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

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

Association of genetic variation in IKZF1, ARID5B, and CEBPE and surrogates for early-life infections with the risk of acute lymphoblastic leukemia in Hispanic children.

BACKGROUND: Genome-wide association studies focusing on European-ancestry populations have identified ALL risk loci on IKZF1, ARID5B, and CEBPE. To capture the impacts of these genes on ALL risk in the California Hispanic population, we comprehensively assessed the variation within the genes and further assessed the joint effects between the genetic variation and surrogates for early-life infections (the presence of older siblings, daycare attendance, and ear infections). METHODS: Genotypic data for 323 Hispanic ALL cases and 454 controls from the California Childhood Leukemia Study were generated using Illumina OmniExpress v1 platform. Logistic regression assuming a log-additive model estimated odds ratios (OR) associated with each SNP, adjusted for age, sex, and the first five principal components. In addition, we examined potential interactions between six ALL risk alleles and surrogates for early-life infections using logistic regression models that included an interaction term. RESULTS: Significant associations between genotypes at IKZF1, ARID5B, and CEBPE and ALL risk were identified: rs7780012, OR 0.50, 95% confidence interval (CI) 0.35-0.71 (p = 0.004); rs7089424, OR 2.12, 95% CI 1.70-2.65 (p = 1.16 × 10(-9)); rs4982731, OR 1.69, 95% CI 1.37-2.08 (p = 2.35 × 10(-6)), respectively. Evidence for multiplicative interactions between genetic variants and surrogates for early-life infections with ALL risk was not observed. CONCLUSIONS: Consistent with findings in non-Hispanic White population, our study showed that variants within IKZF1, ARID5B, and CEBPE were associated with increased ALL risk, and the effects for ARID5B and CEBPE were most prominent in the high-hyperdiploid ALL subtype in the California Hispanic population. Results implicate the ARID5B, CEBPE, and IKZF1 genes in the pathogenesis of childhood ALL.

A road map for efficient and reliable human genome epidemiology.

Networks of investigators have begun sharing best practices, tools and methods for analysis of associations between genetic variation and common diseases. A Network of Investigator Networks has been set up to drive the process, sponsored by the Human Genome Epidemiology Network. A workshop is planned to develop consensus guidelines for reporting results of genetic association studies. Published literature databases will be integrated, and unpublished data, including 'negative' studies, will be captured by online journals and through investigator networks. Systematic reviews will be expanded to include more meta-analyses of individual-level data and prospective meta-analyses. Field synopses will offer regularly updated overviews.

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

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.

Persistent organic pollutants in dust from older homes: learning from lead.

OBJECTIVES: We aimed to (1) evaluate the relation between home age and concentrations of multiple chemical contaminants in settled dust and (2) discuss the feasibility of using lead hazard controls to reduce children's exposure to persistent organic pollutants. METHODS: As part of the California Childhood Leukemia Study, from 2001 to 2007, we used a high-volume small surface sampler and household vacuum cleaners to collect dust samples from 583 homes and analyzed the samples for 94 chemicals with gas chromatography-mass spectrometry and inductively coupled plasma mass spectrometry. We evaluated relations between chemical concentrations in dust and home age with Spearman rank correlation coefficients. RESULTS: Dust concentrations of lead, polychlorinated biphenyls, organochlorine insecticides, and polycyclic aromatic hydrocarbons were correlated with home age (ρ > 0.2; P < .001), whereas concentrations of pyrethroid insecticides and polybrominated diphenyl ethers were not. CONCLUSIONS: Dust in older homes contains higher levels of multiple, persistent chemicals than does dust in newer homes. Further development of strategies to reduce chemical exposures for children living in older homes is warranted.

Genomic ancestry and somatic alterations correlate with age at diagnosis in Hispanic children with B-cell acute lymphoblastic leukemia.

