Risk Of Childhood Acute Lymphoblastic Leukemia Research Articles

Role of polymorphisms of GSTM1, GSTT1 and GSTP1 Ile105Val in childhood acute lymphoblastic leukemia risk: an updated meta-analysis.

The association between glutathione-S-transferase polymorphisms (GSTM1, GSTT1 and GSTP1 Ile105Val) and risk of childhood acute lymphoblastic leukemia (ALL) remains controversial. Therefore, we performed a meta-analysis to derive a more precise estimation of the relationship. We searched Medline (Mainly Pubmed), Embase, Cochrane Library, CNKI (Chinese National Knowledge Infrastructure), Chinese Biomedical Literature (Chinese) and Wanfang (Chinese) Databases to collect articles that evaluated the polymorphism of GSTs gene in child patients with ALL. We also reviewed reference lists from retrieved articles. Two researchers evaluated study eligibility and extracted the data independently, and disagreements were resolved by discussion. Two reviewers independently assessed the methodological quality of each study. The principal outcome measure was the odds ratio (OR) with 95% confidence interval (CI) for the risk of child ALL associated with GSTM1, GSTT1, GSTP1 Ile105Val. The data were analyzed using Stata (Version 12.0) software. This meta-analysis included 30 studies for GSTM1 polymorphism, 27 studies for GSTM1 polymorphism and 10 studies for GSTP1 Ile105Val polymorphism. The combined results based on all studies showed that GSTM1 (OR= 1.297, 95% CI= 1.105-1.523, P=0.001) and GSTT1 polymorphism (OR=1.213, 95% CI=1.031-1.427, P= 020) contributes to the development of childhood ALL, while no association was found in all comparison models of GSTP1 Ile105Val variants (homozygote model: OR=1.234, 95% CI=0.966-1.578, P=0.093, heterozygote model: OR=1.072, 95% CI=0.931-1.235, P=0.331, dominant model: OR=1.104, 95% CI=0.965-1.262, P=0.149, recessive model: OR=1.184, 95% CI=0.934-1.499, P=0.162, and allele comparison model: OR=1.096, 95% CI=0.988-1.216, P=0.083). The current analyses suggests significant association was found between GSTM1 variants and the risk of childhood ALL, while no association were found between GSTT1 and GSTP1 Ile105Val polymorphism and childhood ALL risk.

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.

Cesarean Section and Risk of Childhood Acute Lymphoblastic Leukemia in a Population-Based, Record-Linkage Study in California.

The relationship of mode of delivery to risk of childhood acute lymphoblastic leukemia (ALL) is uncertain. After linking birth records and cancer registry data from California, we conducted a population-based case-control study to investigate the role of delivery by cesarean section (C-section) in the etiology of childhood ALL. This study included 5,081 cases and 18,927 matched controls born in 1978-2009; more detailed data were available on type of C-section (i.e., elective vs. emergency) for a subset of 1,552 cases and 5,688 controls. No association was observed between C-section overall and childhood ALL risk (<15 years of age), but elective C-section was associated with a significantly elevated risk of ALL (odds ratio (OR)=1.17, 95% confidence interval (CI): 1.01, 1.36). At the peak ages of ALL incidence (2-4 years), C-section was associated with an 11% higher risk of ALL (OR=1.11, 95% CI: 1.01, 1.22) compared with vaginal delivery, and the magnitude of the association was larger for elective C-section (OR=1.38, 95% CI: 1.11, 1.70). Emergency C-section was not associated with childhood ALL. Because of design features minimizing nonparticipation and inaccurate recall, this record linkage-based study is less prone to bias. Our results suggest that delivery by elective C-section was associated with a higher risk of childhood ALL, especially at the peak ages of incidence. It is important to evaluate possible mechanisms, because this potential risk factor is modifiable.

