•In most of parental ages strata no association with leukaemia risk was found.•A positive association between risk of childhood ALL was observed with younger parental ages.•A positive association ...between risk of childhood AML was observed with younger parental ages.
The parental age at conception has been reported to be a risk factor for childhood acute leukaemia (AL); however, the relationship is controversial. The aim of the present study was to investigate the association between parental age at conception and the risk of AL in Mexican children, a population with a high incidence of the disease and a high prevalence of pregnancies in adolescents and young adults.
A multicentre case-control study was conducted. Incident AL cases younger than 17 years of age diagnosed between 2010 and 2015 were included. Controls were matched with cases according to age, sex, and health institution. Using logistic regression analysis, adjusted odds ratios (aOR) and 95 % confidence intervals (95 % CI) were calculated for each maternal stratum after adjusting for paternal age at conception of index child. The maternal age between 25 and 29.99 years was selected as the reference category.
In most strata where maternal and paternal ages were assessed, no association was found with the risk of developing acute lymphoblastic leukaemia (ALL) and acute myeloid leukaemia (AML) in their offspring. An increased risk for AML was observed when the mother was between 20 and 24.99 years of age and the father aged 25−29.99 years (aOR, 1.94; 95 % CI, 1.03–3.67). In addition, there was a positive association for ALL when the mother´s age was between 20 and 24.99 years and the father was <20 years of age, however, a very wide confidence interval was noted (aOR, 12.26; 95 % CI, 1.41−106.83).
In the present study, maternal and paternal ages assessed in different strata showed little association with risk of developing ALL and AML in children. Positive associations between risk of both types of childhood AL were observed with younger paternal and maternal ages.
A heterogeneous geographic distribution of childhood acute lymphoblastic leukemia (ALL) cases has been described, possibly, related to the presence of different environmental factors. The aim of the ...present study was to explore the geographical distribution of childhood ALL cases in Greater Mexico City (GMC).
A population-based case-control study was conducted. Children <18 years old, newly diagnosed with ALL and residents of GMC were included. Controls were patients without leukemia recruited from second-level public hospitals, frequency-matched by sex, age, and health institution with the cases. The residence address where the patients lived during the last year before diagnosis (cases) or the interview (controls) was used for geolocation. Kulldorff's spatial scan statistic was used to detect spatial clusters (SCs). Relative risks (RR), associated p-value and number of cases included for each cluster were obtained.
A total of 1054 cases with ALL were analyzed. Of these, 408 (38.7%) were distributed across eight SCs detected. A relative risk of 1.61 (p<0.0001) was observed for the main cluster. Similar results were noted for the remaining seven ones. Additionally, a proximity between SCs, electrical installations and petrochemical facilities was observed.
The identification of SCs in certain regions of GMC suggest the possible role of environmental factors in the etiology of childhood ALL.
There are very few studies that report the incidence of acute leukemias in children in Latin America. This work assesses the incidence of acute leukemias, between 1996 and 2000, in children from 0-14 ...years old who were attended at the Mexican Social Security Institute in Mexico City and in children from 0-11 years old in El Salvador.
Population-based data. Hospitals: In San Salvador, El Salvador, Hospital Nacional de Niños "Benjamin Bloom", the only center in El Salvador which attends all children, younger than 12 years, with oncologic disease. The Pediatric Hospital and the General Hospital of the Mexican Social Security Institute in Mexico City, the only centers in Mexico City which attend all those children with acute leukemia who have a right to this service.
All patients were diagnosed by bone marrow smear and were divided into acute lymphoid leukemia (ALL), acute myeloid leukemia (AML), chronic myeloid leukemia (CML), and unspecified leukemias (UL). The annual incidence rate (AIR) and average annual incidence rate (AAIR) were calculated per million children. Cases were stratified by age and assigned to one of four age strata: 1) <1 year; 2) 1-4 years; 3) 5-9 years, or 4) 10-14 or 10-11 years, for Mexico City and El Salvador, respectively.
The number of cases was 375 and 238 in El Salvador and Mexico City, respectively. AAIRs in Mexico City were 44.9, 10.6, 2.5, 0.5, and 58.4 per million children for ALL, AML, CML, UL, and total leukemias, respectively. The AAIRs in El Salvador could not be calculated because the fourth age stratum in El Salvador included children only from 0-11 years old. The incidence rates for the Salvadorian group of 0-11 year olds were 34.2, 7.1, 0.6, 0.2, and 43.2 per million children for ALL, AML, CML, UL, and total leukemias, respectively.
Reported AIRs for each age group in El Salvador were similar to those from other American countries. The AAIR of ALL in Mexico City is one of the highest reported for North America.