Hispanic children have a higher incidence of acute lymphoblastic leukemia (ALL) than non-Hispanic whites but tend to be diagnosed at older ages. In genome-wide association studies, Native American ancestry and polymorphisms in six genes have been associated with ALL risk. In multivariable regression models, we investigated whether genomic ancestry, inherited risk SNPs, or acquired somatic alterations were associated with differences in age at diagnosis in Hispanic children with B-cell ALL. Genome-wide array data were used to estimate each participant's percent membership in the three Hispanic ancestral populations: Native American, African, and European. Each 20% increase in European ancestry was associated with a six month younger age at diagnosis (95% CI = 0.36-11.6 months, P = 0.037). Correspondingly, each 20% increase in Native American ancestry was associated with a six-month older age at diagnosis (P = 0.037). Both the TEL-AML1 translocation and high-hyperdiploidy were associated with younger age at diagnosis (24.4 months, P = 2.0 x 10(-4) and 12.4 months, P = 0.011, respectively), while CDKN2A and IKZF1 deletions were associated with older age at diagnosis (19.7 months, P = 7.0 x 10(-4) and 18.1 months, P = 0.012, respectively). No associations with age at diagnosis were observed for RAS mutation, PAX5 deletion or for known heritable risk alleles in IKZF1, CDKN2A, PIP4K2A, GATA3, ARID5B, or CEBPE. Because younger age at diagnosis is associated with improved treatment outcomes for children with ALL, the effect of European ancestry on ALL survival may be mediated by its effect on age at diagnosis, or by proxy, its association with more treatable molecular subtypes of ALL.

Polychlorinated biphenyls in residential dust: sources of variability.

We characterized the variability in concentrations of polychlorinated biphenyls (PCBs) measured in residential dust. Vacuum cleaner samples were collected from 289 homes in the California Childhood Leukemia Study during two sampling rounds from 2001 to 2010 and 15 PCBs were measured by high resolution gas chromatography-mass spectrometry. Median concentrations of the most abundant PCBs (i.e., PCBs 28, 52, 101, 105, 118, 138, 153, and 180) ranged from 1.0-5.8 ng per g of dust in the first sampling round and from 0.8-3.4 ng/g in the second sampling round. For each of these eight PCBs, we used a random-effects model to apportion total variation into regional variability (6-11%), intraregional between-home variability (27-56%), within-home variability over time (18-52%), and within-sample variability (9-16%). In mixed-effects models, differences in PCB concentrations between homes were explained by home age, with older homes having higher PCB levels. Differences in PCB concentrations within homes were explained by decreasing time trends. Estimated half-lives ranged from 5-18 years, indicating that PCBs are removed very slowly from the indoor environment. Our findings suggest that it may be feasible to use residential dust for retrospective assessment of PCB exposures in studies of children's health.

Highly-cited estimates of the cumulative incidence and recurrence of vulvovaginal candidiasis are inadequately documented.

BACKGROUND: Available literature concerning the epidemiologic or clinical features of vulvovaginal candidiasis commonly reports that: 75% of women will experience an episode of vulvovaginal candidiasis in their lifetimes, 50% of whom will experience at least a second episode, and 5-10% of all women will experience recurrent vulvovaginal candidiasis (≥4 episodes/1 year). In this debate we traced the three commonly cited statistics to their presumed origins. DISCUSSION: It is apparent that these figures were inadequately documented and lacked supporting epidemiologic evidence. Population-based studies are needed to make reliable estimates of the lifetime risk of vulvovaginal candidiasis and the proportion of women who experience recurrent candidiasis. SUMMARY: The extent to which vulvovaginal candidiasis is a source of population-level morbidity remains uncertain.

Fetal growth and childhood acute lymphoblastic leukemia: findings from the childhood leukemia international consortium.