Home remodeling and risk of childhood leukemia

PurposeWe investigated the relationship between the risk of childhood leukemia and home remodeling, a surrogate for indoor chemical exposures. MethodsWe collected information on remodeling activities carried out between birth and diagnosis in homes of 609 acute lymphoblastic leukemia (ALL) cases, 89 acute myeloid leukemia (AML) cases, and 893 matched controls participating in the California Childhood Leukemia Study (1995–2008). We used multivariable logistic regression to estimate the risk of ALL and AML associated with six remodeling activities: construction, painting, recarpeting, reflooring, roofing, and weatherproofing. Models were adjusted for age, sex, Hispanic ethnicity, race, household annual income, and residential mobility. ResultsConstruction in the home between birth and diagnosis was associated with a significant increase in ALL risk (odds ratio [OR]: 1.52, 95% confidence interval [CI]: 1.14–2.02) and a nonsignificant increase in AML risk (OR: 1.75, 95% CI: 0.98–3.15). No other remodeling activities were associated with ALL or AML risk in the main analysis. When stratifying by Hispanic ethnicity, a positive relationship between ALL risk and painting was evident in Hispanic children (OR: 1.47, 95% CI: 1.04–2.07). ConclusionsSpecific home remodeling activities appeared to be associated with increased risk of childhood ALL.

A childhood acute lymphoblastic leukemia genome-wide association study identifies novel sex-specific risk variants.

Childhood acute lymphoblastic leukemia (ALL) occurs more frequently in males. Reasons behind sex differences in childhood ALL risk are unknown. In the present genome-wide association study (GWAS), we explored the genetic basis of sex differences by comparing genotype frequencies between male and female cases in a case-only study to assess effect-modification by sex.The case-only design included 236 incident cases of childhood ALL consecutively recruited at the Texas Children's Cancer Center in Houston, Texas from 2007 to 2012. All cases were non-Hispanic whites, aged 1 to 10 years, and diagnosed with confirmed B-cell precursor ALL. Genotyping was performed using the Illumina HumanCoreExome BeadChip on the Illumina Infinium platform. Besides the top 100 statistically most significant results, results were also analyzed by the top 100 highest effect size with a nominal statistical significance (P <0.05).The statistically most significant sex-specific association (P = 4 × 10) was with the single nucleotide polymorphism (SNP) rs4813720 (RASSF2), an expression quantitative trait locus (eQTL) for RASSF2 in peripheral blood. rs4813720 is also a strong methylation QTL (meQTL) for a CpG site (cg22485289) within RASSF2 in pregnancy, at birth, childhood, and adolescence. cg22485289 is one of the hypomethylated CpG sites in ALL compared with pre-B cells. Two missense SNPs, rs12722042 and 12722039, in the HLA-DQA1 gene yielded the highest effect sizes (odds ratio [OR] ∼ 14; P <0.01) for sex-specific results. The HLA-DQA1 SNPs belong to DQA1*01 and confirmed the previously reported male-specific association with DQA1*01. This finding supports the proposed infection-related etiology in childhood ALL risk for males. Further analyses revealed that most SNPs (either direct effect or through linkage disequilibrium) were within active enhancers or active promoter regions and had regulatory effects on gene expression levels.Cumulative data suggested that RASSF2 rs4813720, which correlates with increased RASSF2 expression, may counteract the suppressor effect of estrogen-regulated miR-17-92 on RASSF2 resulting in protection in males. Given the amount of sex hormone-related mechanisms suggested by our findings, future studies should examine prenatal or early postnatal programming by sex hormones when hormone levels show a large variation.

