Childhood Cancer Worldwide Research Articles

METB-10. GENOME-WIDE DNA METHYLATION PROFILING OF PRIMARY CELLS FROM PEDIATRIC BRAIN TUMORS IS AN INFORMATIVE TOOL TO ASSESS CELL CULTURE RELIABILITY AND IN VITRO SELECTION

Abstract BACKGROUND Recent genomic and epigenomic profiling analyses have provided remarkable insights into biology of pediatric brain tumors (pBTs). Nonetheless, pBTs represent the deadliest childhood cancer worldwide and are associated with high morbidity. In vitro models of pBT are instrumental for better understanding the mechanisms contributing to oncogenesis and testing new therapies; thus, ideally, they should recapitulate the original tumor. METHODS We applied DNA methylation (DNAm) and copy number variation (CNV) profiling to characterize 241 pBT samples from medulloblastomas, high-grade gliomas, low-grade gliomas, ependymoma, and meningiomas. The cohort included 155 tumors and 86 pBT-derived cell cultures. For the analysis of pBT-derived cell cultures, we have considered the most significant variables: i) cultured medium (serum vs serum-free), ii) passages (late vs early), and iii) dimensionality (2D vs 3D cultures). As a complementary approach, the global relationships between the 241 samples based on the DNAm information were visualized using fast interpolation-based t-distributed stochastic neighbour embedding (t-SNE) and differentially methylated regions in tumors compared to cell models were identified. RESULTS Our findings showed that cell cultures cultured under stem-like cells enriching conditions (serum-free, 3D) and maintained in culture early passages are characterized by a higher degree of faithfulness to the parental tumors, in terms of methylation class and CNV profile, than the counterparts maintained in 2D cultures, in presence of serum, and maintained for extended passages. All divergent cells clustered together acquiring a common deregulated epigenetic signature suggesting a shared selective pressure. We identified a set of hypomethylated genes shared among unfaithful cells converging on response to growth factors and migration pathways, such as signaling cascade activation, tissue organization, and cellular migration. CONCLUSIONS DNAm and CNV are informative tools that should be used to assess the recapitulation of pBT-cells from parental tumors.

Children with cancer at the end of life in a middle-income country: integrated pediatric palliative care improves outcomes

BackgroundIn 2020, the Global Cancer Observatory reported 280,000 cases of childhood cancer worldwide, with a higher burden of disease and mortality rates in low- and middle-income countries. In 2022, the National Institute of Health reported 1708 new cases of childhood cancer in Colombia and an overall survival rate of approximately 55%. The aim of this study is to compare outcomes in children with cancer in the hospital setting during the last 72 h of life who received concurrent Pediatric Palliative Care (PPC) versus oncology care alone.MethodsAn observational descriptive study was conducted between January 2013 and June 2022 in a center for pediatric patients with oncological diagnoses. In 2017, the PPC team was created. Patients between 28 days and 17 years of age who were hospitalized at least 72 h before death were included. A retrospective review of the medical records of patients in the last 72 h of life was performed. Two cohorts were established: oncology-alone group received exclusive management by oncology, and oncology and PPC received concurrent oncology and PPC management since the diagnosis.ResultsWe evaluated 257 medical records of deceased pediatric patients with cancer diagnoses. For the first cohort (2013–2017), 136 patients were included; for the second cohort (2018 and 2022), 121 patients were evaluated. The most frequent diagnosis was leukemia [47.1% (n = 121)]. No significant difference was found in either group between dyspnea, pain, and seizures. Dyspnea was the most frequent symptom in both groups. Agitation and anxiety were reported more frequently in children from the oncology-alone group (22.1% and 13.2%, respectively). The oncology and PPC group received more psychology and social work consultation (94.2% and 70.2% vs. 84.6 and 54.4% in the oncology alone group) and had a higher percentage of advance care planning (79.3% vs. 62.5% in the oncology alone group).ConclusionsThis retrospective study highlights that PPC at the end of life (EoL) offers a holistic approach to the physical and psychosocial symptoms experienced by children with cancer; these patients received more comfort through symptom management and less aggressive treatment at the EoL. The availability of a PPC team may contribute to improvements in the quality of end-of-life care.Trial registrationretrospectively registered.

