Background
B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is the most frequent pediatric cancer worldwide. Despite improvements in treatment regimens, approximately 20% of the cases cannot ...be cured, highlighting the necessity for identifying new biomarkers to improve the current clinical and molecular risk stratification schemes. We aimed to investigate whether
LINC00173
is a biomarker in ALL and to explore its expression level in other human cancer types.
Methods
A nested case–control study including Mexican children with BCP-ALL was conducted.
LINC00173
expression was evaluated by qRT-PCR using hydrolysis probes. To validate our findings, RNA-seq expression data from BCP-ALL and normal tissues were retrieved from Therapeutically Applicable Research to Generate Effective Treatments (TARGET) and Genotype-Tissue Expression (GTEx) repositories, respectively.
LINC00173
expression was also evaluated in solid tumors by downloading available data from The Cancer Genome Atlas (TCGA).
Results
A lower expression of
LINC00173
in BCP-ALL cases compared to normal subjects was observed (
p
< 0.05). ALL patients who carry the
TCF3/PBX1
fusion gene displayed lower expression of
LINC00173
in contrast to other BCP-ALL molecular subtypes (
p
< 0.04).
LINC00173
underexpression was associated with a high risk to relapse (HR = 1.946, 95% CI = 1.213–3.120) and die (HR = 2.073, 95% CI = 1.211–3.547). Patients with
TCF3/PBX1
and underexpression of
LINC00173
had the worst prognosis (DFS: HR = 12.24, 95% CI = 5.04–29.71; OS: HR = 11.19, 95% CI = 26–32). TCGA data analysis revealed that underexpression of
LINC00173
is also associated with poor clinical outcomes in six new reported tumor types.
Conclusion
Our findings suggest that
LINC00173
is a biomarker of poor prognosis in BCP-ALL and other types of cancer. We observed an association between the expression of
LINC00173
and
TCF3/PBX1
and the risk to relapse and die in BCP-ALL, which is worse in
TCF3/PBX1-
positive cases displaying underexpression of
LINC00173.
Experimental studies are needed to provide insight into the
LINC00173
and
TCF3/PBX
relationship.
Epidemiological studies around the world on acute leukemia (AL) and risk factors in infants are scarce. Infant AL has been proposed to originate
, which facilitates its study by establishing a short ...exposure time in pregnant women to environmental and dietary factors that could contribute to the risk of or protection against leukemia. We hypothesized that maternal diet during pregnancy may be an important factor involved in AL in offspring.
We conducted a hospital-based case-control study from 2010 to 2019 on maternal diet during pregnancy in nine high-specialty public hospitals of different health institutions that diagnose and offer treatment to children with AL in Mexico City. Cases (n=109) were children ≤24 months of age with
diagnosis of AL, and controls (n=252) were children obtained in hospitals from second-level medical care matched for age, sex, and health institution. Maternal diet during pregnancy was obtained by a semiquantitative food frequency questionnaire. Unconditional logistic regression models were used to assess the association between food groups and infant AL. Potential confounders were assessed by constructing directed acyclic graphs (DAGs) with Dagitty software in which adjusted options were identified for the construction of unconditional logistic regression models.
Cases were slightly predominantly female (52.3%). The years of education of the mother in cases and controls was 0-9 on average, and those who reported smoking cigarettes and consuming alcohol during pregnancy did so at a low frequency. Regarding the mother's diet, the main findings were that the consumption of allium vegetables during pregnancy was inversely associated with AL for medium and high consumption (OR=0.26, 95% CI 0.14-0.46;
-trend< 0.001). In contrast, the high consumption of high-fat dairy products had a positive association with AL (OR=2.37, 95% CI 1.30-4.34;
-trend<0.001). No association was found between consumption of topoisomerase II inhibitor foods during pregnancy and AL.
The results suggest that maternal intake during pregnancy of allium vegetables, specifically garlic, is inversely associated with the development of AL in children ≤24 months old. On the other hand, consumption of high-fat dairy products is positively associated with AL in children ≤24 months old.