ARID5B, CEBPE and PIP4K2A Germline Genetic Polymorphisms and Risk of Childhood Acute Lymphoblastic Leukemia in Mexican Patients: A MIGICCL Study

Childhood acute lymphoblastic leukemia (ALL) is the leading cause of childhood cancer-related deaths worldwide. Multiples studies have shown that ALL seems to be originated by an interaction between environmental and genetic susceptibility factors. The ARID5B polymorphisms are among the most reproducible ALL associated-risk alleles in different populations. The aim of the present study was to examine the contribution of ARID5B, CEBPE, and PIP4K2 risk alleles for the development of ALL in children from Mexico City and Yucatan, Mexico. A study was conducted with a total of 761 unrelated subjects. Two hundred eighty five ALL cases (111 from Yucatan and 174 from Mexico City) and 476 healthy subjects. Genotyping included the rs7088318 (PIP4K2A), rs10821936 (ARID5B), rs7089424 (ARID5B) and rs2239633 (CEBPE) polymorphisms. Associations between ALL and rs10821936 and rs7089424 ARID5B SNPs were found (OR=1.9, 95% CI (1.5-2.4) and OR=2.0, 95% CI (1.6-2.5), respectively). Moreover, a higher risk was observed in the homozygous risk genotypes of carriers from Mexico City (OR=3.1, 95% CI (2.0-4.9) and OR 3.1, CI 95% (2.0-4.8), respectively). Otherwise, the rs7088318 (PIP4K2A) and rs2239633 (CEBPE) polymorphisms were not associated with ALL risk. Our analysis suggests that ARID5B confers risk for childhood ALL in a Mexican population.

Association between parental exposure to environmental risk factors and the risk of childhood acute lymphoblastic leukemia

Objective: To investigate the association between parental environmental risk factors exposure and the risk for childhood acute lymphoblastic leukemia (ALL). Methods: A total of 179 ALL children cases were selected in Tianjin Blood Disease Hospital and 136 healthy children matched by age, gender and living place were selected in 2015 for a case control study. The data were analyzed with univariate and multivariate non conditional logistic regression models. Results: The results of multivariate logistic regression analysis indicated that sex, history of abortion, exposure in a smoking environment during pregnancy, catching a cold, taking antipyretic analgesics, maternal exposure to air purifying agent, father' s occupational exposure to petroleum products and home decoration during pregnancy were associated with the risk of childhood ALL (P<0.05) and the results of multivariate logistic regression analysis indicated that sex, history of abortion, catching a cold, father's occupational exposure to petroleum products and home decoration during pregnancy were associated with the risk of childhood ALL (P<0.05). Conclusion: The five factors including sex, history of abortion, catching a cold, father' s occupational exposure to petroleum products and home decoration during pregnancy were risk factors for childhood ALL.

Pri-miR-34b/c rs4938723 polymorphism is associated with the risk of childhood acute lymphoblastic leukemia

MicroRNAs (miRNAs), small noncoding regulatory RNAs, are key regulators of gene expression. The impact of Pri-miR-34b/c rs4938723 variant on development of various cancers is still controversial. In the present study, we examined whether a rs4938723 variant located at the promoter region of Pri-miR-34b/c is associated with childhood ALL. A total of 110 children with acute lymphoblastic leukemia (ALL) and 120 healthy children were recruited to participate in this study. The rs4938723 variant was genotyped by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) method. The rs4938723 variant decreased the risk of ALL in heterozygous (TC vs OR = 0.48, 95% CI = 0.28-0.84, p = 0.012, TC vs TT) and overdominant (OR = 0.51, 95% CI = 0.30-0.89, p = 0.0.020, TC vs TT + CC): OR = 1.32, 95% CI = 0.67-2.59, p = 0.498; C vs T: OR = 0.99, 95% CI = 0.75-1.31, p = 0.986) inheritance models tested. The C allele significantly decreased the risk of childhood ALL compared to T allele (OR = 0.52, 95% CI = 0.33-0.83, p = 0.006). Our findings proposed an association between Pri-miR-34 b/c rs4938723 variant and risk of childhood ALL development in a sample of Iranian population.