Population-based overall and net survival of childhood leukemia at 1-, 5-, and 10-years of follow-up in three regions of Colombia.

Childhood leukemia (CL) is the most common type of childhood cancer worldwide and in Colombia. Thanks to therapeutic innovations and improved access, the survival of children and adolescents with leukemia has increased considerably worldwide, especially in high-income countries. In Colombia, a middle-income country, survival has also been observed to increase in big cities. However, the survival rate in intermediate cities is still unknown. This study aimed to assess short- and long-term survival rates of children with leukemia coming from three intermediate Colombian cities as well as to compare overall survival (OS) rates versus relative survival (RS) rates of this population of children. Data from population-based cancer registries in three Colombian cities (Bucaramanga metropolitan area, Manizales and Pasto) were analyzed. OS and RS of up to 10 years were estimated for children who were diagnosed with leukemia at ages 0-18 years between 1998 and 2018 and followed up for vital status. RS was calculated using the Pohar-Perme method. We performed a separate survival analysis by gender and by period of diagnosis (before and after 2010). We included data from 507 children and adolescents diagnosed with leukemia. RS at 1, 5 and 10 years after diagnosis were similar between the populations for the respective timeframes (RS Bucaramanga 86.5%, 66.9% and 52.5%; Manizales 81.1%, 62.8% and 61.1%; Pasto 81.7% at 1 year, 66.2% at 5 years and 59.4% at 10 years). OS and RS were very similar for all estimates and periods. There were no clear differences in RS between genders across the three population-based cancer registries and there was an improvement in RS after 2010, particularly in Bucaramanga and Pasto. Our study reports similar 5-year survival rates for CL in these Colombian cities compared to rates documented in other Latin American countries and larger Colombian cities. These are far below what is reported in high-income settings. This highlights opportunities for improvement in the Colombian health system, where numerous barriers persist in terms of suspicion, diagnosis and continuity of treatment for CL.

Maternal serum concentrations of per- and polyfluoroalkyl substances and childhood acute lymphoblastic leukemia.

Per- and polyfluoroalkyl substances (PFAS) are widespread and environmentally persistent chemicals with immunotoxic properties. Children are prenatally exposed through maternal transfer of PFAS to cord blood, but no studies have investigated the relationship with childhood leukemia. We measured maternal serum levels of 19 PFAS in first-trimester samples collected in 1986-2010 and evaluated associations with acute lymphoblastic leukemia in full-term offspring (aged younger than 15 years) for 400 cases and 400 controls in the Finnish Maternity Cohort, matched on sample year, mother's age, gestational age, birth order, and child's sex. We analyzed continuous and categorical exposures, estimating odds ratios (ORs) and 95% confidence intervals (CIs) via conditional logistic regression adjusted for maternal smoking and correlated PFAS (ρ ≥ ±0.3). We also stratified by calendar period, mean diagnosis age, and the child's sex. N-methyl-perfluorooctane sulfonamidoacetic acid was associated with acute lymphoblastic leukemia in continuous models (per each doubling in levels: ORperlog2 = 1.22, 95% CI = 1.07 to 1.39), with a positive exposure-response across categories (OR>90th percentile = 2.52, 95% CI = 1.33 to 4.78; Ptrend = .01). Although we found no relationship with perfluorooctane sulfonic acid overall, an association was observed in samples collected in 1986-1995, when levels were highest (median = 17.9 µg/L; ORperlog2 = 4.01, 95% CI = 1.62 to 9.93). A positive association with perfluorononanoic acid was suggested among first births (Pinteraction = .06). The N-methyl-perfluorooctane sulfonamidoacetic acid association was mainly limited to children diagnosed before age 5 years (Pinteraction = .02). We found no consistent patterns of association with other PFAS or differences by sex. These novel data offer evidence of a relationship between some PFAS and risk of the most common childhood cancer worldwide, including associations with the highest levels of perfluorooctanesulfonic acid and with a precursor, N-methyl-perfluorooctane sulfonamidoacetic acid.

