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.

Residential levels of polybrominated diphenyl ethers and risk of childhood acute lymphoblastic leukemia in California.

BACKGROUND: House dust is a major source of exposure to polybrominated diphenyl ethers (PBDEs), which are found at high levels in U.S. homes. METHODS: We studied 167 acute lymphoblastic leukemia (ALL) cases 0-7 years of age and 214 birth certificate controls matched on date of birth, sex, and race/ethnicity from the Northern California Childhood Leukemia Study. In 2001-2007, we sampled carpets in the room where the child spent the most time while awake; we used a high-volume small-surface sampler or we took dust from the home vacuum. We measured concentrations of 14 PBDE congeners including penta (28, 47, 99, 100, 153, 154), octa (183, 196, 197, 203), and decaBDEs (206-209). Odds ratios (ORs) were calculated using logistic regression, adjusting for demographics, income, year of dust collection, and sampling method. RESULTS: BDE-47, BDE-99, and BDE-209 were found at the highest concentrations (medians, 1,173, 1,579, and 938 ng/g, respectively). Comparing the highest to lowest quartile, we found no association with ALL for summed pentaBDEs (OR = 0.7; 95% CI: 0.4, 1.3), octaBDEs (OR = 1.3; 95% CI: 0.7, 2.3), or decaBDEs (OR = 1.0; 95% CI: 0.6, 1.8). Comparing homes in the highest concentration (nanograms per gram) tertile to those with no detections, we observed significantly increased ALL risk for BDE-196 (OR = 2.1; 95% CI: 1.1, 3.8), BDE-203 (OR = 2.0; 95% CI: 1.1, 3.6), BDE-206 (OR = 2.1; 95% CI: 1.1, 3.9), and BDE-207 (OR = 2.0; 95% CI: 1.03, 3.8). CONCLUSION: We found no association with ALL for common PBDEs, but we observed positive associations for specific octa and nonaBDEs. Additional studies with repeated sampling and biological measures would be informative.

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.

Potential role of selection bias in the association between childhood leukemia and residential magnetic fields exposure: a population-based assessment.

PURPOSE: Data from the Northern California Childhood Leukemia Study (NCCLS) were used to assess whether selection bias may explain the association between residential magnetic fields (assessed by wire codes) and childhood leukemia as previously observed in case-control studies. METHODS: Wiring codes were calculated for participating cases, n=310; and non-participating cases, n=66; as well as for three control groups: first-choice participating, n=174; first-choice non-participating, n=252; and replacement (non-first choice participating controls), n=220. RESULTS: Participating controls tended to be of higher socioeconomic status than non-participating controls, and lower socioeconomic status was related to higher wire-codes. The odds ratio (OR) for developing childhood leukemia associated with high wire-codes was 1.18 (95% CI: 0.85, 1.64) when all cases were compared to all first-choice controls (participating and non-participating). The OR for developing childhood leukemia in the high current category was 1.43 (95% CI: 0.91, 2.26) when participating cases were compared to first-choice participating controls, but no associations were observed when participating cases were compared to non-participating controls (OR=1.06, 95% CI: 0.71, 1.57) or to replacement controls (OR=1.06, 95% CI: 0.71, 1.60). CONCLUSIONS: The observed risk estimates vary by type of control group, and no statistically significant association between wire codes and childhood leukemia is observed in the California population participating in the NCCLS.

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.

Mode of delivery and risk of childhood leukemia.

BACKGROUND: Childhood infection and immune response have long been suspected in the etiology of childhood leukemia, specifically acute lymphoblastic leukemia (ALL). Normal primary inoculation of the core human microbiome is circumvented by cesarean section (CS) delivery, which is a proposed modulator of both immune response and early-life infection. METHODS: In this study, we examined CS delivery and the risk of childhood leukemia using data from the California Childhood Leukemia Study (CCLS) case-control study and additive logistic regression models. RESULTS: We observed no association between CS and acute myelogenous leukemia [OR, 0.96; 95% confidence interval (CI), 0.52-1.55]. We observed a suggestive association for ALL and CS (OR, 1.22; 95% CI, 0.97-1.54). When examining common ALL (cALL), defined as ALL with expression of CD10 and CD19 surface antigens and diagnosis occurring between 2 and 5.9 years of age, we found a significant association with CS (OR, 1.44; 95% CI, 1.0-2.06). ALL subjects that are not cALL showed a similar risk as ALL overall (OR, 1.15; 95% CI, 0.91-1.44). Because of previous findings suggesting effect modification, we stratified cALL subjects by Hispanic status. Although we observed no relationship for CS in non-Hispanics (OR, 1.14; 95% CI, 0.72-1.79), we did observe a strong association between cALL and CS in Hispanics (OR, 2.34; 95% CI, 1.23-4.46). CONCLUSION: Within the CCLS, CS delivery seems to be associated with cALL and Hispanic subjects may be driving the association. IMPACT: Further research combined with investigations into response to early infection and the microbiome is warranted.

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.

Making prospective registration of observational research a reality.

The vast majority of health-related observational studies are not prospectively registered and the advantages of registration have not been fully appreciated. Nonetheless, international standards require approval of study protocols by an independent ethics committee before the study can begin. We suggest that there is an ethical and scientific imperative to publicly preregister key information from newly approved protocols, which should be required by funders. Ultimately, more complete information may be publicly available by disclosing protocols, analysis plans, data sets, and raw data.

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.

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.

SNP association mapping across the extended major histocompatibility complex and risk of B-cell precursor acute lymphoblastic leukemia in children.

