Risk Of Acute Lymphoblastic Leukemia Research Articles

Mutated IKZF1 is an independent marker of adverse risk in acute myeloid leukemia

Genetic lesions of IKZF1 are frequent events and well-established markers of adverse risk in acute lymphoblastic leukemia. However, their function in the pathophysiology and impact on patient outcome in acute myeloid leukemia (AML) remains elusive. In a multicenter cohort of 1606 newly diagnosed and intensively treated adult AML patients, we found IKZF1 alterations in 45 cases with a mutational hotspot at N159S. AML with mutated IKZF1 was associated with alterations in RUNX1, GATA2, KRAS, KIT, SF3B1, and ETV6, while alterations of NPM1, TET2, FLT3-ITD, and normal karyotypes were less frequent. The clinical phenotype of IKZF1-mutated AML was dominated by anemia and thrombocytopenia. In both univariable and multivariable analyses adjusting for age, de novo and secondary AML, and ELN2022 risk categories, we found mutated IKZF1 to be an independent marker of adverse risk regarding complete remission rate, event-free, relapse-free, and overall survival. The deleterious effects of mutated IKZF1 also prevailed in patients who underwent allogeneic hematopoietic stem cell transplantation (n = 519) in both univariable and multivariable models. These dismal outcomes are only partially explained by the hotspot mutation N159S. Our findings suggest a role for IKZF1 mutation status in AML risk modeling.

Day Care in Infancy and Risk of Childhood Acute Lymphoblastic Leukaemia: Findings from UK Case - Control Study

Day Care in Infancy and Risk of Childhood Acute Lymphoblastic Leukaemia: Findings from UK Case - Control Study

Maternal medically diagnosed infection and antibiotic prescription during pregnancy and risk of childhood cancer: A population-based cohort study in Taiwan, 2004 to 2015.

While associations between maternal infections during pregnancy and childhood leukemia in offspring have been extensively studied, the evidence for other types of childhood cancers is limited. Additionally, antibiotic exposure during pregnancy could potentially increase the risk of childhood cancers. Our study investigates associations between maternal infections and antibiotic prescriptions during pregnancy and the risk of childhood cancer in Taiwan. We conducted a population-based cohort study using the Taiwan Maternal and Child Health Database (TMCHD), linked with national health and cancer registries. The study included 2 267 186 mother-child pairs, and the median follow-up time was 7.96 years. Cox proportional hazard models were utilized to estimate effects. Maternal infections during pregnancy were associated with a moderate increase in the risk of childhood hepatoblastoma (adjusted hazard ratio [HR] = 1.34; 95% confidence interval [CI]: 0.90-1.98) and a weaker increase in the risk of childhood acute lymphoblastic leukemia (ALL) (adjusted HR = 1.15; 95% CI: 0.99-1.35). Antibiotic prescriptions during pregnancy were also associated with an elevated risk of childhood ALL (adjusted HR = 1.30; 95% CI: 1.04-1.63), particularly with tetracyclines (adjusted HR = 2.15; 95% CI: 1.34-3.45). Several specific antibiotics were also associated with an increased risk of hepatoblastoma and medulloblastoma. Children exposed in utero to antibiotic prescription or both infections and antibiotics during pregnancy were at higher risk of developing ALL. Our findings suggest that there are associations between maternal infections, antibiotic use during pregnancy and the risk of several childhood cancers in addition to ALL and highlight the importance of further research in this area.

Gene-Environment Analyses Reveal Novel Genetic Candidates with Prenatal Tobacco Exposure in Relation to Risk for Childhood Acute Lymphoblastic Leukemia.

Associations between maternal tobacco exposure during pregnancy and childhood acute lymphoblastic leukemia (ALL) have yielded mixed results. This may be due to biases in self-reported smoking or other differences in individual-level risk factors. We utilized a biological marker of maternal tobacco exposure to evaluate the association between maternal tobacco exposure during pregnancy, genetics, and subsequent childhood ALL risk in two large population-based studies of childhood ALL in California. Maternal exposure to tobacco smoke was assessed with a validated methylation marker (cg05575921) of the aryl hydrocarbon receptor repressor (AHRR) gene in newborn dried blood spots. We adjusted for sex, birthweight, gestational age, mode of delivery, year of birth, AHRR quantitative trait locus (mQTL) rs77111113, and a polygenetic risk score for childhood ALL. We additionally adjusted for principal components in a gene-environment interaction testing method that incorporates gene-only and environment-only effects along with interactions. AHRR hypomethylation overall was not associated with childhood ALL. In gene-environment interaction testing, several genetic variants displayed significant interaction with AHRR hypomethylation and childhood ALL. Our results suggest that novel candidates in PTPRK and DPP6 may play a role in tobacco-related leukemogenesis. Further research is necessary to better understand the effects of tobacco and these variants on childhood ALL risk. Despite the lack of an overall "main effect," tobacco exposure during pregnancy affects childhood ALL risk depending on specific genetic variants.