Label-free quantitative proteomics reveals differentially expressed proteins in high risk childhood acute lymphoblastic leukemia

Acute lymphoblastic leukemia (ALL) is the most common pediatric cancer. B-ALL is the most common type in pediatric ALL. Risk stratification is critical for setting on chemo-therapeutic regimen that has great impact on the survival rate. But the risk allocation schemas at present were not satisfied. We performed a proteomic study expecting to figure out the critical altered proteins which can indicate the risk rank. We depicted 86 differently expressed proteins in the high-risk childhood B-ALL, and 35 proteins were predicted to have directive interactions. We validated five identified proteins by immunoblot using specimens same as proteomics, and others different from that. We found the differently expressed proteins participated in pre-mRNA spicing, DNA damage response, and stress response which indicated different events happened in the high risk B-ALL. Our result provided new information for children B-ALL. It might aid more accurate risk stratification and might also be valuable to find new therapeutic targets. Biological significanceTo our knowledge, this is the first proteomic analysis comparing the differentially expressed proteins between high risk and low risk of childhood B-ALL by a label-free quantitative proteomics. We found in high risk B-ALL, the aberrant evens happened in pre-mRNA splicing, DNA damage response, and stress response. This study reveals new insights in the high risk B-ALL, and might also be valuable to identify the high-risk more accurately, as well as to find new therapeutic targets.

Inherited genetic variants associated with childhood acute lymphoblastic leukemia risk.

Numerous efforts have been made to elucidate the roles of individual genetic background factors in the risk of childhood acute lymphoblastic leukemia. Most have taken the form of case-control studies focusing on specific candidate gene polymorphisms. Recently, a more rigorous and comprehensive approach referred to as a genome-wide association study (GWAS) has been widely utilized and has achieved success. Case-control studies evaluating candidate gene associations have shown cumulative evidence of a role for folate metabolism and xenobiotic metabolism/transport pathway genetic variants. In addition, single nucleotide polymorphism (SNP)s identified by GWAS appear to indicate a strong role for genes encoding transcription factors involved in cellular differentiation. Further studies are needed to clarify the accumulating evidence obtained from both candidate gene and genome-wide investigations.

Maternal prenatal intake of one-carbon metabolism nutrients and risk of childhood leukemia.

Folate, vitamins B12 and B6, riboflavin, and methionine are critical nutrients for the one-carbon metabolism cycle involved in DNA synthesis and epigenetic processes. We examined the association between maternal intake of these nutrients before pregnancy and risk of childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) in a matched case-control study. Maternal dietary intake and vitamin supplement use in the year before pregnancy was assessed by food frequency questionnaire for 681 ALL cases, 103 AML cases, and 1076 controls. Principal component analysis was used to construct a variable representing combined nutrient intake, and conditional logistic regression estimated the odds ratio (OR) and 95% confidence interval (CI) for the association of ALL and AML with the principal component and each nutrient. Higher maternal intake of one-carbon metabolism nutrients from food and supplements combined was associated with reduced risk of ALL (OR for one-unit change in the principal component=0.91, CI 0.84-0.99) and possibly AML (OR for the principal component=0.83, CI 0.66-1.04). When analyzed separately, intake of supplements high in these nutrients was associated with a reduced risk of ALL in children of Hispanic women only. In conclusion, these data suggest that higher maternal intake of one-carbon metabolism nutrients may reduce risk of childhood leukemia.

Identification of a novel susceptibility locus at 16q23.1 associated with childhood acute lymphoblastic leukemia in Han Chinese.

Recently, genome-wide association studies (GWAS) have identified several susceptibility loci for childhood acute lymphoblastic leukemia (ALL) in populations of European descent; only a few loci could be confirmed in Asian populations because of those populations' genetic heterogeneity. To identify genetic factors associated with childhood ALL risk in the Chinese population, we performed a three-stage GWAS of 1184 childhood ALL cases and 3219 non-ALL controls. The combined analysis identified a new locus (rs1121404 in WWOX) at 16q23.1 associated with childhood ALL susceptibility (odds ratio (OR) = 1.38, P = 5.29 × 10-10), especially in the subtype of B-ALL (OR = 1.39, P = 2.47 × 10-9). The functional studies subsequently revealed that the expression of WWOX in ALL bone marrow was significantly lower than that in normal bone marrow. The G allele of rs1121404 displayed significantly decreased levels of mRNA expression of WWOX These results suggest that WWOX plays an important role in the development of childhood ALL and provide new insights into the etiology of childhood ALL.