Abordare multidisciplinară în oncologia pediatrică

Children’s cancer is par excellence a disease of a multidisciplinary nature. It is therefore unrealistic to expect a single person with a single qualification to have the skills and capabilities to carry out a comprehensive assessment and institute competent interventions in all these areas. Decisions and interventions will be in accordance with the decision of the multidisciplinary committee of therapeutic indications.According to the WHO, every year approximately 400,000 children and adolescents between the ages of 0 and 19 develop cancer. The most common childhood cancers include leukemias, brain cancers, lymphomas, and solid tumors such as neuroblastoma and Wilms tumors [1, 2, 3]. In 2019 globally there were 291.3 thousand new cases and 98.8 thousand deaths from childhood cancer worldwide, with a prevalence of 1.8 million [4]. However, the 5-year survival of childhood cancer patients has increased impressively to more than 80% in recent decades, mainly attributed to improved diagnostic technologies and multiagent cytotoxic regimens.

ABSORBING MARKOV CHAINS TO CHARACTERIZE AND PREDICT METASTASIS PATHWAYS IN CHILDHOOD CANCER

Cancer and its metastasis in children have a high degree of lethality and side effects, so its characteristics need to be studied independently of adult cancer. The aim of this work is to model the metastasis pathways of the main childhood cancers worldwide by Absorbing Markov Chains, an important mathematical tool used for different applications in science. Statistical information was collected to detect the main affected organs (primary sites) and those where cancer cells generally spread and metastasize (secondary sites). Taking into account that it is a branching process, a directed graph was developed, and the associated transition matrices for the first and second metastases were constructed. Organs whose cancers generally remain encapsulated and do not spread their cancer cells are considered absorbing states in terms of Markov processes. For the selected organs, the probability of ending up in each of the absorption states according to the primary site was calculated, as well as the number of possible previous metastases until reaching one of these states. Although the lung in childhood cancer is not a characteristic primary site, it is one of the main sites of metastasis. Therefore, this work dedicates a section to including this organ as a site of possible metastasis.

Optimizing a Deep Residual Neural Network with Genetic Algorithm for Acute Lymphoblastic Leukemia Classification.

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer worldwide, and it is characterized by the production of immature malignant cells in the bone marrow. Computer vision techniques provide automated analysis that can help specialists diagnose this disease. Microscopy image analysis is the most economical method for the initial screening of patients with ALL, but this task is subjective and time-consuming. In this study, we propose a hybrid model using a genetic algorithm (GA) and a residual convolutional neural network (CNN), ResNet-50V2, to predict ALL using microscopy images available in ALL-IDB dataset. However, accurate prediction requires suitable hyperparameters setup, and tuning these values manually still poses challenges. Hence, this paper uses GA to find the best hyperparameters that lead to the highest accuracy rate in the models. Also, we compare the performance of GA hyperparameter optimization with Random Search and Bayesian optimization methods. The results show that GA optimization improves the accuracy of the classifier, obtaining 98.46% in terms of accuracy. Additionally, our approach sheds new perspectives on identifying leukemia based on computer vision strategies, which could be an alternative for applications in a real-world scenario.

Trends in paediatric central nervous system tumour incidence by global region from 1988 to 2012.

Central nervous system (CNS) tumours comprise 20% of childhood cancers worldwide. Whether childhood CNS tumour incidence has increased over time across geographic regions remains to be explored. We identified CNS cancers in the Cancer in Five Continents (CI5) data and estimated age standardized incidence rates (ASRs; cases/million children) and 95% confidence intervals (95% CI), male-to-female incidence rate ratios (IRR; 95% CI) and average annual percent change in incidence (AAPC; 95% CI) by geographic region for children aged 0-19 years where data were available using Poisson regression and generalized estimating equations (GEE). Cancers included: astrocytic tumours, medulloblastoma, ependymal, oligodendroglial and mixed glioma, glioma of uncertain origin, and other embryonal tumours. Geographic regions were defined using the United Nations geoscheme. There were 56 468 CNS cancers included in the study. ASRs were highest for astrocytic tumours globally in 2012 (ASR: 5.83; 95% CI: 5.68-5.99). Globally, all cancers exhibited a male excess in incidence. Regionally, only medulloblastoma had a consistently elevated male-to-female IRR at 1.4-2.2. Globally, incidence decreased for astrocytic tumours in GEE models (AAPC: -1.66; 95% CI: -3.04 to -0.26) and increased for medulloblastoma (AAPC 0.66; 95% CI: 0.19-1.14), ependymal tumours (AAPC: 1.49; 95% CI: 1.49; 95%: 0.69-2.30), glioma of uncertain origin (AAPC: 4.76; 95% CI: 1.17-1.14) and other embryonal tumours (AAPC: 3.58; 95% CI: 2.03-5.15). Regional variation in incidence trends was observed. Countries moving from lower to higher Human Development Index (HDI) over time did not appear to drive observed incidence trends. Epidemiologic and molecular studies on underlying mechanisms for changes in the global incidence of CNS tumours are necessary.