Association of methionine synthase reductase (MTRR A66G) polymorphism with susceptibility to acute lymphoblastic leukemia

Background and Objectives. The enzyme methionine synthase reductase is involved in cellular methylation reactions, DNA synthesis, and epigenetic processes. It is encoded by the MTRR gene, which garnered a lot of attention in current medical genetics research. This study was conducted to study the association between MTRR (A66G) polymorphism and the risk of developing acute lymphoblastic leukemia among Sudanese patients. Materials and Methods. This is a case-control study in which 150 patients with acute lymphoblastic leukemia (ALL) and 150 healthy participants as a control group were enrolled. DNA was extracted and analyzed for the MTRR (A66G) polymorphism using the real-time polymerase chain reaction. Results. Based on flow cytometry results, B-ALL was more common (79%) than T-ALL (21%). The comparison of hematological parameters in acute lymphoblastic leukemia subtypes showed a statistically significant high mean total white blood count (P=0.000) and mean blast percentage (P=0.050) in patients with T-ALL. The molecular analysis showed that the incidence of the MTRR homozygous genotypes AA and GG were higher in the patients (44% and 9.3%, respectively) compared to the control group (40% and 6.7%, respectively). In comparison, the heterozygous genotype AG was lower in the patients (46.7%) than in the control group (53.3%). However, the association between the polymorphism and acute lymphoblastic leukemia risk was not statistically significant (OR: 1.179, 95% CI 0.7459-1.865, P=0.445). Conclusions. This study concluded that MTRR A66G polymorphism was not associated with the risk of acute lymphoblastic leukemia among the Sudanese population.

Preeclampsia, antihypertensive medication use in pregnancy and risk of childhood cancer in offspring

PurposePreeclampsia is a serious pregnancy complication that presents a significant risk to both the mother and the fetus. Preeclampsia and medications associated with its treatment are potentially linked to increased childhood cancer risk. Therefore, we examined the association between preeclampsia, antihypertensive medications, and childhood cancer in offspring.MethodsCases (n = 6,420) and controls (n = 160,484) were obtained from Danish national registries. We performed conditional logistic regression analyses to estimate the association between preeclampsia and childhood cancer risk, and examined the effects of antihypertensive medication use in pregnancy in relation to childhood cancer risk in the offspring with adjustment for relevant covariates.ResultsWe observed an increased risk of acute lymphoblastic leukemia (ALL) among those whose mothers had preeclampsia (OR = 1.36, 95% CI 1.03, 1.79), especially for severe preeclampsia (OR = 2.36, 95% CI 1.37, 4.08). We also estimated an increased cancer risk in children born to mothers who were prescribed diuretics during pregnancy [OR = 2.09, 95% confidence interval (CI) 1.39, 3.14]. Intake of other antihypertensive medications was not associated with childhood cancer (OR = 0.78, 95% CI 0.50, 1.23). Among women who did not take diuretics in pregnancy, preeclampsia was associated with neuroblastoma (OR = 2.22, 95% CI 1.08, 4.55).ConclusionOur findings suggested an increased risk for certain types of cancer in the offspring of mothers with preeclampsia and an increased risk of cancer with diuretic intake during pregnancy.

ARID5B regulates fatty acid metabolism and proliferation at the Pre-B cell stage during B cell development.