Caesarean delivery and risk of childhood leukaemia: a pooled analysis from the Childhood Leukemia International Consortium (CLIC)

Results from case-control studies have shown an increased risk of acute lymphoblastic leukaemia (ALL) in young children born by caesarean delivery, and prelabour caesarean delivery in particular; however, an association of method of delivery with childhood leukaemia subtypes has yet to be established. We therefore did a pooled analysis of data to investigate the association between childhood leukaemia and caesarean delivery. We pooled data from 13 case-control studies from the Childhood Leukemia International Consortium done in nine countries (Canada, Costa Rica, Egypt, France, Germany, Greece, Italy, New Zealand, and the USA) for births from 1970-2013. We analysed caesarean delivery overall and by indications that probably resulted in prelabour caesarean delivery or emergency caesarean delivery. We used multivariable logistic regression models, adjusted for child's birthweight, sex, age, ethnic origin, parental education, maternal age, and study, to estimate odds ratios (ORs) and 95% CIs for the risk of ALL and acute myeloid leukaemia (AML) in children aged 0-14 years at diagnosis. The studies provided data for 8780 ALL cases, 1332 AML cases, and 23 459 controls, of which the birth delivery method was known for 8655 (99%) ALL cases, 1292 (97%) AML cases, and 23 351 (>99%) controls. Indications for caesarean delivery were available in four studies (there were caesarean deliveries for 1061 of 4313 ALL cases, 138 of 664 AML cases, and 1401 of 5884 controls). The OR for all indications of caesarean delivery and ALL was 1·06 (95% CI 0·99-1·13), and was significant for prelabour caesarean delivery and ALL (1·23 [1·04-1·47]; p=0·018). Emergency caesarean delivery was not associated with ALL (OR 1·02 [95% CI 0·81-1·30]). AML was not associated with caesarean delivery (all indications OR 0·99 [95% CI 0·84-1·17]; prelabour caesarean delivery 0·83 [0·54-1·26]; and emergency caesarean delivery 1·05 [0·63-1·77]). Our results suggest an increased risk of childhood ALL after prelabour caesarean delivery. If this association is causal, maladaptive immune activation due to an absence of stress response before birth in children born by prelabour caesarean delivery could be considered as a potential mechanism. National Cancer Institute.

IKZF1 gene polymorphisms increased the risk of childhood acute lymphoblastic leukemia in an Iranian population.