Prevalence, Demographic Patterns, and Outcome of Childhood Malignancies in a Tertiary Hospital in Nigeria: A 15-Year Retrospective Study

Abstract Objectives Childhood cancers are increasingly recognized as a cause of childhood morbidity and mortality following improvement in immunization programs and sanitation against communicable diseases. With improvement in health care, better survival outcomes have been reported in childhood cancers worldwide. However, mortality associated with childhood cancers remains high in developing countries. This study aims to determine the prevalence, demographic characteristics, and outcome of childhood cancers seen in Lagos University Teaching Hospital, Lagos, Nigeria. Methods A retrospective study analyzed 749 cases of childhood malignancies between 2003 and 2017. Data on gender, age at diagnosis, diagnosis, and outcome were extracted using a data extraction proforma. Data were analyzed using SPSS v23. P value of .05 was considered statistically significant. Results Median age at diagnosis was 4.75 years with a male to female ratio of 1.3:1. Highest prevalence was noticed with hematological malignancies (41%), Wilm’s tumor (18%), retinoblastoma (13%), and soft tissue tumors (6.5%) and lowest prevalence with testicular cancers (0.3%). Apart from liver malignancy, males had a higher incidence in all malignancies. Median age at diagnosis was 12 years for nasopharyngeal carcinoma, 11 years for bone cancers, 8 years for gynecological cancers, 6 years for hematological cancers, and 0.47 years for testicular cancers. Overall mortality rate was 30%, and a significant number (53%) were lost to follow-up (discharged against medical advice, defaulted, financial burden, medical tourism). Hematological malignancies had the highest mortality rates, with Wilm’s tumor having best survival chances (lowest mortality). Conclusion Prevalence patterns mirror what was obtained in other centers (Jos, Ife, and Ibadan). A mortality rate of 30% is significant. Financial burden, religious beliefs, delay in presentation, and ignorance are major hindrances to health care and might contribute significantly to overall mortality and outcome. More needs to be done concerning childhood cancers.

MYC gene associated polymorphisms and Wilms tumor risk in Chinese children: a four-center case-control study.

Wilms tumor (WT) is a common embryonal malignancy in the kidney, ranking fourth in childhood cancer worldwide. MYC, a critical proto-oncogene, plays an important role in tumorigenesis. Single nucleotide polymorphisms in the MYC gene may lead to the deregulation of MYC proto-oncogene protein and thereby promote the initiation and development of tumors. Here, we assessed the association between MYC gene associated polymorphisms and WT susceptibility by performing a case-control study with 355 cases and 1070 controls. Two MYC gene associated polymorphisms (rs4645943 C > T, rs2070583 A > G) were genotyped by TaqMan technique. Odds ratios (ORs) and 95% confidence intervals (CIs) were used for evaluating the association between these two polymorphisms and WT susceptibility. No significant association was detected between the selected polymorphisms and WT risk in the overall analysis as well as stratification analysis. These results indicate that neither of two selected MYC gene associated polymorphisms might affect WT susceptibility in the Chinese population. Large well-designed studies with diverse ethnicities are warranted to verify these results.

Identification and Characterization of Novel Fusion Genes with Potential Clinical Applications in Mexican Children with Acute Lymphoblastic Leukemia.