Positive associations have been reported between the measures of accelerated fetal growth and risk of childhood acute lymphoblastic leukemia (ALL). We investigated this association by pooling individual-level data from 12 case-control studies participating in the Childhood Leukemia International Consortium. Two measures of fetal growth-weight-for-gestational-age and proportion of optimal birth weight (POBW)-were analysed. Study-specific odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using multivariable logistic regression, and combined in fixed effects meta-analyses. Pooled analyses of all data were also undertaken using multivariable logistic regression. Subgroup analyses were undertaken when possible. Data on weight for gestational age were available for 7,348 cases and 12,489 controls from all 12 studies and POBW data were available for 1,680 cases and 3,139 controls from three studies. The summary ORs from the meta-analyses were 1.24 (95% CI: 1.13, 1.36) for children who were large for gestational age relative to appropriate for gestational age, and 1.16 (95% CI: 1.09, 1.24) for a one-standard deviation increase in POBW. The pooled analyses produced similar results. The summary and pooled ORs for small-for-gestational-age children were 0.83 (95% CI: 0.75, 0.92) and 0.86 (95% CI: 0.77, 0.95), respectively. Results were consistent across subgroups defined by sex, ethnicity and immunophenotype, and when the analysis was restricted to children who did not have high birth weight. The evidence that accelerated fetal growth is associated with a modest increased risk of childhood ALL is strong and consistent with known biological mechanisms involving insulin-like growth factors. © 2013 UICC.

Current perspective on the global and United States cancer burden attributable to lifestyle and environmental risk factors.

Our objective is to provide a current perspective on the avoidable causes of global and US cancer incidence and mortality. Cancer registry-based incidence patterns, population behavioral risk-factor survey data, and systematic reviews of epidemiologic studies are the basis for estimates of relative risk, the prevalence of exposures to various lifestyle and environmental risk factors, and their impact expressed as population attributable fractions (PAFs). Of the total 59 million global deaths in 2008, 12-13% were attributed to cancer. The increasing burden of cancers in low- and middle-income countries (LMICs) is attributable in part to increasing urbanization, expansion of the adult population at risk, and increasing or persistent exposures to infectious agents, tobacco, and dietary deficiencies. Attributable fractions for lifestyle and environmental risk factors are summarized for the United States, the United Kingdom, and France. Assuming minimal overlap in the distribution of risk factors in the population and discounting the potential for interaction in their combined effects, we estimate that a maximum of 60% of cancer deaths in the United States may be attributed to eight risk factors: tobacco, alcohol, ionizing and solar radiations, occupations, infectious agents, obesity, and physical inactivity.

Genetic variants in ARID5B and CEBPE are childhood ALL susceptibility loci in Hispanics.

Recent genome-wide studies conducted in European Whites have identified novel susceptibility genes for childhood acute lymphoblastic leukemia (ALL). We sought to examine whether these loci are susceptibility genes among Hispanics, whose reported incidence of childhood ALL is the highest of all ethnic groups in California, and whether their effects differ between Hispanics and non-Hispanic Whites (NHWs). We genotyped 13 variants in these genes among 706 Hispanic (300 cases, 406 controls) and 594 NHW (225 cases, 369 controls) participants in a matched population-based case-control study in California. We found significant associations for the five studied ARID5B variants in both Hispanics (p values of 1.0 × 10(-9) to 0.004) and NHWs (p values of 2.2 × 10(-6) to 0.018). Risk estimates were in the same direction in both groups (ORs of 1.53-1.99 and 1.37-1.84, respectively) and strengthened when restricted to B-cell precursor high-hyperdiploid ALL (>50 chromosomes; ORs of 2.21-3.22 and 1.67-2.71, respectively). Similar results were observed for the single CEBPE variant. Hispanics and NHWs exhibited different susceptibility loci at CDKN2A. Although IKZF1 loci showed significant susceptibility effects among NHWs (p < 1 × 10(-5)), their effects among Hispanics were in the same direction but nonsignificant, despite similar minor allele frequencies. Future studies should examine whether the observed effects vary by environmental, immunological, or lifestyle factors.

Socioeconomic status and lung cancer: unraveling the contribution of genetic admixture.