Acute lymphoblastic leukemia (ALL) is the most common cancer in children around the globe. Mexico City has one of the highest incidence rates of childhood leukemia worldwide with 49.5 cases per ...million children under the age of 15 which is similar to that reported for Hispanic populations living in the United States. In addition, it has been noted a dismal prognosis in Mexican and Hispanic ALL pediatric population. Although ALL, like cancer in general, has its origins in endogenous, exogenous, and genetic factors, several studies have shown that the immune system also plays a deterministic role in cancer development. Among various elements of the immune system, T lymphocytes and NK cells seem to dominate the immune response against leukemia. The aim of the present study was to perform a phenotypic and functional characterization of NK cells in ALL Mexican children at the moment of diagnosis and before treatment initiation. A case-control study was conducted by the Mexican Interinstitutional Group for the Identification of the Causes of Childhood Leukemia (MIGICCL). 41 cases were incident ALL children younger than 17 years old and residents of Mexico City. 14 controls were children without leukemia, matched by age and sex with cases. NK cell function was evaluated by degranulation assays towards K562 cells and SLAM-associated protein (SAP) expression was measured by intracellular staining. All assays were performed using peripheral blood mononuclear cells from controls and patients. The results indicate that NK mediated cytotoxicity, measured by CD107a degranulation assays in response to K562 cells, was reduced in ALL patients compared to controls. Interestingly, an impaired NK cell killing of target cells was not equally distributed among ALL patients. In contrast to patients classified as high-risk, standard-risk patients did not display a significant reduction in NK cell-mediated cytotoxicity. Moreover, patients presenting a leukocyte count ≥ 50,000xmm3 displayed a reduction in NK-cell mediated cytotoxicity and a reduction in SAP expression, indicating a positive correlation between a reduced SAP expression and an impaired NK cell-mediated citotoxicity. In the present study it was observed that unlike patients with standard-risk, NK cells from children presenting high-risk ALL, harbor an impaired cytotoxicity towards K562 at diagnosis. In addition, NK cell function was observed to be compromised in patients with a leukocyte count ≥50,000xmm3, where also it was noticed a decreased expression of SAP compared to patients with a leukocyte count <50,000xmm3. These data indicate NK cell-mediated cytotoxicity is not equally affected in ALL patients, nevertheless a positive correlation between low SAP expression and decreased NK cell-mediated cytotoxicity was observed in ALL patients with a leukocyte count ≥50,000xmm3. Finally, an abnormal NK cell-mediated cytotoxicity may represent a prognostic factor for high-risk acute lymphoblastic leukemia.
Introduction
Maternal dietary consumption during pregnancy has been inconclusively associated with acute leukemia (AL) in infants, probably because epidemiological evidence has emerged mainly from ...the analysis of one-by-one nutrient, which is not a real-life scenario. Our objective was to evaluate the association between AL in Mexican children under 2 years of age and their mothers’ nutrients concomitant intake during pregnancy, as well as to explore whether there are differences between girls and boys.
Methods
We conducted a study of 110 cases of AL and 252 hospital-based controls in the Mexico City Metropolitan area from 2010 to 2019. We obtained information on maternal intake of 32 nutrients by a food frequency questionnaire and used weighted quantile sum regression to identify nutrient concomitant intakes.
Results
We found a concomitant intake of nutrients negatively associated with AL (OR 0.17; CI95% 0.03,0.88) only among girls; and we did not find a nutrient concomitant intake positively associated with AL.
Discussion
This is the first study that suggests nutrients that have been individually associated with AL are not necessarily the same in the presence of other nutrients (concomitant intake); as well as that maternal diet might reduce AL risk only in girls.
Background
In Mexico, the incidence of acute myeloid leukemia (AML) has increased in the last few years. Mortality is higher than in developed countries, even though the same chemotherapy protocols ...are used. CCAAT Enhancer Binding Protein Alpha (
CEBPA
) mutations are recurrent in AML, influence prognosis, and help to define treatment strategies.
CEBPA
mutational profiles and their clinical implications have not been evaluated in Mexican pediatric AML patients.
Aim of the Study
To identify the mutational landscape of the
CEBPA
gene in pediatric patients with
de novo
AML and assess its influence on clinical features and overall survival (OS).
Materials and Methods
DNA was extracted from bone marrow aspirates at diagnosis. Targeted massive parallel sequencing of
CEBPA
was performed in 80 patients.
Results
CEBPA
was mutated in 12.5% (10/80) of patients. Frameshifts at the N-terminal region were the most common mutations 57.14% (8/14).
CEBPA
biallelic (
CEBPA
BI
) mutations were identified in five patients. M2 subtype was the most common in
CEBPA
positive patients (
CEBPA
POS
) (
p
= 0.009); 50% of the
CEBPA
POS
patients had a WBC count > 100,000 at diagnosis (
p
= 0.004). OS > 1 year was significantly better in
CEBPA
negative (
CEBPA
NEG
) patients (
p
= 0.0001).
