K2A (e.g. rs10828317, rs7088318) were not associated in Japanese. This highlights the importance of considering regional genetic variation comprehensively when testing the role of previously implicated candidate regions in a different racial/ethnic population. Characterization of the role of CEBPE, CDKN2A, and GATA3 genetic variation in Japanese may benefit from greater statistical power and potentially additional coverage of SNPs within these regions. Disclosures No relevant conflicts of interest to declare.

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