The extended major histocompatibility complex (xMHC) is the most gene-dense region of the genome and harbors a disproportionately large number of genes involved in immune function. The postulated role of infection in the causation of childhood B-cell precursor acute lymphoblastic leukemia (BCP-ALL) suggests that the xMHC may make an important contribution to the risk of this disease. We conducted association mapping across an approximately 4 megabase region of the xMHC using a validated panel of single nucleotide polymorphisms (SNPs) in childhood BCP-ALL cases (n=567) enrolled in the Northern California Childhood Leukemia Study (NCCLS) compared with population controls (n=892). Logistic regression analyses of 1,145 SNPs, adjusted for age, sex, and Hispanic ethnicity indicated potential associations between several SNPs and childhood BCP-ALL. After accounting for multiple comparisons, one of these included a statistically significant increased risk associated with rs9296068 (OR=1.40, 95% CI=1.19-1.66, corrected p=0.036), located in proximity to HLA-DOA. Sliding window haplotype analysis identified an additional locus located in the extended class I region in proximity to TRIM27 tagged by a haplotype comprising rs1237485, rs3118361, and rs2032502 (corrected global p=0.046). Our findings suggest that susceptibility to childhood BCP-ALL is influenced by genetic variation within the xMHC and indicate at least two important regions for future evaluation.

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.

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.

Tobacco smoke exposure and the risk of childhood acute lymphoblastic and myeloid leukemias by cytogenetic subtype.

BACKGROUND: Tobacco smoke contains carcinogens known to damage somatic and germ cells. We investigated the effect of tobacco smoke on the risk of childhood acute lymphoblastic leukemia (ALL) and myeloid leukemia (AML), especially subtypes of prenatal origin such as ALL with translocation t(12;21) or high-hyperdiploidy (51-67 chromosomes). METHODS: We collected information on exposures to tobacco smoking before conception, during pregnancy, and after birth in 767 ALL cases, 135 AML cases, and 1,139 controls (1996-2008). Among cases, chromosome translocations, deletions, or aneuploidy were identified by conventional karyotype and fluorescence in situ hybridization. RESULTS: Multivariable regression analyses for ALL and AML overall showed no definite evidence of associations with self-reported (yes/no) parental prenatal active smoking and child's passive smoking. However, children with history of paternal prenatal smoking combined with postnatal passive smoking had a 1.5-fold increased risk of ALL [95% confidence interval (CI), 1.01-2.23], compared to those without smoking history (ORs for pre- or postnatal smoking only were close to one). This joint effect was seen for B-cell precursor ALL with t(12;21) (OR = 2.08; 95% CI, 1.04-4.16), but not high hyperdiploid B-cell ALL. Similarly, child's passive smoking was associated with an elevated risk of AML with chromosome structural changes (OR = 2.76; 95% CI, 1.01-7.58), but not aneuploidy. CONCLUSIONS: Our data suggest that exposure to tobacco smoking was associated with increased risks of childhood ALL and AML; and risks varied by timing of exposure (before and/or after birth) and cytogenetic subtype, based on imprecise estimates. IMPACT: Parents should limit exposures to tobacco smoke before and after the child's birth.

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 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.

Polybrominated diphenyl ethers in residential dust: sources of variability.

We characterized the sources of variability for polybrominated diphenyl ethers (PBDEs) in residential dust and provided guidance for investigators who plan to use residential dust to assess exposure to PBDEs. We collected repeat dust samples from 292 households in the Northern California Childhood Leukemia Study during two sampling rounds (from 2001 to 2007 and during 2010) using household vacuum cleaners and measured 22 PBDEs using high resolution gas chromatography-high resolution mass spectrometry. Median concentrations for individual PBDEs ranged from <0.1-2500ng per g of dust. For each of eight representative PBDEs, we used a random-effects model to apportion total variance into regional variability (0-11%), intra-regional between-household variability (17-50%), within-household variability over time (38-74%), and within-sample variability (0-23%) and we used a mixed-effects model to identify determinants of PBDE levels. Regional differences in PBDE dust levels were associated with residential characteristics that differed by region, including the presence of furniture with exposed or crumbling foam and the recent installation of carpets in the residence. Intra-regional differences between households were associated with neighborhood urban density, racial and ethnic characteristics, and to a lesser extent, income. For some PBDEs, a decreasing time trend explained a modest fraction of the within-household variability; however, most of the within-household variability was unaccounted for by our mixed-effects models. Our findings indicate that it may be feasible to use residential dust for retrospective assessment of PBDE exposures in studies of children's health (e.g., the Northern California Childhood Leukemia Study).

Blood levels of folate at birth and risk of childhood leukemia.

BACKGROUND: A role for folate in cancer etiology has long been suspected because of folate's function as a cofactor in DNA methylation and maintenance of DNA synthesis. Previous case-control studies examining the association between risk of childhood acute lymphoblastic leukemia (ALL) and mothers' self-reported folate intake and supplementation have been inconclusive. MATERIALS AND METHODS: We used a quantitative microbiologic assay to measure newborn folate concentrations in archived dried bloodspots collected at birth from 313 incident ALL cases, 44 incident acute myeloid leukemia (AML) cases, and 405 matched population-based controls. RESULTS: Overall, we found no difference in hemoglobin-normalized newborn folate concentrations (HbFol, nmol/g) between ALL cases and controls (2.76 vs. 2.77, P = 0.97) or between AML cases and controls (2.93 vs. 2.76, P = 0.32). Null results persisted after stratification by both birth period (1982-94, 1995-98, and 1999-2002) to account for the start of folate fortification of grain products in the United States, and by self-reported maternal prepregnancy supplement use. Similarly, no association was observed for major ALL subgroups. CONCLUSIONS: Our results do not support an association between birth folate concentrations and risk of childhood AML or major ALL subgroups. IMPACT: However, they do not rule out a role for folate through exposures after birth or in early stages of fetal development.