Genome-wide association studies (GWAS) have proved the association of IKZF1 polymorphisms with childhood acute lymphoblastic leukemia (ALL). In the present study, we aimed to inspect the impact of IKZF1 gene polymorphisms and childhood ALL in a sample of Iranian population who live in south east of Iran. This case-control study was done on 110 children diagnosed with ALL and 120 healthy children. The IKZF1 (rs4132601 T > G, rs11978267 A > G, rs11980379 T > C, and rs10272724 T > C) polymorphisms were determined using polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP). The results showed that rs4132601 T > G polymorphism increased the risk of ALL in the codominant (OR = 2.96, 95% CI = 1.58-5.54, p = 0.0008, TG vs TT; and OR = 2.75, 95% CI = 1.31-5.76, p = 0.0094, GG vs TT) and dominant (OR = 2.89, 95% CI = 1.61-5.19, p = 0.0004, TG + GG vs TT) inheritance models. On the other hand, the rs4132601 G allele increased the risk of ALL (OR = 1.86, 95% CI = 1.28-2.96; p = 0.0011) in comparison with the T allele. We have also showed that rs11980379 T > C variant increased the risk of ALL in codominant (OR = 2.43, 95% CI = 1.28-4.60, p = 0.0076, TC vs TT; and OR = 2.35, 95% CI = 1.14-4.85, p = 0.0291, CC vs TT) and dominant (OR = 2.40, 95% CI = 1.32-4.36, p = 0.0038, TC + CC vs TT) inheritance models. The rs11980379 C allele increased the risk of ALL (OR = 1.59, 95% CI = 1.10-2.31, p = 0.0151) compared with T allele. Our study also revealed that the rs10272724 T > C polymorphism increased the risk of ALL in codominant (OR = 2.18, 95% CI = 1.19-3.99, p = 0.0115, TC vs TT; and OR = 2.67, 95% CI = 1.24-5.77, p = 0.0131, CC vs TT) and dominant (OR = 2.31, 95% CI = 1.30-4.08, p = 0.0049, TC + CC vs TT) inheritance models. On the one hand, the rs11980379 C allele increased the risk of ALL (OR = 1.70, 95% CI = 1.17-2.46, p = 0.0062) compared with T allele, while the rs11978267 A/G polymorphism was not associated with ALL risk. In conclusion, our findings confirm the impact of IKZF1 polymorphisms on childhood ALL risk in a sample of Iranian population. Further studies with larger sample sizes and different ethnicities are needed to confirm our findings.

Association of lnc-LAMC2-1:1 rs2147578 and CASC8 rs10505477 Polymorphisms with Risk of Childhood Acute Lymphoblastic Leukemia

Long non-coding RNAs (lncRNAs) are a novel class of non-protein coding RNAs that are involved in a wide variety of biological processes. There are limited data regarding the impact of lnc-LAMC2-1:1 rs2147578 as well as CASC8 rs10505477 T>C polymorphisms on cancer development. Here we examined for the first time whether rs2147578 and rs10505477 polymorphisms are associated with childhood acute lymphoblastic leukemia (ALL) in a total of 110 cases and 120 healthy controls. Genotyping was achieved by the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The rs2147578 variant increased the risk of ALL in codominant (OR=4.33, 95%CI=2.00-9.37, p<0.0001, CG vs CC, and OR=5.81, 95%CI=2.30-14.69, p=0.0002, GG vs CC), dominant (OR=4.63, 95%CI=2.18-9.86, p<0.0001, CG+GG vs CC), overdominant (OR=1.74, 95%CI=1.02-2.97, p=0.0444, CG vs CC+GG) and allele (OR=1.91, 95%CI=1.32-2.77, p=0.0008, G vs C) inheritance models tested. No significant association was found between the CASC8 rs10505477 T>C variant and risk of childhood ALL. In conclusion, the present study revealed that the lnc-LAMC2-1:1 rs2147578 polymorphism may be a risk factor for developing childhood ALL. Further studies with larger sample sizes with different ethnicities are now required to confirm our findings.

Genetic Susceptibility Loci for Childhood Acute Lymphoblastic Leukemia Among Japanese

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. DisclosuresNo relevant conflicts of interest to declare.

