Family Characteristics as Risk Factors for Childhood Acute Lymphoblastic Leukemia: A Population-Based Case-Control Study

Background

To date, few risk factors for childhood acute lymphoblastic leukemia (ALL) have been confirmed and the scientific literature is full of controversial “evidence.” We examined if family characteristics, particularly maternal and paternal age and number of older siblings, were risk factors for childhood acute lymphoblastic leukemia (ALL).

Methodology/Principal Findings

In this population-based nationwide matched case-control study, patients 0–14 years of age with ALL diagnosed 1991–2006 and registered in the Swiss Childhood Cancer Registry were linked with their census records of 1990 and 2000. Eight controls per case were selected from the census. The association between family characteristics and ALL was analyzed by conditional logistic regressions. We found that increasing maternal age was associated with incidence of ALL in the offspring (OR per 5-year increase in maternal age 1.18, 95% CI 1.05–1.31; p = 0.004), remaining stable (trend OR 1.14, 95% CI 0.99–1.31; p = 0.060) after adjustment for other risk factors. The association with paternal age was weaker (OR per 5-year increase 1.14, 95% CI 1.01–1.28, p = 0.032) and disappeared after adjustments. Number of older siblings was not associated with risk of ALL in the overall group of children aged 0–14 years at diagnosis. However, we found a negative trend between number of older siblings and ALL diagnosed at age 0–4 years (OR per sibling 0.85, 95% CI 0.68–1.06; p = 0.141) and a positive trend for ALL diagnosed at age 5–9 (OR 1.34, 95% CI 1.05–1.72; p = 0.019), with some evidence for an effect modification (p-value for interaction  = 0.040).

Conclusions

As in other studies, increasing maternal, but not paternal age was associated with risk of ALL. We found only a weak association with the number of older siblings, suggesting a delay in disease manifestation rather than a decrease in incidence.     

Association between CEBPE Variant and Childhood Acute Leukemia Risk: Evidence from a Meta-Analysis of 22 Studies

The CCAAT/enhancer binding proteins (CEBPs) have been involved in the etiology of acute leukemia (AL) and investigated in numerous genetic association studies, however, the results were inconclusive. The current meta-analysis was conducted to clarify the effect of CEBPE rs2239633 variant on childhood AL risk. Electronic literature search was performed on August 15, 2014, from databases of Medline, PubMed, Embase, and Web of Science. A total of 22 case-control studies were eligible for the pooled analysis. The results demonstrated that rs2239633 A allele was significantly associated with a decreased risk of childhood AL (A vs G: OR=0.87, 95%CI = 0.80, 0.94, p<0.001), especially in B-cell ALL subgroup (A vs G: OR = 0.79, 95%CI = 0.74, 0.83, p<0.001), but not among T-cell ALL or AML subgroups. In the stratified analysis by ethnicity, the association was observed in Europeans (A vs G: OR = 0.80, 95%CI = 0.76, 0.84, p<0.001) but not in Asian and mixed populations. Moreover, the results of sensitivity and cumulative meta-analysis indicated the robustness of our results. Also, Begg’s and Egger’s tests did not indicate any evidence of obvious asymmetry. In summary, our study provided evidence that CEBPE rs2239633 variant is associated with decreased risk of childhood B-cell ALL in Europeans.     

GSTM1 and GSTT1 Null Polymorphisms and Childhood Acute Leukemia Risk: Evidence from 26 Case-Control Studies