During B cell development in bone marrow, large precursor B cells (large Pre-B cells) proliferate rapidly, exit the cell cycle, and differentiate into non-proliferative (quiescent) small Pre-B cells. Dysregulation of this process may result in the failure to produce functional B cells and pose a risk of leukemic transformation. Here, we report that AT rich interacting domain 5B (ARID5B), a B cell acute lymphoblastic leukemia (B-ALL) risk gene, regulates B cell development at the Pre-B stage. In both mice and humans, we observed a significant upregulation of ARID5B expression that initiates at the Pre-B stage and is maintained throughout later stages of B cell development. In mice, deletion of Arid5b in vivo and ex vivo exhibited a significant reduction in the proportion of immature B cells but an increase in large and small Pre-B cells. Arid5b inhibition ex vivo also led to an increase in proliferation of both Pre-B cell populations. Metabolic studies in mouse and human bone marrow revealed that fatty acid uptake peaked in proliferative B cells then decreased during non-proliferative stages. We showed that Arid5b ablation enhanced fatty acid uptake and oxidation in Pre-B cells. Furthermore, decreased ARID5B expression was observed in tumor cells from B-ALL patients when compared to B cells from non-leukemic individuals. In B-ALL patients, ARID5B expression below the median was associated with decreased survival particularly in subtypes originating from Pre-B cells. Collectively, our data indicated that Arid5b regulates fatty acid metabolism and proliferation of Pre-B cells in mice, and reduced expression of ARID5B in humans is a risk factor for B cell leukemia.

Association of CDKN2A/B mutations, PD-1, and PD-L1 with the risk of acute lymphoblastic leukemia in children

PurposeCurrently, the significance of CDKN2A/B mutations in the pathogenesis and prognosis of acute lymphoblastic leukemia (ALL) is inconclusive. In this study, we analyzed the genetic and clinical features of children with CDKN2A/B mutations in ALL. In addition, we evaluated the expression and significance of programmed cell death protein 1 (PD-1) and programmed cell death ligand 1 (PD-L1) in serum and explored their role in the susceptibility of childhood ALL.MethodsWe sequenced CDKN2A/B in the peripheral blood of 120 children with ALL and 100 healthy children with physical examination. The levels of CD4+ T, CD8+ T, and NK cells were measured by flow cytometry (FCM). Furthermore, the expression of PD-1 and PD-L1 was detected by ELISA.ResultsWe found 32 cases of CDKN2A rs3088440 and 11 of CDKN2B rs2069426 in 120 ALL children. Children with ALL in the CDKN2A rs3088440 were more likely to have hepatosplenomegaly (P = 0.019) and high risk (P = 0.014) than the wild group. In contrast, CDKN2B rs2069426 was more likely to develop lymph node metastasis (P = 0.017). The level of PD-L1 in the serum of ALL children was significantly higher than that of the control group, and there was no significant difference in PD-1 (P < 0.001). Additionally, children with CDKN2A rs3088440 had reduced CD8+ T cell counts than the wild group (P = 0.039).ConclusionCDKN2A rs3088440 and CDKN2B rs2069426 may be related to the occurrence and development of ALL in Chinese children. Additionally, PD-1/PD-L1 may be involved in the immune escape process of ALL, which is expected to become a new target for the treatment of the disease.

Residential exposure to magnetic fields from high-voltage power lines and risk of childhood leukemia

BackgroundSeveral studies have suggested an excess risk of leukemia among children living close to high-voltage power lines and exposed to magnetic fields. However, not all studies have yielded consistent results, and many studies may have been susceptible to confounding and exposure misclassification. MethodsWe conducted a case-control study to investigate the risk of leukemia associated with magnetic field exposure from high-voltage power lines. Eligible participants were children aged 0–15 years residing in the Northern Italian provinces of Modena and Reggio Emilia. We included all 182 registry-identified childhood leukemia cases diagnosed in 1998–2019, and 726 age-, sex- and province-matched population controls. We assessed exposure by calculating distance from house to nearest power line and magnetic field intensity modelling at the subjects’ residence. We used conditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs), with adjustment for potential confounders (distance from nearest petrol station and fuel supply within the 1000 m-buffer, traffic-related particulate and benzene concentrations, presence of indoor transformers, percentage of urban area and arable crops). ResultsIn multivariable analyses, the OR comparing children living <100 m from high-voltage power-lines with children living ≥400 m from power-lines was 2.0 (95% CI 0.8–5.0). Results did not differ substantially by age at disease diagnosis, disease subtype, or when exposure was based on modeled magnetic field intensity, though estimates were imprecise. Spline regression analysis showed an excess risk for both overall leukemia and acute lymphoblastic leukemia among children with residential distances <100 m from power lines, with a monotonic inverse association below this cutpoint. ConclusionsIn this Italian population, close proximity to high-voltage power lines was associated with an excess risk of childhood leukemia.