Background Recurrent genetic alterations contributing to leukemogenesis have been identified in pediatric B-cell Acute Lymphoblastic Leukemia (B-ALL), and some are useful for refining classification, ...prognosis, and treatment selection. IKZF1 plus is a complex biomarker associated with a poor prognosis. It is characterized by IKZF1 deletion coexisting with PAX5 , CDKN2A/2B , or PAR1 region deletions. The mutational spectrum and clinical impact of these alterations have scarcely been explored in Mexican pediatric patients with B-ALL. Here, we report the frequency of the IKZF1 plus profile and the mutational spectrum of IKZF1, PAX5, CDKN2A/2B , and ERG genes and evaluate their impact on overall survival (OS) in a group of patients with B-ALL. Methods A total of 206 pediatric patients with de novo B-ALL were included. DNA was obtained from bone marrow samples at diagnosis before treatment initiation. A custom-designed next-generation sequencing panel was used for mutational analysis. Kaplan-Meier analysis was used for OS estimation. Results We identified the IKZF1 plus profile in 21.8% of patients, which was higher than that previously reported in other studies. A significantly older age ( p=0.04 ), a trend toward high-risk stratification ( p=0.06 ), and a decrease in 5-year Overall Survival (OS) ( p=0.009 ) were observed, although heterogeneous treatment protocols in our cohort would have impacted OS. A mutation frequency higher than that reported was found for IKZF1 (35.9%) and CDKN2A/2B (35.9%) but lower for PAX5 (26.6%). IKZF1 MUT group was older at diagnosis ( p=0.0002 ), and most of them were classified as high-risk (73.8%, p=0.02 ), while patients with CDKN2A/2B MUT had a higher leukocyte count ( p=0.01 ) and a tendency toward a higher percentage of blasts (98.6%, >50% blasts, p=0.05 ) than the non-mutated patients. A decrease in OS was found in IKZF1 MUT and CDKN2A/2B MUT patients, but the significance was lost after IKZF1 plus was removed. Discussion Our findings demonstrated that Mexican patients with B-ALL have a higher prevalence of genetic markers associated with poor outcomes. Incorporating genomic methodologies into the diagnostic process, a significant unmet need in low- and mid-income countries, will allow a comprehensive identification of relevant alterations, improving disease classification, treatment selection, and the general outcome.
Refining risk stratification to avoid very early relapses (VER) in Mexican patients with B-lineage acute lymphoblastic leukemia (B-ALL) could lead to better survival rates in our population.
The ...purpose of this study was to investigate the association between the United Kingdom ALL (UKALL)-CNA classifier and VER risk in Mexican patients with childhood B-ALL.
A nested case-control study of 25 cases with VER and 38 frequency-matched controls without relapse was conducted within the MIGICCL study cohort. They were grouped into the categories of the UKALL-CNA risk classifier (good reference, intermediate and poor), according to the results obtained by multiplex ligation dependent probe amplification. Overall and disease-free survival (DFS) were estimated using the Kaplan-Meier method. Univariate and multivariate Cox proportional hazards analyses were conducted.
The CDKN2A/B genes were most frequently deleted in the group with relapse. According to UKALL-CNA classifier, 33 (52.4%) patients were classified as good, 21 (33.3%) intermediate and 9 (14.3%) poor-risk B-ALL. The intermediate and poor risk groups were associated with an increased risk of VER (HR = 4.94, 95% CI = 1.87-13.07 and HR = 7.42, 95% CI = 2.37-23.26, respectively) in comparison to the good-risk patients. After adjusting by NCI risk classification and chemotherapy scheme in a multivariate model, the risks remained significant.
Our data support the clinical utility of profiling CNAs to potentially refine current risk stratification strategies of patients with B-ALL.
Background and Aims Childhood acute lymphoblastic leukemia (ALL) is the leading cause of childhood cancer-related deaths worldwide. Multiples studies have shown that ALL seems to be originated by an ...interaction between environmental and genetic susceptibility factors. The ARID5B polymorphisms are among the most reproducible ALL associated-risk alleles in different populations. The aim of the present study was to examine the contribution of ARID5B, CEBPE, and PIP4K2 risk alleles for the development of ALL in children from Mexico City and Yucatan, Mexico. Methods A study was conducted with a total of 761 unrelated subjects. Two hundred eighty five ALL cases (111 from Yucatan and 174 from Mexico City) and 476 healthy subjects. Genotyping included the rs7088318 ( PIP4K2A ), rs10821936 ( ARID5B ), rs7089424 ( ARID5B ) and rs2239633 ( CEBPE ) polymorphisms. Results Associations between ALL and rs10821936 and rs7089424 ARID5B SNPs were found (OR = 1.9, 95% CI (1.5–2.4) and OR = 2.0, 95% CI (1.6–2.5), respectively). Moreover, a higher risk was observed in the homozygous risk genotypes of carriers from Mexico City (OR = 3.1, 95% CI (2.0–4.9) and OR 3.1, CI 95% (2.0–4.8), respectively). Otherwise, the rs7088318 ( PIP4K2A ) and rs2239633 ( CEBPE ) polymorphisms were not associated with ALL risk. Conclusions Our analysis suggests that ARID5B confers risk for childhood ALL in a Mexican population.