Several molecular epidemiological studies have been conducted to examine the association between glutathione S-transferase mu-1 (GSTM1) and glutathione S-transferase theta-1 (GSTT1) null polymorphisms and childhood acute leukemia; however, the conclusions remain controversial. We performed an extensive meta-analysis on 26 published case-control studies with a total of 3252 cases and 5024 controls. Crude odds ratios (ORs) with 95% confidence interval were used to assess the strength of association between childhood acute leukemia risk and polymorphisms of GSTM1 and GSTT1. With respect to GSTM1 polymorphism, significantly increased risk of childhood acute leukemia was observed in the overall analysis (OR = 1.30; 95%CI, 1.11-1.51). Furthermore, a stratification analysis showed that the risk of GSTM1 polymorphism are associated with childhood acute leukemia in group of Asians (OR = 1.94; 95%CI, 1.53-2.46), Blacks (OR = 1.76; 95%CI, 1.07-2.91), ALL (OR = 1.33; 95%CI, 1.13-1.58), ‘< 100 cases and <100 controls’ (OR = 1.79; 95%CI, 1.21-2.64), ‘≥ 100 cases and ≥ 100 controls’ (OR = 1.25; 95%CI, 1.02-1.52), and population-based control source (OR = 1.40; 95%CI, 1.15-1.69). With respect to GSTT1 polymorphism, significant association with childhood acute leukemia risk was only found in subgroup of Asian. This meta-analysis supports that GSTM1 null polymorphism is capable of causing childhood acute leukemia susceptibility.     

Maternal Benzene Exposure during Pregnancy and Risk of Childhood Acute Lymphoblastic Leukemia: A Meta-Analysis of Epidemiologic Studies

Background

The prevalence of childhood leukemia is increasing rapidly all over the world. However, studies on maternal benzene exposure during pregnancy and childhood acute lymphoblastic leukemia (ALL) have not been systematically assessed. Therefore, we performed a meta-analysis to investigate the association between maternal solvent, paint, petroleum exposure, and smoking during pregnancy and risk of childhood ALL.

Methods

Relevant studies up to September 1^st, 2013 were identified by searching the PubMed, EMBASE, Cochrane library and the Web of Science databases. The effects were pooled using either fixed or random effect models based on the heterogeneity of the studies.

Results

Twenty-eight case-control studies and one cohort study were included for analysis, with a total of 16,695 cases and 1,472,786 controls involved. Pooled odds ratio (OR) with 95% confidence interval (CI) for ALL was 1.25 (1.09, 1.45) for solvent, 1.23 (1.02, 1.47) for paint, 1.42 (1.10, 1.84) for petroleum exposure, and 0.99 (0.93, 1.06) for maternal smoking during pregnancy. No publication bias was found in this meta-analysis and consistent results were observed for subgroup and sensitivity analyses.

Conclusions

Childhood ALL was associated with maternal solvent, paint, and petroleum exposure during pregnancy. No association was found between ALL and maternal smoking during pregnancy. Avoidance of maternal occupational and environmental benzene exposure during pregnancy could contribute to a decrease in the risk of childhood ALL.     