CEBPA
POS
patients (either bi- or monoallelic) had a significantly lower OS (
p
= 0.002). Concurrent mutations in
FLT3
,
CSF3R
, and
WT1
genes were found in
CEBPA
POS
individuals. Their contribution to poor OS cannot be ruled out.
Conclusion
CEBPA mutational profiles in Mexican pediatric AML patients and their clinical implications were evaluated for the first time. The frequency of
CEBPA
POS
was in the range reported for pediatric AML (4.5–15%).
CEBPA
mutations showed a negative impact on OS as opposed to the results of other studies.
Background
Childhood cancer is the leading cause of disease-related mortality among children aged 5–14 years in Mexico, with acute leukemia being the most common cancer among infants. Examining the ...overall dietary patterns allows for a comprehensive assessment of food and nutrient consumption, providing a more predictive measure of disease risk than individual foods or nutrients. This study aims to evaluate the association between maternal dietary patterns during pregnancy and the risk of acute leukemia in Mexican infants.
Methods
A hospital-based case–control study was conducted, comparing 109 confirmed acute leukemia cases with 152 age-matched controls. All participants (≤24 months) were identified at hospitals in Mexico City between 2010 and 2019. Data on
a posteriori
dietary patterns and other relevant variables were collected through structured interviews and dietary questionnaires. Multivariate logistic regression was employed to estimate the association between maternal dietary patterns during pregnancy and the risk of acute leukemia in infants.
Results
The “Balanced & Vegetable-Rich” pattern, characterized by a balanced consumption of various food groups and higher vegetable intake, exhibited a negative association with acute leukemia when compared to the “High Dairy & Cereals” Pattern (adjusted odds ratio OR = 0.51; 95% confidence interval CI: 0.29, 0.90). We observed that mothers who gave birth to girls and adhered to a healthy dietary pattern during pregnancy exhibited significantly lower odds of their children developing AL compared to those who gave birth to boys OR = 0.32 (95% CI 0.11, 0.97). Our results underscore the significance of maternal nutrition as a modifiable factor in disease prevention and the importance of prenatal health education.
Advances in the understanding of the pathobiology of childhood B-cell acute lymphoblastic leukemia (B-ALL) have led towards risk-oriented treatment regimens and markedly improved survival rates. ...However, treatment-related toxicities remain a major cause of mortality in developing countries. One of the most common adverse effects of chemotherapy in B-ALL is the hematologic toxicity, which may be related to genetic variants in membrane transporters that are critical for drug absorption, distribution, and elimination. In this study we detected genetic variants present in a selected group genes of the
and
families that are associated with the risk of high-grade hematologic adverse events due to chemotherapy treatment in a group of Mexican children with B-ALL.
Next generation sequencing (NGS) was used to screen six genes of the ABC and seven genes of the SLC transporter families, in a cohort of 96 children with B-ALL. The grade of hematologic toxicity was classified according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) version 5.0, Subsequently, two groups of patients were formed: the null/low-grade (grades 1 and 2) and the high-grade (grades 3 to 5) adverse events groups. To determine whether there is an association between the genetic variants and high-grade hematologic adverse events, logistic regression analyses were performed using co-dominant, dominant, recessive, overdominant and log-additive inheritance models. Odds ratio (OR) and 95% confidence intervals (95% CI) were calculated.
We found two types of associations among the genetic variants identified as possible predictor factors of hematologic toxicity. One group of variants associated with high-grade toxicity risk:
rs129081;
rs227409;
rs939338, rs1132776, rs3749442, rs4148575, rs4148579 and rs4148580; and another group of protective variants that includes
rs212087 and rs212090;
rs4149170, rs4149171 and rs955434.
There are genetic variants in the
and
transporter families present in Mexican children with B-ALL that can be considered as potential risk markers for hematologic toxicity secondary to chemotherapeutic treatment, as well as other protective variants that may be useful in addition to conventional risk stratification for therapeutic decision making in these highly vulnerable patients.