Background and Aims It has been demonstrated that heterozygote and homozygote thiopurine S-methyltransferase ( TPMT ) mutant allele carriers are at high risk to develop severe and potentially fatal ...hematopoietic toxicity after treatment with standard doses of 6-mercaptopurine (6-MP) and methotrexate (MX). Those drugs are the backbone of acute lymphoblastic leukemia (ALL) and several autoimmune disease treatments. We undertook this study to determine the frequency of the TPMT deficient alleles in children with ALL and non-ALL subjects from Mexico City and Yucatan, Mexico. Methods We included 849 unrelated subjects, of which 368 ALL children and 342 non-ALL subjects were from Mexico City, and 60 ALL cases and 79 non-ALL individuals were from Yucatan. Genotyping of the rs1800462, rs1800460 and rs1142345 SNPs was performed by 5′exonuclease technique using TaqMan probes (Life Technologies Foster City, CA). Results The mutant TPMT alleles were present in 4.8% (81/1698 chromosomes) and only 0.2% were homozygote TPMT*3A/TPMT*3A . We did not find statistically significant differences in the distribution of the mutant alleles between patients from Mexico City and Yucatan in either ALL cases or non-ALL. Nonetheless, the TPMT*3C frequency in ALL patients was higher than non-ALL subjects ( p = 0.03). To note, the null homozygous TPMT*3A/TPMT*3A genotype was found in 2.5% of the non-ALL subjects. Conclusions TPMT mutant alleles did not exhibit differential distribution between both evaluated populations; however, TPMT*3C is overrepresented in ALL cases in comparison with non-ALL group. Assessing the TPMT mutant alleles could benefit the ALL children and those undergoing 6-MP and MX treatment.
Medical research has not been able to establish whether a father's occupational exposures are associated with the development of acute leukemia (AL) in their offspring. The studies conducted have ...weaknesses that have generated a misclassification of such exposure. Occupations and exposures to substances associated with childhood cancer are not very frequently encountered in the general population; thus, the reported risks are both inconsistent and inaccurate. In this study, to assess exposure we used a new method, an exposure index, which took into consideration the industrial branch, specific position, use of protective equipment, substances at work, degree of contact with such substances, and time of exposure. This index allowed us to obtain a grade, which permitted the identification of individuals according to their level of exposure to known or potentially carcinogenic agents that are not necessarily specifically identified as risk factors for leukemia. The aim of this study was to determine the association between a father's occupational exposure to carcinogenic agents and the presence of AL in their offspring.
From 1999 to 2000, a case-control study was performed with 193 children who reside in Mexico City and had been diagnosed with AL. The initial sample-size calculation was 150 children per group, assessed with an expected odds ratio (OR) of three and a minimum exposure frequency of 15.8%. These children were matched by age, sex, and institution with 193 pediatric surgical patients at secondary-care hospitals. A questionnaire was used to determine each child's background and the characteristics of the father's occupation(s). In order to determine the level of exposure to carcinogenic agents, a previously validated exposure index (occupational exposure index, OEI) was used. The consistency and validity of the index were assessed by a questionnaire comparison, the sensory recognition of the work area, and an expert's opinion.
The adjusted ORs and 95% confidence intervals (CI) were 1.69 (0.98, 2.92) during the preconception period; 1.98 (1.13, 3.45) during the index pregnancy; 2.11 (1.17, 3.78) during breastfeeding period; 2.17 (1.28, 3.66) after birth; and 2.06 (1.24, 3.42) for global exposure.
This is the first study in which an OEI was used to assess a father's occupational exposure to carcinogenic agents as a risk factor for the development of childhood AL in his offspring. From our results, we conclude that children whose fathers have been exposed to a high level of carcinogenic agents seem to have a greater risk of developing acute leukemia. However, confounding factors cannot be disregarded due to an incomplete control for confounding.
One of the highest incidences of acute lymphoblastic leukemia (ALL) in the world has been reported in Mexico City. In the current study (26 cases), the frequencies of the most frequent genetic ...rearrangements TEL-AML1, MLL AF4, BCR-ABL (major and minor) in ALL in children from Mexico City were determined. For the ALL, the frequency of MLL AF4 was 65.4%, for TEL-AML1 and that of BCR ABL was 3.8%. Only 6 of the 17 children with the MLL AF4 rearrangement were less than 26 months old. The frequency reported for MLL AF4 in Mexican children with ALL is one of the highest worldwide. These findings could potentially explain the higher frequency of ALL with poor prognosis for children in Mexico City.
Background: We analyzed effects of exposure to magnetic fields on the expression of acute leukemia in children with Down syndrome (who have a 20-fold higher risk of leukemia). Methods: We performed a ...case-control study that included 42 children with both acute leukemia and Down syndrome as cases and 124 healthy children with Down syndrome as controls. We obtained demographic information concerning the children and took spot measurements of magnetic fields at each residence. Results: The odds ratio for direct measurements of magnetic fields ≥6.00 mG was 3.7 (95% confidence interval = 1.05-13.1). Conclusion: The association between magnetic fields and leukemia in children with Down syndrome suggests the possibility of a causal role for magnetic fields in the etiology of leukemia among a genetically susceptible subgroup of children.
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