Definition and Prognostic Value of Ph-like and IKZF1plus Status in Children With Down Syndrome and B-cell Precursor Acute Lymphoblastic Leukemia.

Children with Down syndrome have an augmented risk for B-cell acute lymphoblastic leukemia (DS-ALL), which is associated with lower survival than in non-DS-ALL. It is known that cytogenetic abnormalities common in childhood ALL are less frequent in DS-ALL, while other genetic aberrancies (ie, CRLF2 overexpression and IKZF1 deletions) are increased. A possible cause for the lower survival of DS-ALL that we herewith evaluated for the first time was the incidence and prognostic value of the Philadelphia-like (Ph-like) profile and the IKZF1plus pattern. These features have been associated with poor outcome in non-DS ALL and therefore introduced in current therapeutic protocols. Forty-six out of 70 DS-ALL patients treated in Italy from 2000 to 2014 displayed Ph-like signature, mostly characterized by CRLF2 (n = 33) and IKZF1 (n = 16) alterations; only 2 cases were positive for ABL-class or PAX5-fusion genes. Moreover, in an Italian and German joint cohort of 134 DS-ALL patients, we observed 18% patients positive for IKZF1plus feature. Ph-like signature and IKZF1 deletion were associated with poor outcome (cumulative incidence of relapse: 27.7 ± 6.8% versus 13 ± 7%; P = 0.04 and 35.2 ± 8.6% versus 17 ± 3.9%; P = 0.007, respectively), which further worsens when IKZF1 deletion was co-occurring with P2RY8::CRLF2, qualifying for the IKZF1plus definition (13/15 patients had an event of relapse or treatment-related death). Notably, ex vivo drug screening revealed sensitivity of IKZF1plus blasts for drugs active against Ph-like ALL such as Birinapant and histone deacetylase inhibitors. We provided data in a large setting of a rare condition (DS-ALL) supporting that these patients, not associated with other high-risk features, need tailored therapeutic strategies.

Killer immunoglobulin-like receptors and HLA C1/C2 genes diversities and susceptibility to acute myeloid leukemia in Saudi Arabian patients

ObjectiveNatural Killer cells activation depends on the interaction with killer cell immunoglobin-like receptors (KIRs), which bind the peptide-binding region of several class-I Human Leukocyte Antigens (HLA class-I). In addition, KIR and HLA loci are highly polymorphic and display significant variation between individuals. MethodsWe attempted to investigate the association of 16 KIR complexes and the HLA-C1 and C2 ligands to the genetic predisposition and development of Acute Lymphoblastic leukemia (AML) in Saudi Arabian patients. We genotyped 16 KIR genes for 100 patients with Acute Lymphoblastic leukemia and 114 healthy controls, and all samples were considered for evaluating combined KIR-HLA C1/C2 associations. ResultsKIR genotype frequency differed significantly between AML patients and healthy controls. KIR2DL1, KIR2DL5, and KIR2DS2 increased significantly in patients than in controls. The 2DL5 gene contributed to the highest risk of AML (OR = 2.9906, p < 0.00059), followed by 2DS2 (OR = 1.8068; p < 0.039). However, the incidence of KIR 2DL3, KIR2DS4, and KIR2DL2 was significantly elevated in healthy controls compared to myeloid leukemia patients. The distributions of HLA-C1 and C2 ligands were not significantly different between patients and controls. Analyses of different combinations of KIR/HLA class I ligand profile show that the frequency of KIR2DL3 + in the presence of the allotype C1 was decreased among AML patients compared to controls. Similarly, KIR2DL3 and KIR2DL2/2DL3, when combined with their respective ligands, HLA-C2/C1, were significantly less prevalent in AML patients when compared to controls. ConclusionOur data suggested a potential predictive role for a specific KIR genotype, and HLA-I encoding genes to AML risk.

L-asparaginase activity and anti-L-asparaginase antibody as biomarkers in estimating PEG-asp-related anaphylaxis risk in childhood acute lymphoblastic leukemia patients.