High-resolution Antibody Array Analysis of Childhood Acute Leukemia Cells

Acute leukemia is a disease pathologically manifested at both genomic and proteomic levels. Molecular genetic technologies are currently widely used in clinical research. In contrast, sensitive and high-throughput proteomic techniques for performing protein analyses in patient samples are still lacking. Here, we used a technology based on size exclusion chromatography followed by immunoprecipitation of target proteins with an antibody bead array (Size Exclusion Chromatography-Microsphere-based Affinity Proteomics, SEC-MAP) to detect hundreds of proteins from a single sample. In addition, we developed semi-automatic bioinformatics tools to adapt this technology for high-content proteomic screening of pediatric acute leukemia patients.To confirm the utility of SEC-MAP in leukemia immunophenotyping, we tested 31 leukemia diagnostic markers in parallel by SEC-MAP and flow cytometry. We identified 28 antibodies suitable for both techniques. Eighteen of them provided excellent quantitative correlation between SEC-MAP and flow cytometry (p < 0.05). Next, SEC-MAP was applied to examine 57 diagnostic samples from patients with acute leukemia. In this assay, we used 632 different antibodies and detected 501 targets. Of those, 47 targets were differentially expressed between at least two of the three acute leukemia subgroups. The CD markers correlated with immunophenotypic categories as expected. From non-CD markers, we found DBN1, PAX5, or PTK2 overexpressed in B-cell precursor acute lymphoblastic leukemias, LAT, SH2D1A, or STAT5A overexpressed in T-cell acute lymphoblastic leukemias, and HCK, GLUD1, or SYK overexpressed in acute myeloid leukemias. In addition, OPAL1 overexpression corresponded to ETV6-RUNX1 chromosomal translocation.In summary, we demonstrated that SEC-MAP technology is a powerful tool for detecting hundreds of proteins in clinical samples obtained from pediatric acute leukemia patients. It provides information about protein size and reveals differences in protein expression between particular leukemia subgroups. Forty-seven of SEC-MAP identified targets were validated by other conventional method in this study.Acute leukemia (AL)¹ is the most common childhood cancer, accounting for a quarter of all pediatric malignancies (1). Accumulated chromosomal translocations and mutations in proto-oncogenes alter proliferation, differentiation, apoptosis and death in developing hematogones, ultimately leading to the development of leukemia (2, 3). The most recent understanding of these cancer-related changes is based on molecular genetic studies that focused primarily on DNA and mRNA alterations. High-throughput molecular genetic technologies, such as mRNA expression profiling and next generation sequencing, are widely used in clinical research. These techniques can provide new classification schemes, define new prognostic subgroups and outline the background of some pathological mechanisms (2, 4, 5, 6, 7) but they cannot easily elucidate the functional consequences at the cellular level. Proteins are the principal carriers of cellular functions. Thus, the analysis of proteins and protein modifications can elucidate the pathological mechanisms of leukemia or clarify the response mechanisms to current and emerging therapies. Currently, flow cytometry is used in clinical laboratories to analyze dozens of proteins that are expressed by leukemic cells (8, 9). These proteins, which are mostly surface CD markers, can reflect lineage commitment, developmental status and even the underlying genetic lesion (10, 11) but they do not carry information about the intracellular processes that control malignant transformation. Moreover, many cancer alterations are manifested only at the functional level, including changes in subcellular localization, post-translational modification (e.g. phosphorylation), protein cleavage, or protein–protein interactions (12). Proteomic techniques that can capture disease-associated changes are needed. Mass spectrometry (MS) is presently the technique of choice for large-scale proteomic analysis. MS can uncover thousands of molecules without an a priori probe selection, e.g. new disease-associated features in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) (13, 14). Despite its tremendous analytical power, MS is complex and not widely accessible. Unlike MS, affinity proteomics is a simple technology suitable for large-scale protein analysis in primary cancer samples in the clinical laboratories. Recently, a technique linking size exclusion chromatography (SEC) to microsphere-based antibody arrays (microsphere-based affinity proteomics (MAP)) has been developed (15, 16). SEC-MAP enables the detection of hundreds of proteins in a single sample and provides essential information about protein size. Because only five to ten million cells are necessary, SEC-MAP can serve as a sensitive, sample-sparing and high-content tool for protein profiling in leukemia samples probing the relative amounts of different proteins, as well as protein size and cleavage (17). Our in-house-assembled MAP array is a set of 1152 populations of fluorescent-labeled microbeads, each carrying an antibody against a single human antigen. Native cellular proteins (and their complexes) are isolated from cellular compartments using detergents, labeled with biotin (biotin-PEO4-NHS) and subjected to SEC to obtain 24 size fractions. The SEC fractions are incubated with MAP microbeads, and antibody-protein binding is detected using phycoerythrin (PE)-labeled streptavidin with flow cytometry. The flow cytometer resolves the color code of each microbead population and reads the amount of bound protein. The data from 24 SEC fractions are combined, and a protein''s binding relative to its size is detected as a “protein entity.” Data are analyzed with in-house R-based software. This approach permits automatic batch processing of raw flow cytometry standard (FCS) files in addition to advanced analyses including quality control steps (the minimal number of microspheres required in a population and the unimodality of the signal in the PE channel is checked) (17). We wanted to find out whether SEC-MAP can be used in the clinical laboratory to bring a biologically important information, e.g. to classify acute leukemias or to find the marker with a prognostic relevance. We assembled MAP arrays to carry antibodies against proteins that are known to be important for leukemia diagnostics (18, 9) and against components of intracellular signaling networks (16). Through extensive testing on leukemia samples, we have identified antibodies that are suitable for immunoprecipitation-based techniques. Furthermore, we have improved the software tools to allow for large-scale data normalization, fast automatic protein entity detection with manual correction, and the discovery of differentially expressed entities in multiple samples. Using innovative software tools, we have identified entities that were differentially expressed between particular AL subgroups. To ensure the specificity we have validated the data collected by SEC-MAP with classical flow cytometry-based immunophenotyping (FACS), Western blot (WB) and quantitative real-time PCR (qRT-PCR). Moreover, we have addressed practical sample processing issues related to patient material handling and logistics. Based on the protein size profile, we were able to discriminate proteolytically degraded samples from those with an uncleaved proteome. Importantly, proteolysis would be missed by conventional protein load controls in Western blots. Thus, the SEC-MAP array was demonstrated to be a useful, reproducible and accurate high-content proteomic tool for the assessment of primary leukemia samples.     