Germline Genetic Variation in ETV6 and Predisposition to Childhood Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is the most common cancer in children, and the etiology of this aggressive cancer is not fully understood. Common germline polymorphisms in lymphoid development genes and tumor suppressor genes have been associated with ALL susceptibility, although most have modest effects. Only a small fraction of ALL cases are thought to be related to congenital genetic disorders and consequently hereditary predisposition is rarely considered in clinical practice. However, a growing number of rare germline genetic mutations have been discovered in familial ALL (e.g., PAX5, TP53), raising the possibility that the proportion of ALL attributable to inherited predisposition may be higher than currently proposed. In particular, germline ETV6 variations were recently reported in families with hereditary thrombocytopenia and dramatically increased susceptibility to hematologic malignancies (Nat Genet 2015 47: 180 and 535). ETV6 is a transcriptional repressor essential for hematopoiesis and is frequently targeted by somatic genomic aberrations in childhood ALL (e.g., the ETV6-RUNX1 fusion). Therefore, we sought to comprehensively identify ALL predisposition variants in ETV6 and to determine the extent to which these variants contribute to childhood ALL risk in general.We first identified a family with three cases of childhood ALL at St. Jude Children's Research Hospital. Whole exome sequencing of this family (mother and 2 daughters with ALL, the unaffected father and 1 unaffected daughter) identified a single variant in ETV6 (p.R359X) in the 3 cases with ALL and also in the healthy daughter. This nonsense variant is predicted to create a stop codon within the ETS domain of ETV6, resulting in a truncated protein without DNA-binding function. This highly damaging variant is likely to be responsible for the ALL predisposition in this family with a high albeit incomplete penetrance. To comprehensively determine the prevalence of ALL-predisposing alleles in ETV6, we performed targeted sequencing of this gene in 4,405 children with newly-diagnosed ALL enrolled on the Children's Oncology Group (COG) AALL0232, P9904, P9905 and P9906 protocols and St. Jude Total Therapy XIIIA, XIIIB and XV studies. We identified a total of 43 germline variants in the exonic regions of ETV6. Thirty-one of the 43 ETV6 variants were defined as "ALL-related" because they were not found or extremely rare in non-ALL populations (N=60,706). These ALL risk variants included 4 nonsense, 21 missense, 1 splice site, and 5 frameshift variants occurring in 35 children (0.79% of ALL cases studied). Fifteen of the 31 ALL-relatedvariants (48.4%) were clustered in the ETS DNA-binding domain of ETV6. We used the combined annotation dependent depletion algorithm (CADD) to predict deleterious effects of each variant. ALL-related ETV6 variants were significantly more likely to be damaging compared to germline variants observed in the non-ALL population (mean CADD phred-like score of 25.6 vs 15.2, respectively, p<0.0001). Interestingly, of the 18 most deleterious ETV6 variants, 10 (55.6%) resided in the ETS domain although none were located within the helix directly interacting with target DNA. Instead, 7 of the 10 variants in ETS domain were between the first and second helices.We next analyzed the relationship between germline risk variants in ETV6 and clinical features of ALL in a subset of 2,021 cases enrolled on St. Jude and COG frontline ALL trials. These cases were comprehensively evaluted for ALL charateristics and representative of the US childhood ALL population. Children with ALL-related ETV6 variants were significantly older at the time of diagnosis than those without these variants (9.5 years vs 6.4 years; P=0.009). The hyperdiploid leukemia karyotype was strikingly overrepresented in ALL cases harboring germline ETV6 risk variants compared to the wildtype group (64.3% vs 26.8%; P=0.0045). In contrast, the frequency of somatic ETV6 -RUNX1 fusion was much lower in cases with ETV6 germline risk variants, compared to cases with wildtype ETV6 (7.1% vs 22.7%), even though this difference did not reach statistical significance. Of note, there was also a trend towards overrepresentation of females in carriers of ALL-related ETV6 variants (71.4% vs 45.7%; P=0.063).In conclusion, our findings indicate that germline ETV6 variations are important determinants for genetic predisposition to childhood ALL. DisclosuresMartin:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gentium SpA/Jazz Pharmaceuticals: Research Funding. Evans:Prometheus Labs: Patents & Royalties: Royalties from licensing TPMT genotyping. Hunger:Spectrum Pharmaceuticals: Consultancy; Jazz Pharmaceuticals: Consultancy; Merck: Equity Ownership; Sigma Tau: Consultancy.

A Heritable Missense Polymorphism in CDKN2A Confers Strong Risk of Childhood Acute Lymphoblastic Leukemia and Is Preferentially Selected during Clonal Evolution.