Acute lymphoblastic leukemia is the most common type of childhood cancer worldwide. Mexico City has one of the highest incidences and mortality rates of this cancer. It has previously been recognized that chromosomal translocations are important in cancer etiology. Specific fusion genes have been considered as important treatment targets in childhood acute lymphoblastic leukemia (ALL). The present research aimed at the identification and characterization of novel fusion genes with potential clinical implications in Mexican children with acute lymphoblastic leukemia. The RNA-sequencing approach was used. Four fusion genes not previously reported were identified: CREBBP-SRGAP2B, DNAH14-IKZF1, ETV6-SNUPN, ETV6-NUFIP1. Although a fusion gene is not sufficient to cause leukemia, it could be involved in the pathogenesis of the disease. Notably, these new translocations were found in genes encoding for hematopoietic transcription factors which are known to play an important role in leukemogenesis and disease prognosis such as IKZF1, CREBBP, and ETV6. In addition, they may have an impact on the prognosis of Mexican pediatric patients with ALL, with the potential to be included in the current risk stratification schemes or used as therapeutic targets.

Estimating the total incidence of global childhood cancer: a simulation-based analysis.

Accurate estimates of childhood cancer incidence are important for policy makers to inform priority setting and planning decisions. However, many countries do not have cancer registries that quantify the incidence of childhood cancer. Moreover, even when registries do exist, they might substantially underestimate the true incidence, since children with cancer might not be diagnosed. We therefore aimed to provide estimates of total childhood cancer incidence accounting for underdiagnosis. We developed a microsimulation model to simulate childhood cancer incidence for 200 countries and territories worldwide, taking into account trends in population growth and urbanicity, geographical variation in cancer incidence, and health system barriers to access and referral that contribute to underdiagnosis. To ensure model results were consistent with epidemiological data, we calibrated the model to publicly available cancer registry data using a Bayesian approach in which the observed data are fixed and the model parameters (cancer incidence and probabilities of health system access and referral) are random variables. We estimated the total incidence of childhood cancer (diagnosed and undiagnosed) in each country in 2015 and projected the number of cases from 2015 to 2030. Our model estimated that there were 397 000 (95% uncertainty interval [UI] 377 000-426 000) incident cases of childhood cancer worldwide in 2015, of which only 224 000 (95% UI 216 000-237 000) were diagnosed. This finding suggests that 43% (172 000 of 397 000) of childhood cancer cases were undiagnosed globally, with substantial variation by region, ranging from 3% in western Europe (120 of 4300) and North America (300 of 10 900) to 57% (43 000 of 76 000) in western Africa. In south Asia (including southeastern Asia and south-central Asia), the overall proportion of undiagnosed cases was estimated to be 49% (67 000 of 137 000). Taking into account population projections, we estimated that there will be 6·7 million (95% UI 6·3-7·2) cases of childhood cancer worldwide from 2015 to 2030. At current levels of health system performance, we estimated that 2·9 million (95% UI 2·7-3·3) cases of childhood cancer will be missed between 2015 and 2030. Childhood cancer is substantially underdiagnosed, especially in south Asia and sub-Saharan Africa (including western, eastern, and southern Africa). In addition to improving treatment for childhood cancer, health systems must be strengthened to accurately diagnose and effectively care for all children with cancer. As countries expand universal health coverage, these estimates of total incidence will hopefully help guide efforts to appropriately increase health system capacity to ensure access to effective childhood cancer care. Boston Children's Hospital, Dana-Farber Cancer Institute, Harvard T H Chan School of Public Health, Harvard Medical School, National Cancer Institute, SickKids, St Jude Children's Research Hospital, and Union for International Cancer Control.