Risk of neuroblastoma,maternal characteristics and perinatal exposures: The SETIL study

PurposeNeuroblastoma (NB) is the most common extra-cranial paediatric solid tumour. Incidence peaks in infancy, suggesting a role of in-utero and neonatal exposures but its aetiology is largely unknown. The aim of the present study is to evaluate the association between maternal characteristics and perinatal factors with the risk of NB, using data from the SETIL database.MethodsSETIL is a large Italian population-based case-control study established to evaluate several potential cancer risk factors in 0–10 year olds. Information about maternal characteristics, reproductive history, environmental and occupational exposures during pregnancy, as well as newborns’ characteristics were obtained using a structured questionnaire. Extremely low frequency magnetic field (ELF-MF) home exposure was measured. The study included 1044 healthy controls and 153 NB cases, diagnosed between 1998 and 2001.ResultsA twofold risk was associated to exposure in pregnancy to chemical products for domestic work and to hair dye. The risk associated with the latter was higher among 0–17 month old children (OR = 5.5, 95%CI: 1.0–29.3). Risk was increased for children whose mothers had suffered work related exposure in the preconception period to solvents (OR = 2.0 95%CI: 1.0–4.1) and in particular to aromatic hydrocarbons (OR = 9.2, 95%CI: 2.4–34.3). No association was observed with ELF-MF exposure. A higher risk was found among children with congenital malformations (OR = 4.9, 95%CI: 1.8–13.6) or neurofibromatosis (2 cases and 0 controls, p = 0.016).ConclusionsOur study suggests maternal exposure to hair dyes and aromatic hydrocarbons plays a role and deserves further investigation. The association with congenital malformations might also be explained by over-diagnosis.External exposure, in particular during and before pregnancy might contribute to NB occurrence.     

Association between the Polymorphism rs3217927 of CCND2 and the Risk of Childhood Acute Lymphoblastic Leukemia in a Chinese Population

CyclinD proteins, the ultimate recipients of mitogenic and oncogenic signals, play a crucial role in cell-cycle regulation. CyclinD2, one of the cyclinD family, is overexpressed in T-acute lymphoblastic leukemia (ALL) and B-cell chronic lymphocytic leukemia and involved in the pathogenesis of leukemias. Recent reports indicated that CCND2 polymorphisms are associated with human cancer risk, thusly we hypothesized that CCND2 gene polymorphisms may contribute to childhood ALL susceptibility. We selected the polymorphism rs3217927 located in the 3′UTR region of CCND2 to assess its associations with childhood ALL risk in a case-control study. A significant difference was found in the genotype distributions of rs3217927 polymorphism between cases and controls (P = 0.019) and homozygous GG genotype may be an increased risk factor for childhood ALL (adjusted OR  =  1.84, 95% CI  =  1.14 —2.99). Furthermore, this increased risk was more pronounced with GG genotype among high-risk ALL (adjusted OR  = 1.95, 95% CI  =  1.04–3.67), low-risk ALL (adjusted OR  =  2.09, 95% CI  =  1.13–3.87), B-phenotype ALL patients (adjusted OR  =  1.78, 95% CI  =  1.08–2.95) and T-phenotype ALL patients (adjusted OR  =  2.87, 95% CI  =  1.16–7.13). Our results provide evidence that CCND2 polymorphism rs3217927 may be involved in the etiology of childhood ALL, and the GG genotype of rs3217927 may modulate the genetic susceptibility to childhood ALL in the Chinese population. Further functional studies and investigations in larger populations should be conducted to validate our findings.     