L-Asparaginase (L-asp), the unconjugated form of polyethylene glycol-conjugated L-asparaginase (PEG-asp), regulates T cell stimulation, antibody production, and lysosomal protease activity to mediate PEG-asp-related anaphylaxis. This study aimed to investigate the relation of L-asp activity and anti-L-asp antibody with anaphylaxis risk and non-anaphylaxis adverse reaction risk in childhood acute lymphoblastic leukemia (ALL) patients who underwent PEG-asp contained therapy. In total, 170 childhood ALL patients underwent PEG-asp-contained treatment and their L-asp activity and anti-L-asp antibody were detected on the 7th day after treatment initiation. There were 27 (15.9%) patients who had PEG-asp-related adverse reaction: 17 (10.0%) patients experienced PEG-asp-related anaphylaxis and 14 (8.2%) patients experienced PEG- asp-related non-anaphylaxis adverse reaction. Moreover, L-asp activity was negatively related to anti-L-asp antibody in childhood ALL patients (P<0.001). Elevated L-asp activity was associated with the absence of PEG-asp-related anaphylaxis (P<0.001), PEG-asp-related non-anaphylaxis adverse reaction (P=0.004), and PEG-asp-related adverse reaction (P<0.001). However, the anti- L-asp antibody displayed opposite trend similar to L-asp activity. Receiver operating characteristic (ROC) curve analyses exhibited L-asp activity and anti-L-asp antibody exhibited superior predictive values in estimating PEG-asp-related anaphylaxis risk with area under curve (AUC) of 0.955 and 0.905, respectively compared to PEG-asp-related non-anaphylaxis adverse reaction risk with AUC of 0.730 and 0.675, respectively. Besides, patients with de novo disease, higher risk stratification, and allergic history showed trends linked with PEG-asp-related anaphylaxis risk. The monitoring of L-asp activity and anti-L-asp antibody maybe useful for early estimation and prevention of PEG-asp-related anaphylaxis in childhood ALL management.

Role of Maternal Diet in the Risk of Childhood Acute Leukemia: A Systematic Review and Meta-Analysis.

Many studies have investigated the etiology of acute leukemia, one of the most common types of cancer in children; however, there is a lack of clarity regarding preventable risk factors. This systematic review and meta-analysis aimed to summarize the current evidence regarding the role of maternal dietary factors in the development of childhood leukemia. All epidemiological studies published until July 2022 that evaluated maternal dietary risk factors for childhood acute leukemia were identified in two electronic databases (PubMed and Web of Science) without limits of publication year or language. A total of 38 studies (1 prospective cohort study, 34 case-control studies and 3 studies with pooled analysis) were included. The published risk estimates were combined into a meta-analysis, using the Generic Inverse Variance method. The maternal consumption of fruits (two or more daily servings vs. less) was inversely associated with acute lymphoblastic leukemia (odds ratio = 0.71; 95% CI, 0.59-0.86), whereas maternal coffee intake (higher than two cups per day vs. no consumption) was associated with an increased risk of acute lymphoblastic leukemia (odds ratio = 1.45; 95% CI, 1.12-1.89). Despite these findings, more high-quality research from cohort studies and the identification of causal factors are needed to develop evidence-based and cost-effective prevention strategies applicable at the population level. Review Registration: PROSPERO registration no. CRD42019128937.

Genomic landscape of Down syndrome–associated acute lymphoblastic leukemia

AbstractTrisomy 21, the genetic cause of Down syndrome (DS), is the most common congenital chromosomal anomaly. It is associated with a 20-fold increased risk of acute lymphoblastic leukemia (ALL) during childhood and results in distinctive leukemia biology. To comprehensively define the genomic landscape of DS-ALL, we performed whole-genome sequencing and whole-transcriptome sequencing (RNA-Seq) on 295 cases. Our integrated genomic analyses identified 15 molecular subtypes of DS-ALL, with marked enrichment of CRLF2-r, IGH::IGF2BP1, and C/EBP altered (C/EBPalt) subtypes compared with 2257 non–DS-ALL cases. We observed abnormal activation of the CEBPD, CEBPA, and CEBPE genes in 10.5% of DS-ALL cases via a variety of genomic mechanisms, including chromosomal rearrangements and noncoding mutations leading to enhancer hijacking. A total of 42.3% of C/EBP-activated DS-ALL also have concomitant FLT3 point mutations or insertions/deletions, compared with 4.1% in other subtypes. CEBPD overexpression enhanced the differentiation of mouse hematopoietic progenitor cells into pro-B cells in vitro, particularly in a DS genetic background. Notably, recombination-activating gene–mediated somatic genomic abnormalities were common in DS-ALL, accounting for a median of 27.5% of structural alterations, compared with 7.7% in non–DS-ALL. Unsupervised hierarchical clustering analyses of CRLF2-rearranged DS-ALL identified substantial heterogeneity within this group, with the BCR::ABL1-like subset linked to an inferior event-free survival, even after adjusting for known clinical risk factors. These results provide important insights into the biology of DS-ALL and point to opportunities for targeted therapy and treatment individualization.