Genome-wide association studies (GWAS) have identified SNPs in six genes that are associated with childhood acute lymphoblastic leukemia (ALL). A lead SNP was found to occur on chromosome 9p21.3, a region that is deleted in 30% of childhood ALLs, suggesting the presence of causal polymorphisms linked to ALL risk. We used SNP genotyping and imputation-based fine-mapping of a multiethnic ALL case-control population (Ncases = 1,464, Ncontrols = 3,279) to identify variants of large effect within 9p21.3. We identified a CDKN2A missense variant (rs3731249) with 2% allele frequency in controls that confers three-fold increased risk of ALL in children of European ancestry (OR, 2.99; P = 1.51 × 10(-9)) and Hispanic children (OR, 2.77; P = 3.78 × 10(-4)). Moreover, of 17 patients whose tumors displayed allelic imbalance at CDKN2A, 14 preferentially retained the risk allele and lost the protective allele (PBinomial = 0.006), suggesting that the risk allele provides a selective advantage during tumor growth. Notably, the CDKN2A variant was not significantly associated with melanoma, glioblastoma, or pancreatic cancer risk, implying that this polymorphism specifically confers ALL risk but not general cancer risk. Taken together, our findings demonstrate that coding polymorphisms of large effect can underlie GWAS "hits" and that inherited polymorphisms may undergo directional selection during clonal expansion of tumors.

Socio-Economic Status and Childhood Leukemia in California

Objective: To investigate the association between individual- and community-level socio-economic status (SES) and childhood leukemia, particularly its subtypes: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Study design: We conducted a large case-control registry-based study in California. Methods: Information on 5788 cases and 5788 controls was obtained by linking California cancer and birth registries. We evaluated relative risk of childhood leukemia by community- (census-based) and individual-level SES measures (parental education and source of payment for delivery) using conditional logistic regression. Results: Children in higher census-based SES categories had a tendency toward slightly decreased risk of total childhood leukemia and ALL compared to children of the lowest SES. Compared to < 12 years of school, 13 and more years of parental education were associated with slightly decreased risk of total childhood leukemia, ALL and AML; however, confidence intervals were imprecise. Source of payment for delivery was not associated with either childhood leukemia nor with its subtypes. Conclusion: We found little evidence to support the suggestion that SES is associated with risk of childhood leukemia or either major subtype. It is likely that results of many previous studies that found an association between childhood leukemia and SES were influenced by selection or ecological bias.

Risk for childhood leukemia associated with maternal and paternal age.

The role of reproductive factors, such as parental age, in the pathogenesis of childhood leukemias is being intensively examined; the results of individual studies are controversial. This meta-analysis aims to quantitatively synthesize the published data on the association between parental age and risk of two major distinct childhood leukemia types in the offspring. Eligible studies were identified and pooled relative risk (RR) estimates were calculated using random-effects models, separately for childhood acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Subgroup analyses were performed by study design, geographical region, adjustment factors; sensitivity analyses and meta-regression analyses were also undertaken. 77 studies (69 case-control and eight cohort) were deemed eligible. Older maternal and paternal age were associated with increased risk for childhood ALL (pooled RR = 1.05, 95 % CI 1.01-1.10; pooled RR = 1.04, 95 % CI 1.00-1.08, per 5 year increments, respectively). The association between maternal age and risk of childhood AML showed a U-shaped pattern, with symmetrically associated increased risk in the oldest (pooled RR = 1.23, 95 % CI 1.06-1.43) and the youngest (pooled RR = 1.23, 95 % CI 1.07-1.40) extremes. Lastly, only younger fathers were at increased risk of having a child with AML (pooled RR = 1.28, 95 % CI 1.04-1.59). In conclusion, maternal and paternal age represents a meaningful risk factor for childhood leukemia, albeit of different effect size by leukemia subtype. Genetic and socio-economic factors may underlie the observed associations. Well-adjusted studies, scheduled by large consortia, are anticipated to satisfactorily address methodological issues, whereas the potential underlying genetic mechanisms should be elucidated by basic research studies.