Extremely Low-Frequency Magnetic Fields and the Risk of Childhood B-Lineage Acute Lymphoblastic Leukemia in a City With High Incidence of Leukemia and Elevated Exposure to ELF Magnetic Fields

It is important to study the relationship between extremely low-frequency magnetic fields (ELF-MFs) and childhood leukemia, particularly in locations with a high incidence of this neoplasm in children and an elevated exposure to ELF-MF, such as Mexico City. The aim was to investigate the association between ELF-MF exposure and the risk of B-lineage acute lymphoblastic leukemia (B-ALL). A case–control study was conducted in Mexico City during the period from 2010 to 2011. Residential 24-h ELF-MF measurements were obtained for 290 incident B-ALL patients and 407 controls, aged less than 16 years. Controls were frequency-matched by sex, age (±18 months), and health institution. The adjusted odds ratios (aOR) and 95% confidence intervals (CIs) were calculated. ELF-MF exposure at <0.2 μT was used to define the reference group. ELF-MF exposure at ≥0.3 μT was observed in 11.3% of the controls. Different ELF-MF intensity cutoff values were used to define the highest exposure category; the highest exposure category for each cutoff value was associated with an increased risk of B-ALL compared with the corresponding lower exposure categories. The aORs were as follows: ≥0.2 μT = 1.26 (95% CI: 0.84–1.89); ≥0.3 μT = 1.53 (95% CI: 0.95–2.48); ≥0.4 μT = 1.87 (95% CI: 1.04–3.35); ≥0.5 μT = 1.80 (95% CI 0.95–3.44); ≥0.6 μT = 2.32 (95% CI: 1.10–4.93). ELF-MF exposure as a continuous variable (per 0.2 μT intervals) was associated with B-ALL risk (aOR = 1.06; 95% CI: 1.01–1.12). In the present study, the proportion of children exposed to ≥0.3 μT is among the highest reported worldwide. Additionally, an ELF-MF exposure ≥0.4 μT may be associated with the risk of B-ALL. Bioelectromagnetics. © 2020 Bioelectromagnetics Society     

Aberrant Expression of Some Circulating miRNAs in Childhood Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is a heterogeneous cancer commonly affecting children due to dysregulation of miRNA expression. In the current study, authors investigated the expression profile for miRNA-125b-1 and miRNA-203 among childhood ALL. Blood samples were collected from newly diagnosed childhood ALL and healthy control children. The expression profile for candidate miRNAs was detected using quantitative RT-PCR analysis. Statistical analysis were performed using receiver operating characteristic curve (ROC) to examine the diagnostic efficacy of the two miRNA and their levels among ALL clinicopathological factors and phenotypes. The median expression level for miRNA-125b-1 was significantly high in childhood ALL; while miRNA-203 level was significantly low in childhood ALL as compared to control ones. MiRNA-125-1 reported significant increase in T-ALL as compared to other ALL phenotypes. Median miRNA-203 level was high in T-ALL followed by pre-B-ALL although no significant difference was reported. Clinicopathological factors did not emphasize significance with either detected miRNAs. Using ROC curve the diagnostic efficacy was significant with an area under the curve 0.858 for miRNA-125b-1 (83.72, 100%) and 0.878 for miRNA-203 (97.67, 86.96%). The combination of the two key miRNAs revealed absolute sensitivity (100%). MiRNA-125b-1 and miRNA-203 can be useful molecular markers for diagnosis of ALL. Further studies with large cohort are warranted to validate these results.     

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

Background

Acute lymphoblastic leukemia (ALL) is the most prevalent type of pediatric cancer, the causes of which are likely to involve an interaction between genetic and environmental factors. To evaluate the effects of the genotypic polymorphisms in methylenetetrahydrofolate reductase (MTHFR) on childhood ALL risk in Taiwan, two well-known polymorphic genotypes of MTHFR, C677T (rs1801133) and A1298C (rs1801131), were analyzed to examine the extent of their associations with childhood ALL susceptibility and to discuss the MTHFR genotypic contribution to childhood ALL risk among different populations.