OBJECTIVES: We examined the relationship between genetic ancestry, socioeconomic status (SES), and lung cancer among African Americans and Latinos. METHODS: We evaluated SES and genetic ancestry in a Northern California lung cancer case-control study (1998-2003) of African Americans and Latinos. Lung cancer case and control participants were frequency matched on age, gender, and race/ethnicity. We assessed case-control differences in individual admixture proportions using the 2-sample t test and analysis of covariance. Logistic regression models examined associations among genetic ancestry, socioeconomic characteristics, and lung cancer. RESULTS: Decreased Amerindian ancestry was associated with higher education among Latino control participants and greater African ancestry was associated with decreased education among African lung cancer case participants. Education was associated with lung cancer among both Latinos and African Americans, independent of smoking, ancestry, age, and gender. Genetic ancestry was not associated with lung cancer among African Americans. CONCLUSIONS: Findings suggest that socioeconomic factors may have a greater impact than genetic ancestry on lung cancer among African Americans. The genetic heterogeneity and recent dynamic migration and acculturation of Latinos complicate recruitment; thus, epidemiological analyses and findings should be interpreted cautiously.

Levels of nicotine in dust from homes of smokeless tobacco users.

BACKGROUND: Smokeless tobacco products, such as chewing tobacco or moist snuff, contain many of the same constituents as tobacco smoke and are also known to cause cancer; however, little attention has been paid to indirect exposure of children to tobacco constituents via parental smokeless tobacco use. METHODS: As part of the California Childhood Leukemia Study, we collected dust samples from 6 residences occupied by smokeless tobacco users, 6 residences occupied by active smokers, and 20 tobacco-free residences. Children's potential for exposure to tobacco constituents was assessed using nicotine concentrations in vacuum dust measured by gas chromatography-mass spectrometry. RESULTS: Median nicotine concentrations for residences with smokeless tobacco users were significantly greater than median nicotine concentrations for tobacco-free homes and similar to median nicotine concentrations in homes of active smokers. Using generalized estimating equations derived from a multivariable marginal model to adjust for a history of parental smoking, income, residence construction date, and mother's age and race/ethnicity, we found nicotine levels from homes of smokeless tobacco users to be 21-fold higher than nicotine levels from tobacco-free homes. Based on mass balance equations, we hypothesize that nicotine is transferred to floors in homes of smokeless tobacco users primarily as a constituent of tobacco that is spilled or expectorated. CONCLUSIONS: Based on our findings, we conclude that children living with smokeless tobacco users may be exposed to nicotine and other constituents of tobacco via contact with contaminated dust and household surfaces.

Fetal growth and body size genes and risk of childhood acute lymphoblastic leukemia.

Accumulating evidence suggests that childhood acute lymphoblastic leukemia (ALL) may be initiated in utero or early in the postnatal period. High birth weight (or rapid fetal growth) is associated with risk of ALL, but the mechanisms are not understood. In a population-based epidemiologic study of childhood ALL, we utilized a haplotype-based approach to assess the role of eight genes involved in fetal growth and body size regulation in 377 childhood ALL cases and 448 controls. We found significant haplotype associations with risk of childhood ALL for IGF1 among non-Hispanics and Hispanics together (p = 0.002), for IGF2 among Hispanics (p = 0.040), and for IGF2R among Hispanics and non-Hispanics (p = 0.051 and 0.009, respectively). No haplotype associations were observed for IGF1R or the studied genes involved in body size regulation, including LEP, LEPR, GHRL, and NPY. Our study is the first to identify an association between the genes involved in the IGF axis and risk of childhood ALL. These findings for childhood ALL emphasize the importance of fetal growth, when lymphoid progenitor cells are not yet fully differentiated and therefore more susceptible to malignant transformation. Additional studies are needed to confirm these findings and identify specific causal variants.

Variation in xenobiotic transport and metabolism genes, household chemical exposures, and risk of childhood acute lymphoblastic leukemia.