LMO1 Super-Enhancer rs2168101 G>T Polymorphism Reduces Wilms Tumor Risk

Wilms tumor is one of the most prevalent pediatric malignancies in childhood cancer worldwide. A genome-wide association study recognized that LIM domain only 1 (LMO1) increases the risk of oncogenic potential. An association has been found that LMO1 gene polymorphisms are associated with the susceptibility to Wilms tumor. One hundred forty-five children with Wilms tumor and 531 cancer-free children were included in this hospital-based case-control study. Five potentially functional polymorphisms in the LMO1 gene (rs2168101 G>T, rs1042359 A>G, rs11041838 G>C, rs2071458 C>A and rs3750952 G>C) were genotyped by the TaqMan method. The association between selected polymorphisms and Wilms tumor susceptibility was measured by calculating the odds ratio (OR) and the 95% confidence interval (CI). Only rs2168101 G>T polymorphism was found to have a significant protective effect against Wilms tumor (GT vs. GG: adjusted OR=0.58, 95% CI=0.39-0.88, P=0.010; GT/TT vs. GG: adjusted OR=0.67, 95% CI=0.46-0.97, P=0.034). Moreover, carriers of 3-5 protective genotypes had significantly lower tumor risk than carriers of 0-2 protective genotypes (adjusted OR=0.62, 95% CI=0.42-0.91, P=0.022). The stratified analysis showed that the protective effect of rs2168101 GT/TT was predominant in males, and rs2071458 GT/TT was predominant in females. Regarding the combined risk genotypes, the analysis indicated that the 3-5 protective genotypes collectively decreased Wilms tumor risk in females. These results suggest that LMO1 gene rs2168101 G>T polymorphism may help prevent Wilms tumor, but this conclusion should be verified in other populations and additional studies.

Improving diagnosis and treatment of acute childhood leukemia in Uganda: impact of flow cytometry

Acute leukemia is the most common childhood cancer worldwide. Over the last few decades, survival rates have improved dramatically, with current 5-year overall survival rates for acute lymphoblastic leukemia (ALL) in high-income countries estimated at >90%.[1][1] This improvement in survival is

Association between <em>TP53</em> gene Arg72Pro polymorphism and Wilms’ tumor risk in a Chinese population

Wilms’ tumor is one of the most prevalent pediatric malignancies, ranking fourth in childhood cancer worldwide. TP53 is a critical tumor suppressor gene, which encodes a 53 kDa protein, p53. The p53 functions to protect against cancer by regulating cell cycle and apoptosis and maintaining DNA integrity. TP53 gene is highly polymorphic. Several TP53 gene polymorphisms have been considered to be associated with cancer risk. Of them, a nonsynonymous polymorphism, Arg72Pro (rs1042522 C>G), has been most extensively studied for the association with cancer risk; however, few studies have investigated its effect on Wilms’ tumor. Because of the central role of p53 in cell cycle control, the TP53 gene Arg72Pro polymorphism is also a good potential candidate predisposition locus for this pediatric cancer. We genotyped this polymorphism in 145 patients and 531 cancer-free controls recruited from Chinese children by Taqman methodology. Overall, our result suggested a lack of association between the TP53 gene Arg72Pro polymorphism and Wilms’ tumor. In the stratified analysis, we found that carriers of CG/GG genotypes had a significantly increased Wilms’ tumor risk in children not older than 18 months (adjusted odds ratio =2.04, 95% confidence interval =1.003–4.13, P=0.049) compared with CC genotype carriers. Our study indicated that the TP53 gene Arg72Pro polymorphism may have a weak, age-related effect on Wilms’ tumor risk in Chinese children. These findings need further validations in other populations with larger sample size.