Methodology/Principal Findings

In total, 266 patients with childhood ALL and an equal number of non-cancer controls recruited were genotyped utilizing PCR-RFLP methodology. The MTHFR C677T genotype, but not the A1298C, was differently distributed between childhood ALL and control groups. The CT and TT of MTHFR C677T genotypes were significantly more frequently found in controls than in childhood ALL patients (odds ratios=0.60 and 0.48, 95% confidence intervals=0.42–0.87 and 0.24–0.97, respectively). As for gender, the boys carrying the MTHFR C677T CT or TT genotype conferred a lower odds ratio of 0.51 (95% confidence interval=0.32–0.81, P=0.0113) for childhood ALL. As for age, those equal to or greater than 3.5 years of age at onset of disease carrying the MTHFR C677T CT or TT genotype were of lower risk (odds ratio= 0.43 and 95% confidence interval=0.26–0.71, P=0.0016).

Conclusions

Our results indicated that the MTHFR C677T T allele was a protective biomarker for childhood ALL in Taiwan, and the association was more significant in male patients and in patients 3.5 years of age or older at onset of disease.     

Minimal Residual Disease-Based Risk Stratification in Chinese Childhood Acute Lymphoblastic Leukemia by Flow Cytometry and Plasma DNA Quantitative Polymerase Chain Reaction

Minimal residual disease, or MRD, is an important prognostic indicator in childhood acute lymphoblastic leukemia. In ALL-IC-BFM 2002 study, we employed a standardized method of flow cytometry MRD monitoring for multiple centers internationally using uniformed gating, and determined the relevant MRD-based risk stratification strategies in our local patient cohort. We also evaluated a novel method of PCR MRD quantitation using peripheral blood plasma. For the bone marrow flow MRD study, patients could be stratified into 3 risk groups according to MRD level using a single time-point at day-15 (Model I) (I-A: <0.1%, I-B: 0.1–10%, I-C: >10%), or using two time-points at day-15 and day-33 (Model II) (II-A: day-15<10% and day-33<0.01%, II-B: day-15≥10% or day-33≥0.01% but not both, II-C: day-15≥10% and day-33≥0.01%), which showed significantly superior prediction of relapse (p = .00047 and <0.0001 respectively). Importantly, patients with good outcome (frequency: 56.0%, event-free survival: 90.1%) could be more accurately predicted by Model II. In peripheral blood plasma PCR MRD investigation, patients with day-15-MRD≥10⁻⁴ were at a significantly higher risk of relapse (p = 0.0117). By multivariate analysis, MRD results from both methods could independently predict patients’ prognosis, with 20–35-fold increase in risk of relapse for flow MRD I-C and II-C respectively, and 5.8-fold for patients having plasma MRD of ≥10⁻⁴. We confirmed that MRD detection by flow cytometry is useful for prognostic evaluation in our Chinese cohort of childhood ALL after treatment. Moreover, peripheral blood plasma DNA MRD can be an alternative where bone marrow specimen is unavailable and as a less invasive method, which allows close monitoring.     

Using a Bayesian Hierarchical Model for Identifying Single Nucleotide Polymorphisms Associated with Childhood Acute Lymphoblastic Leukemia Risk in Case-Parent Triads

Childhood acute lymphoblastic leukemia (ALL) is a condition that arises from complex etiologies. The absence of consistent environmental risk factors and the presence of modest familial associations suggest ALL is a complex trait with an underlying genetic component. The identification of genetic factors associated with disease is complicated by complex genetic covariance structures and multiple testing issues. Both issues can be resolved with appropriate Bayesian variable selection methods. The present study was undertaken to extend our hierarchical Bayesian model for case-parent triads to incorporate single nucleotide polymorphisms (SNPs) and incorporate the biological grouping of SNPs within genes. Based on previous evidence that genetic variation in the folate metabolic pathway influences ALL risk, we evaluated 128 tagging SNPs in 16 folate metabolic genes among 118 ALL case-parent triads recruited from the Texas Children’s Cancer Center (Houston, TX) between 2003 and 2010. We used stochastic search gene suggestion (SSGS) in hierarchical Bayesian models to evaluate the association between folate metabolic SNPs and ALL. Using Bayes factors among these variants in childhood ALL case-parent triads, two SNPs were identified with a Bayes factor greater than 1. There was evidence that the minor alleles of NOS3 rs3918186 (OR = 2.16; 95% CI: 1.51-3.15) and SLC19A1 rs1051266 (OR = 2.07; 95% CI: 1.25-3.46) were positively associated with childhood ALL. Our findings are suggestive of the role of inherited genetic variation in the folate metabolic pathway on childhood ALL risk, and they also suggest the utility of Bayesian variable selection methods in the context of case-parent triads for evaluating the role of SNPs on disease risk.     