Maternal and Paternal Household Pesticide Exposure During Pregnancy and Risk of Childhood Acute Lymphoblastic Leukemia.

The aim of this study was to investigate whether risk estimates for childhood acute lymphoblastic leukemia change when restricting model comparison groups to "nonpesticide exposure" (NPE10) households. Cases ( n = 1810) 15 years or younger were identified through Children's Cancer Group institutions between 1989 and 1993 and age-/sex-matched to controls ( n = 1951). Household pesticide use during pregnancy/month prior was collected via telephone. NPE10 comparison group reporting no parental exposure to 10 pesticide classes was identified. Adjusted odds ratios increased from 15% to 49% when limiting the comparison to NPE10. Maternal termite insecticide exposure was associated with greatest risk (adjusted odds ratio, 4.21; 95% confidence interval, 2.00-8.88). There was minimal evidence of interaction by child sex or occupational pesticide exposure, and no monotonic dose-response pattern with frequency of use (times per year). Elevated risks are consistent with published pooled-/meta-analyses and DNA damage. The consistency and magnitude of these associations warrant product labeling, exposure reduction interventions, or both.

Abstract 4516: Rare high-penetrance and common low-penetrance variants associated with risk of pediatric acute lymphoblastic leukemia

Abstract Leveraging existing genetic data for survivors of pediatric acute lymphoblastic leukemia (ALL) from the St. Jude Lifetime Cohort Study (SJLIFE) and Childhood Cancer Survivor Study (CCSS; the CCSS original cohort data was downloaded from dbGaP, phs001327.v2), genetic variants across the full allelic spectrum were analyzed for their associations with ALL risk. A total of 2,695 ALL cases with whole-genome or whole-exome sequencing were available for rare variant analyses. Pathogenic/likely pathogenic (P/LP) variants in 60 genes associated with autosomal dominant cancer predisposition syndromes were characterized and classified with “PeCanPIE” - the Pediatric Cancer Variant Pathogenicity Information Exchange, a web- and cloud-based platform. We subsequently carried out an enrichment analysis of P/LP variants by comparing ALL survivors with a general population from the GnomAD database and found seven significant genes after adjustment for multiple testing (P&amp;lt; 8.3 × 10-4, i.e., 0.05/60) including: BRCA1 (odds ratio [OR]=4.06; 95% CI, 2.00-7.59; P=1.21 × 10-4), BRCA2 (OR=3.48; 95% CI, 1.82-6.15; P=1.50 × 10-4), CDKN2A (OR=22.30; 95% CI, 5.13-96.68; P=3.07 × 10-5), PALB2 (OR=5.12; 95% CI, 2.39-10.00, P=3.77 × 10-5), PAX5 (OR=44.58; 95% CI, 6.49-490.68; P=4.77 × 10-5), PTPN1 (OR=66.85; 95% CI, 11.96-670.57, P=1.63 × 10-7), and TP53 (OR=17.86; 95% CI, 6.12-50.36; P=3.43 × 10-7). Two of these genes have also been previously linked with pediatric ALL (CDKN2A and TP53). Repeating these analyses with 309 newly diagnosed patients from the Pediatric Cancer Genome Project, we observed similar results for five of these genes (BRCA1, BRCA2, CDKN2A, PALB2, and TP53). To further investigate common germline variants associated with ALL risk, we performed a genome-wide association analysis using 2,777 ALL cases and 6,255 controls (5,881 other pediatric cancer cases and 374 non-cancer controls) with whole-genome sequencing or imputed SNP-array data. In addition to replicating known associations at ARID5B, IKZF1, CDKN2A, BMI1, PIP4K2A, CCDC26 and CEPBE, we identified a novel variant (rs112425636, chr17:82324152:G:A; OR=1.65; 95% CI, 1.42-1.93; P=2.48 × 10-10) mapped to the intronic region of SECTM1 gene. Based on RNA sequencing data for 164 pediatric hematological cancer samples, we found that the expression of SECTM1 gene was significantly higher among patients with GG genotype than patients with AA or AG genotypes for rs112425636 (FPKM=1.34 vs. 0.71, P&amp;lt;0.01). Among the subset of 32 B-ALL samples, the magnitude of difference was larger (FPKM=1.90 vs. 0.70, P=0.017). In summary, we found statistical evidence for several cancer predisposition genes harboring rare high-penetrance variants and a novel common low-penetrance variant associated with risk of pediatric ALL. Our novel findings add new knowledge to the full allelic spectrum of genetic architecture of pediatric ALL susceptibility. Citation Format: Zhaoming Wang, Cheng Chen, Na Qin, Nan Song, Hui Wang, Gregory T. Armstrong, Kirsten K. Ness, Melissa M. Hudson, Jinghui Zhang, Leslie L. Robison, Cindy Im. Rare high-penetrance and common low-penetrance variants associated with risk of pediatric acute lymphoblastic leukemia. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 4516.