Background and Aims Acute lymphoblastic leukemia (ALL) is the most common childhood cancer worldwide. Mexican patients have high mortality rates, low frequency of good prognosis biomarkers (i.e., ...ETV6-RUNX1 ) and a high proportion is classified at the time of diagnosis with a high risk to relapse according to clinical features. In addition, very early relapses are more frequently observed than in other populations. The aim of the study was to identify new potential biomarkers associated with very early relapse in Mexican ALL children through transcriptome analysis. Methods Microarray gene expression profiling on bone marrow samples of 54 pediatric ALL patients, collected at time of diagnosis and/or at relapse, was performed. Eleven patients presented relapse within the first 18 months after diagnosis. Affymetrix Human Transcriptome Array 2.0 (HTA 2.0) was used to perform gene expression analysis. Annotation and functional enrichment analyses were carried out using Gene Ontology, KEGG pathway analysis and Ingenuity Pathway Analysis tools. Results BLVRB, ZCCHC7, PAX5, EBF1, TMOD1 and BLNK were differentially expressed (fold-change >2.0 and p value <0.01) between relapsed and non-relapsed patients. Functional analysis of abnormally expressed genes revealed their important role in cellular processes related to the development of hematological diseases, cancer, cell death and survival and in cell-to-cell signaling interaction. Conclusions Our data support previous findings showing the relevance of PAX5 , EBF1 and ZCCHC7 as potential biomarkers to identify a subgroup of ALL children in high risk to relapse.
Background Mexico City has one of the highest incidences and mortality rates of acute lymphoblastic leukemia (ALL) in the world and a high frequency of early relapses (17%) and early mortality (15%). ...Otherwise, childhood overweight and obesity are reaching epidemic proportions. They have been associated with poor outcomes in children with ALL. The aim of present study was to identify if overweight and obesity are predictors of early mortality and relapse in Mexican children with ALL. Methods A multicenter cohort study was conducted. ALL children younger than 15 years old were included and followed-up during the first 24 months after diagnosis. Overweight and obesity were classified according World Health Organization (WHO) and Centers for Disease Control and Prevention (CDC) criteria. Early mortality and early relapses were the main outcomes. Results A total of 1070 children were analyzed. Overweight/obesity at diagnosis were predictors of early mortality (WHO: HR = 1.4, 95%CI:1.0-2.0; CDC: HR = 1.6, 95%CI:1.1-2.3). However, no associations between overweight (WHO: HR = 1.5, 95%CI:0.9-2.5; CDC: HR = 1.0; 95% CI:0.6-1.6) and obesity (WHO: HR = 1.5, 95%CI:0.7-3.2; CDC: HR = 1.4; 95%CI:0.9-2.3) with early relapse were observed. Conclusions Overweight and obese patients embody a subgroup with high risk of dying during leukemia treatment. Keywords: Children, Leukemia, Overweight, Obesity, Early mortality, Mexico
Background:
Acute lymphoblastic leukemia (ALL) is the main type of cancer in children. In Mexico and other Hispanic populations, the incidence of this neoplasm is one of the highest reported ...worldwide. Functional polymorphisms of various enzymes involved in the metabolism of xenobiotics have been associated with an increased risk of developing ALL, and the risk is different by ethnicity. The aims of the present study were to identify whether
NQO1, CYP2E1
, and
NAT2
polymorphisms or some genotype-environmental interactions were associated with ALL risk in Mexican children.
Methods:
We conducted a case-control study including 478 pediatric patients diagnosed with ALL and 284 controls (children without leukemia). Ancestry composition of a subset of cases and controls was assessed using 32 ancestry informative markers. Genetic-environmental interactions for the exposure to hydrocarbons were assessed by logistic regression analysis.
Results:
The polymorphisms rs1801280 (OR 1.54, 95% CI 1.21–1.93), rs1799929 (OR 1.96, 95% CI 1.55–2.49), and rs1208 (OR 1.44, 95% CI 1.14–1.81) were found to increase the risk of ALL; being the risks higher under a recessive model (OR 2.20, 95% CI 1.30–1.71, OR 3.87, 95% CI 2.20–6.80, and OR 2.26, 95% CI 1.32–3.87, respectively). Gene-environment interaction analysis showed that
NAT2
rs1799929 TT genotype confers high risk to ALL under exposure to fertilizers, insecticides, hydrocarbon derivatives, and parental tobacco smoking. No associations among
NQO1, CYP2E1
, and ALL were observed.
Conclusion:
Our study provides evidence for the association between
NAT2
polymorphisms/gene-environment interactions, and the risk of childhood ALL in Mexican children.
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