BACKGROUND: Recent studies suggest that environmental exposures to pesticides, tobacco, and other xenobiotic chemicals may increase risk of childhood acute lymphoblastic leukemia (ALL). We sought to evaluate the role of genes involved in xenobiotic transport and metabolism in childhood ALL risk, both alone and in conjunction with household chemical exposures previously found to be associated with childhood ALL risk. METHODS: We conducted a population-based epidemiologic study of 377 cases and 448 controls in California, utilizing a haplotype-based approach to evaluate 42 xenobiotic transport and metabolism genes in conjunction with data on self-reported household chemical exposures. RESULTS: We identified significant associations of childhood ALL risk with haplotypes of ABCB1, ARNT, CYP2C8, CYP1A2, CYP1B1, and IDH1. In addition, certain haplotypes showed significant joint effects with self-reported household chemical exposures on risk of childhood ALL. Specifically, elevated risks associated with use of paints in the home (ever) and indoor insecticides (pre-birth) were limited to subjects carrying specific haplotypes of CYP2C8 and ABCB1, respectively. CONCLUSIONS: Our results provide support for a role of xenobiotic transport and metabolism pathways in risk of childhood ALL and indicate that genes in these pathways may modulate the risk of disease associated with use of common household chemicals. Additional studies are needed to confirm these findings and localize specific causal variants.

Early life exposure to infections and risk of childhood acute lymphoblastic leukemia.

Evidence from a growing number of studies indicates that exposure to common infections early in life may be protective against childhood acute lymphoblastic leukemia (ALL). We examined the relationship between three measures of early life exposure to infections-daycare attendance, birth order and common childhood infections in infancy-with the risk of ALL in non-Hispanic white and Hispanic children, two ethnicities that show sociodemographic differences. The analysis included 669 ALL cases (284 non-Hispanic whites and 385 Hispanics) and 977 controls (458 non-Hispanic whites and 519 Hispanics) ages 1-14 years enrolled in the Northern California Childhood Leukemia Study (NCCLS). When the three measures were evaluated separately, daycare attendance by the age of 6 months (odds ratio [OR] for each thousand child-hours of exposure = 0.90, 95% confidence interval [CI]: 0.82-1.00) and birth order (OR for having an older sibling = 0.68, 95% CI: 0.50-0.92) were associated with a reduced risk of ALL among non-Hispanic white children but not Hispanic children, whereas ear infection before age 6 months was protective in both ethnic groups. When the three measures were assessed simultaneously, the influence of daycare attendance (OR = 0.83, 95% CI: 0.73-0.94) and having an older sibling (OR = 0.59, 95% CI: 0.43-0.83) became stronger for non-Hispanic white children. In Hispanic children, a strong reduction in risk associated with ear infections persisted (OR = 0.45, 95% CI: 0.25-0.79). Evidence of a protective role for infection-related exposures early in life is supported by findings in both the non-Hispanic white and Hispanic populations within the NCCLS.

Is diabetes mellitus an independent risk factor for colon cancer and rectal cancer?