Abstract 5221: Identifying acute lymphoblastic leukemia risk loci in latino children via admixture mapping

Abstract Acute lymphoblastic leukemia (ALL) is the most common childhood cancer and accounts for 25% of malignancies before the age of 20. Despite decades of inquiry into ALL causes, Latino children have up to 1.4 times the rate of ALL compared to their non-Latino White counterparts. The etiology of ALL is complex and this disparity in risk has not been fully explained by social factors alone, suggesting the role of genetic variants and ancestry. Previous literature has implicated variants in IKZF1, ARID5B, GATA3, PIP42KA, and ERG with greater risk allele frequencies or population-specific risk effects in Latinos. Indigenous American ancestry has also been previously associated with ALL risk, relapse, and poor prognosis. To elucidate the genetic and ancestral etiology of ALL, we conducted the first admixture mapping analysis of 1930 childhood ALL cases and 8520 controls of self-identified Latino ethnicity. We uncovered putative admixture associations on chromosomes 2, 7, 10, and 15 (P = 3.21 x 10−5 to 7.32 x 10−8 among top associations across the four loci). Two of the four loci, on chromosomes 2 and 15, were previously not known to be associated with ALL. Following imputation with the TOPMed reference panel, we fine-mapped each putative locus by testing the ALL risk association of each variant with a minor allele frequency greater than 1%. The top associated variants at each locus showed substantial frequency differences between ancestries from the gnomAD or 1000Genomes project. For example, the top associated variant on chromosome 2 has a risk allele frequency of 43% in Native Americans from the Human Genome Diversity Panel, but a frequency of 0.10% in Non-Finnish Europeans in gnomAD. Including these variants in the admixture mapping model greatly attenuated the admixture signals at each locus, suggesting that they are likely the causal SNPs or close proxies of the causal SNPs. The top associated variants from three out of the four loci passed regional multiple testing burden and mapped to genes MGAT5, IKFZ1 and ARID5B on chromosomes 2, 7 and 10, respectively. The top two SNPs on chromosome 15, which narrowly missed the regional threshold, mapped to genes RAB11A and MEGF11. We are pursuing replication of putative novel loci on chromosomes 2 and 15 in additional Latino GWAS datasets. Our results suggest that ALL risk variants with higher frequencies in individuals with Native American ancestry may contribute to the observed increased risk of ALL in Latino children. Investigation of such risk loci can contribute to the identification of new target genes for ALL prediction and therapeutics and new insights for precision medicine, which will reduce the burden of ALL. Citation Format: Jalen Langie, Soyoung Jeon, Xiaomei Ma, Catherine Metayer, Adam J. de Smith, Joseph L. Wiemels, Charleston W. Chiang. Identifying acute lymphoblastic leukemia risk loci in latino children via admixture mapping. [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 5221.

New association between splicing factor-coding gene polymorphisms and the risk of acute lymphoblastic leukemia in southern Chinese children: A five-center case-control study.