ARID5B,IKZF1 and Non-Genetic Factors in the Etiology of Childhood Acute Lymphoblastic Leukemia: The ESCALE Study

Genome-wide association studies (GWAS) have identified that frequent polymorphisms in ARID5B and IKZF1, two genes involved in lymphoid differentiation, increase the risk of childhood acute lymphoblastic leukemia (ALL). These findings markedly modified the current field of research on the etiology of ALL. In this new context, the present exploratory study investigated the possible interactions between these at-risk alleles and the non-genetic suspected ALL risk factors that were of sufficient prevalence in the French ESCALE study: maternal use of home insecticides during pregnancy, preconception paternal smoking, and some proxies for early immune modulation, i.e. breastfeeding, history of common infections before age one year, and birth order. The analyses were based on 434 ALL cases and 442 controls of European origin, drawn from the nationwide population-based case-control study ESCALE. Information on non-genetic factors was obtained by standardized telephone interview. Interactions between rs10740055 in ARID5B or rs4132601 in IKZF1 and each of the suspected non-genetic factors were tested, with the SNPs coded as counts of minor alleles (trend variable). Statistical interactions were observed between rs4132601 and maternal insecticide use (p = 0.012), breastfeeding p = 0.017) and repeated early common infections (p = 0.0070), with allelic odds ratios (OR) which were only increased among the children not exposed to insecticides (OR = 1.8, 95%CI: 1.3, 2.4), those who had been breastfed (OR = 1.8, 95%CI: 1.3, 2.5) and those who had had repeated early common infections (OR = 2.4, 95%CI: 1.5, 3.8). The allelic ORs were close to one among children exposed to insecticides, who had not been breastfed and who had had no or few common infections. Repeated early common infections interacted with rs10740055 (p = 0.018) in the case-only design. Further studies are needed to evaluate whether these observations of a modification of the effect of the at-risk alleles by non-genetic factors are chance findings or reflect true underlying mechanisms.     

Exposure to Secondhand Smoke and Risk of Tuberculosis: Prospective Cohort Study

Background

Prospective evidence on the association between secondhand-smoke exposure and tuberculosis is limited.

Methods

We included 23,827 never smokers from two rounds (2001 and 2005) of Taiwan National Health Interview Survey. Information on exposure to secondhand smoke at home as well as other sociodemographic and behavioral factors was collected through in-person interview. The participants were prospectively followed for incidence of tuberculosis through cross-matching the survey database to the national tuberculosis registry of Taiwan.

Results

A total of 85 cases of active tuberculosis were identified after a median follow-up of 7.0 years. The prevalence of exposure to secondhand smoke at home was 41.8% in the study population. In the multivariable Cox proportional hazards analysis, secondhand smoke was not associated with active tuberculosis (adjusted hazard ratio [HR], 1.03; 95% CI, 0.64 to 1.64). In the subgroup analysis, the association between secondhand smoke and tuberculosis decreased with increasing age; the adjusted HR for those <18, > = 18 and <40, > = 40 and <60, and > = 60 years old was 8.48 (0.77 to 93.56), 2.29 (0.75 to 7.01), 1.33 (0.58 to 3.01), and 0.66 (0.35 to 1.23) respectively. Results from extensive sensitivity analyses suggested that potential misclassification of secondhand-smoke exposure would not substantially affect the observed associations.