OBJECTIVES: Diabetes mellitus (DM) has been associated with an increased risk of colorectal cancer (CRC). The American College of Gastroenterology Guidelines for Colorectal Cancer Screening 2008 recommend that clinicians be aware of an increased CRC risk in patients with smoking and obesity, but do not highlight the increase in CRC risk in patients with DM. To provide an updated quantitative assessment of the association of DM with colon cancer (CC) and rectal cancer (RC), we conducted a meta-analysis of case-control and cohort studies. We also evaluated whether the association varied by sex, and assessed potential confounders including obesity, smoking, and exercise. METHODS: We identified studies by searching the EMBASE and MEDLINE databases (from inception through 31 December 2009) and by searching bibliographies of relevant articles. Summary relative risks (RRs) with 95% confidence intervals (CIs) were calculated with fixed- and random-effects models. Several subgroup analyses were performed to explore potential study heterogeneity and bias. RESULTS: DM was associated with an increased risk of CC (summary RR 1.38, 95% CI 1.26-1.51; n=14 studies) and RC (summary RR 1.20, 95% CI 1.09-1.31; n=12 studies). The association remained when we limited the meta-analysis to studies that either controlled for smoking and obesity, or for smoking, obesity, and physical exercise. DM was associated with an increased risk of CC for both men (summary RR 1.43, 95% CI 1.30-1.57; n=11 studies) and women (summary RR 1.35, 95% CI 1.14-1.53; n=10 studies). For RC, there was a significant association between DM and cancer risk for men (summary RR 1.22, 95% CI 1.07-1.40; n=8 studies), but not for women (summary RR 1.09, 95% CI=0.99-1.19; n=8 studies). CONCLUSIONS: These data suggest that DM is an independent risk factor for colon and rectal cancer. Although these findings are based on observational epidemiological studies that have inherent limitations due to diagnostic bias and confounding, subgroup analyses confirmed the consistency of our findings across study type and population. This information can inform risk models and specialty society CRC screening guidelines.

Genetic variants in the folate pathway and risk of childhood acute lymphoblastic leukemia.

OBJECTIVE: Folate is involved in the one-carbon metabolism that plays an essential role in the synthesis, repair, and methylation of DNA. We examined whether child's germline genetic variation in the folate pathway is associated with childhood acute lymphoblastic leukemia (ALL), and whether periconception maternal folate and alcohol intake modify the risk. METHODS: Seventy-six single nucleotide polymorphisms (SNPs), including 66 haplotype-tagging SNPs in 10 genes (CBS, DHFR, FOLH1, MTHFD1, MTHFR, MTR, MTRR, SHMT1, SLC19A1, and TYMS), were genotyped in 377 ALL cases and 448 controls. Log-additive associations between genotypes and ALL risk were adjusted for age, sex, Hispanic ethnicity (when appropriate), and maternal race. RESULTS: Single and haplotype SNPs analyses showed statistically significant associations between SNPs located in (or adjacent to) CBS, MTRR, TYMS/ENOFS, and childhood ALL. Many regions of CBS were associated with childhood ALL in Hispanics and non-Hispanics (p < 0.01). Levels of maternal folate intake modified associations with SNPs in CBS, MTRR, and TYMS. CONCLUSION: Our data suggest the importance of genetic variability in the folate pathway and childhood ALL risk.

Haplotypes of DNA repair and cell cycle control genes, X-ray exposure, and risk of childhood acute lymphoblastic leukemia.

BACKGROUND: Acute leukemias of childhood are a heterogeneous group of malignancies characterized by cytogenetic abnormalities, such as translocations and changes in ploidy. These abnormalities may be influenced by altered DNA repair and cell cycle control processes. METHODS: We examined the association between childhood acute lymphoblastic leukemia (ALL) and 32 genes in DNA repair and cell cycle pathways using a haplotype-based approach, among 377 childhood ALL cases and 448 controls enrolled during 1995-2002. RESULTS: We found that haplotypes in APEX1, BRCA2, ERCC2, and RAD51 were significantly associated with total ALL, while haplotypes in NBN and XRCC4, and CDKN2A were associated with structural and numerical change subtypes, respectively. In addition, we observed statistically significant interaction between exposure to 3 or more diagnostic X-rays and haplotypes of XRCC4 on risk of structural abnormality-positive childhood ALL. CONCLUSIONS: These results support a role of altered DNA repair and cell cycle processes in the risk of childhood ALL, and show that this genetic susceptibility can differ by cytogenetic subtype and may be modified by exposure to ionizing radiation. To our knowledge, our study is the first to broadly examine the DNA repair and cell cycle pathways using a haplotype approach in conjunction with X-ray exposures in childhood ALL risk. If confirmed, future studies are needed to identify specific functional SNPs in the regions of interest identified in this analysis.