The role of splicing factor-coding gene polymorphisms in pediatric acute lymphoblastic leukemia (ALL) susceptibility is still unclear. A case-control designed model was used to estimate the overall risk of pediatric ALL and five single nucleotide polymorphisms (SNPs) of splicing factor-coding genes in 808 cases and 1,340 controls, which were genotyped using a TaqMan assay. Stratified analysis was performed to explore the association of rs2233911 genotype and pediatric ALL susceptibility. The influence of splicing factor arginine/serine-rich 1 (SFRS1) polymorphisms on the sensitivity to different chemotherapeutic regimens based on minimal residual disease (MRD) levels was analyzed. The haplotype analysis was adopted to evaluate the association between inferred haplotypes of the splicing factor-coding genes and pediatric ALL risk. Among the five analyzed SNPs, SFRS1 rs2233911 AG/GG exhibited a significant association with increased pediatric ALL risk. The stratified analysis further identified the harmful effect of SFRS1 rs2233911 AG/GG in specific subgroups. Moreover, rs2233911 AG/GG had a protective effect on MRD in marrow of ≥0.01% 12 weeks of Chinese Children Cancer Group chemotherapeutics, but provided a harmful effect on MRD in the marrow of ≥0.01% at days 15-19 of the South China Children Leukemia Group chemotherapeutics. Haplotype analysis of these five SNPs yielded haplotypes ACGCC and ACGTC significantly correlating with increased pediatric ALL susceptibility. On the contrary, haplotypes GCATG and GTACC were linked with remarkably decreased pediatric ALL risk. SFRS1 gene polymorphism was associated with increased pediatric ALL risk and indicated that rs2233911 AG/GG might be a potential biomarker for choosing chemotherapeutics.

One-Carbon (Folate) Metabolism Pathway at Birth and Risk of Childhood Acute Lymphoblastic Leukemia: A Biomarker Study in Newborns.

Leukemia is the most common cancer in children in industrialized countries, and its initiation often occurs prenatally. Folic acid is a key vitamin in the production and modification of DNA, and prenatal folic acid intake is known to reduce the risk of childhood leukemia. We characterized the one-carbon (folate) metabolism nutrients that may influence risk of childhood acute lymphoblastic leukemia (ALL) among 122 cases diagnosed at age 0-14 years during 1988-2011 and 122 controls matched on sex, age, and race/ethnicity. Using hydrophilic interaction chromatography (HILIC) applied to neonatal dried blood spots, we evaluated 11 folate pathway metabolites, overall and by sex, race/ethnicity, and age at diagnosis. To conduct the prediction analyses, the 244 samples were separated into learning (75%) and test (25%) sets, maintaining the matched pairings. The learning set was used to train classification methods which were evaluated on the test set. High classification error rates indicate that the folate pathway metabolites measured have little predictive capacity for pediatric ALL. In conclusion, the one-carbon metabolism nutrients measured at birth were unable to predict subsequent leukemia in children. These negative findings are reflective of the last weeks of pregnancy and our study does not address the impact of these nutrients at the time of conception or during the first trimester of pregnancy that are critical for the embryo's DNA methylation programming.

Glyphosate in house dust and risk of childhood acute lymphoblastic leukemia in California

BackgroundResidential use of pesticides has been associated with increased risk of childhood acute lymphoblastic leukemia (ALL). We evaluated determinants of glyphosate concentrations in house dust and estimated ALL risk in the California Childhood Leukemia Study (CCLS). MethodsThe CCLS is a population-based case-control study of childhood leukemia in California. Among those < 8-years (no move since diagnosis/reference date), we collected dust (2001–2007) from the room where the child spent the most time while awake and measured > 40 pesticides. Three-to-eight years later, we collected a second sample from non-movers. We used Ultra-Performance Liquid Chromatography Tandem Mass Spectrometry to measure glyphosate (µg/g dust) for 181 ALL cases and 225 controls and for 45 households with a second dust sample. We used multivariable Tobit regression to evaluate determinants of glyphosate concentrations. Odds ratios (ORs) and 95 % confidence intervals (CI) were calculated for ALL and quartiles of the concentration (first samples) using unconditional logistic regression. We computed the within- and between-home variance and intraclass correlation coefficient (ICC). ResultsGlyphosate was frequently detected (cases: 98 %; controls: 99 %). Higher concentrations were associated with occupational pesticide exposure, nearby agricultural use, treatment for lawn weeds and bees/wasps, and sampling season. Increasing concentrations were not associated with ALL risk (adjusted ORQ4vsQ1 = 0.8, CI: 0.4–1.4). We observed similar null associations for boys and girls, Hispanics and non-Hispanic whites, and among those who resided in their home since birth (76 cases/117 controls) or age two (130 cases/176 controls). The ICC was 0.32 indicating high within-home temporal variability during the years of our study. ConclusionsWe observed higher concentrations in homes associated with expected predictors of exposure but no association with childhood ALL risk. Due to continuing use, potential exposure to young children is high. It will be important to evaluate risk in future studies with multiple dust measurements or biomarkers of exposure.