Displacement of Coilin in Cajal Body Is Related to Drug Resistance of Childhood Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is one of the most prevalent childhood cancers worldwide. Although the 5-year event-free survival rate of ALL patients have been improved to about 80% in latest years, there are approximately 15% of ALL cases in China remained to be poorly responsive to chemotherapy treatments, and therefore manifested in poor prognosis. Daunorubicin (DNR) is a key agent (Fig.1), as a chemical can cause DNA damages, in the formula for the treatments of ALL patients, the drug resistance to DNR will directly contributed to the failing of treatments and poor prognosis. In clinic, there is an urgent need for the development of assays that can be used for the prediction of DNR resistance, especially the involvement of visual indicators. Coilin is a major scaffold and marker protein of the functional nuclear structure - Cajal body (CB). We found that DNR was able to induce vast nucleolar accumulation of coilin in ALL leukemia cell lines of RS4;11 and Reh. Such accumulation of coilin was dose-dependently correlated to the increase of drug concentrations (Fig.2). At the molecular level, we also observed that the expression levels of coilin increased based on treatment of DNR(Fig.3B), while the expression levels of p27 protein was much lower in DNR insensitive cells with less significant changes of Coilin-indicated CB morphology as compared to the sensitive cells (Fig.3A). The over-expression of Coilin inhibited p27 expression and coilin knock-down increased the expression of p27(Fig.3 C,D). Our study suggested that coilin could be considered as a visual maker for the detection of daunorubicin resistance in ALL cells, and the mechanism possibly involved the regulation of drug sensitivity -related protein p27 through Cajal body -mediated RNA processing, during which coilin is an important participator with crucial functions.Results1.Daunorubicin inhibits topoisomerase II activity2.Daunorubicin(DNR)-induced DNA damage triggers the nucleolar accumulation of coilin3.Coilin inhibit the expression of p27 and may play a role in the drug resistance of leukemia through p27 [Display omitted] [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Gene Expression Profiling of Acute Lymphoblastic Leukemia in Children with Very Early Relapse

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. 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 18months 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. 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. 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.

Minimal Residual Disease Detection and Evolved IGH Clones Analysis in Acute B Lymphoblastic Leukemia Using IGH Deep Sequencing.

Acute B lymphoblastic leukemia (B-ALL) is one of the most common types of childhood cancer worldwide and chemotherapy is the main treatment approach. Despite good response rates to chemotherapy regiments, many patients eventually relapse and minimal residual disease (MRD) is the leading risk factor for relapse. The evolution of leukemic clones during disease development and treatment may have clinical significance. In this study, we performed immunoglobulin heavy chain (IGH) repertoire high throughput sequencing (HTS) on the diagnostic and post-treatment samples of 51 pediatric B-ALL patients. We identified leukemic IGH clones in 92.2% of the diagnostic samples and nearly half of the patients were polyclonal. About one-third of the leukemic clones have correct open reading frame in the complementarity determining region 3 (CDR3) of IGH, which demonstrates that the leukemic B cells were in the early developmental stage. We also demonstrated the higher sensitivity of HTS in MRD detection and investigated the clinical value of using peripheral blood in MRD detection and monitoring the clonal IGH evolution. In addition, we found leukemic clones were extensively undergoing continuous clonal IGH evolution by variable gene replacement. Dynamic frequency change and newly emerged evolved IGH clones were identified upon the pressure of chemotherapy. In summary, we confirmed the high sensitivity and universal applicability of HTS in MRD detection. We also reported the ubiquitous evolved IGH clones in B-ALL samples and their response to chemotherapy during treatment.

The surgeon's role in childhood cancer worldwide

The surgeon's role in childhood cancer worldwide

Childhood Pre-B acute lymphoblastic leukemia and glutathione S-transferase omega 1 and 2 polymorphisms.

Acute lymphoblastic leukemia (ALL) is the most prevalent malignancy among children and makes up 23% of total childhood cancers worldwide. Pre-B ALL is one of the most common ALLs, comprising about 80% of childhood cases. A variety of genes are involved in metabolizing carcinogens. These gene polymorphisms can result in less efficient or overly-down metabolic pathways, which may contribute to the susceptibility to develop cancer. Glutathione S-transferase omega (GSTO) is a new known class among GSTs superfamily. GSTO1 and GSTO2 polymorphisms have been reported to be related to several types of disease. We assessed the association between GSTO1 and GSTO2 polymorphisms and childhood pre-B ALL risk in Iran. This case-control study analyzed GSTO1 A140D (rs. 4925) and GSTO2 N142D (rs. 156697) gene polymorphisms using a polymerase chain reaction-restriction fragment length polymorphism method, in 100 patients and 120 healthy controls. The genotype frequencies were not significantly different between patients and healthy controls. Odds ratio (95% confidence intervals) for mutant homozygotes were 1.54 (0.628-3.778) and 0.791 (0.349-1.793) for GSTO1 A140D and GSTO2 N142D, respectively. This study found no significant association between Pre-B ALL and GSTO1 A140D and GSTO2 N142D polymorphisms.