Conclusions

The results from this prospective cohort study did not support an overall association between secondhand smoke and tuberculosis. However, the finding that adolescents might be particularly susceptible to secondhand smoke''s effect warrants further investigation.     

急性单核细胞白血病M5转为急性红白血病M6一例病例分析及文献复习

目的:红白血病为临床少见的急性髓系白血病亚型,白血病克隆转换不常见,在国内外文献中有关报道少见.通过对一例由急性单核细胞白血病转化的急性红白血病(acute erythroid leukemias,AEL)的病例分析,学习并探讨急性红白血病的临床特点及实验室检查特征,提高对急性红白血病疾病特点及白血病克隆转化的认识.方法:报道一例初诊为急性单核细胞白血病,后转为急性红白血病的患者.期间对其进行持续的细胞形态学,遗传学及分子生物学监测.结果:患者首次入院诊断为急性单核细胞白血病,经过一个疗程化疗后,骨穿显示从急性单核细胞白血病转为急性红白血病.随后再进行了一个疗程化疗,化疗结束后患者好转出院.后因经济原因,患者未继续治疗,2月后随访,患者死亡.结论:本例急性单核细胞性白血病化疗后转为红白血病.究其机制,可能有:一.发病是粒-单定向祖细胞和红系定向祖细胞同时受损,只是早期单核细胞系异常表现明显,红系异常早期表现不明显.或疾病起源于更早期造血干细胞,导致单核系和红系均有异常.二.在疾病过程中,骨髓微环境的变化,诱导红系异常而导致红白血病的发生.经过分析,本病例中,疾病可能起源于更早期造血干细胞的可能性较大,而骨髓微环境在疾病变化过程中则起到了重要的作用.这一结果有待进一步临床观察研究和肯定.提醒临床医生,提高动态的诊断和治疗意识,将有助于该疾病的预防、诊断和治疗.     

Osteocalcin Is Not Associated with the Risk of Type 2 Diabetes: Findings from the EPIC-NL Study

Objective

To investigate whether total osteocalcin (tOC), uncarboxylated osteocalcin (ucOC) and percentage of uncarboxylated osteocalcin (%ucOC) are associated with the risk of type 2 diabetes.

Methods

This nested case control study included 1,635 participants, 833 incident diabetes cases and 802 non-diabetic control participants, aged 21–70 years from the EPIC-NL cohort. Baseline concentrations of tOC, ucOC and %ucOC were assessed. During 10 years of follow-up, diabetes cases were self-reported and verified against information from general practitioners or pharmacists. The association between the different forms of osteocalcin and diabetes risk was assessed with logistic regression adjusted for diabetes risk factors (waist circumference, age, sex, cohort, smoking status, family history of diabetes, hypertension, alcohol intake, physical activity and education) and dietary factors (total energy intake and energy adjusted intake of fat, fiber, protein and calcium).

Results

TOC concentration was not associated with diabetes risk, with an odds ratio (OR) of 0.97 (0.91–1.03) for each ng/ml increment after adjustment for diabetes risk factors and dietary factors. No association between ucOC and %ucOC and the risk of diabetes was observed either. In sex stratified analyses (P interaction = 0.07), higher %ucOC tended to be associated with an increased risk of type 2 diabetes in a multivariable model in women (OR 1.05 for each increment of 5% ucOC (1.00–1.11), P_trend = 0.08), but not in men (OR 0.96 for each increment of 5% ucOC (0.88–1.04)). When waist circumference was replaced by body mass index, none of the osteocalcin forms were associated with the risk of type 2 diabetes in the final model among both women and men.

Conclusions

Available evidence suggests that tOC, ucOC and %ucOC are each not associated with the risk of type 2 diabetes. However, more large-scale cohort studies are needed to clarify the presence of any association between the different forms of osteocalcin and the risk of type 2 diabetes.     

Determination of the Subclonal Tumor Structure in Childhood Acute Myeloid Leukemia and Acral Melanoma by Next-Generation Sequencing

Molecular Biology - Intratumoral heterogeneity and clonal variability are among the central problems of clinical oncology, leading to resistance to therapy, relapse, and metastasis. High-throughput...