Epigenome-wide analysis across the development span of pediatric acute lymphoblastic leukemia: backtracking to birth.

Background: Cancer is the leading cause of disease-related mortality in children. Causes of leukemia, the most common form, are largely unknown. Growing evidence points to an origin in-utero, when global redistribution of DNA methylation occurs driving tissue differentiation.

Backtracking childhood leukaemia to birth: A battle of addition.

Paediatric leukaemia has a long tail of driver mutations each of which must be 'backtracked' to samples taken at birth to identify the prenatal origin of a subtype. Presently, Bardini et al. describe the first successful backtracking of an NUTM1 rearrangement, which sheds light on the biology of this particular alteration.

Genetic variation near GRB10 associated with bone growth and osteosarcoma risk in canine and human populations.

Background: Canine and human osteosarcoma are similar in clinical presentation and tumor genomics. Giant breed dogs experience elevated osteosarcoma incidence, and taller stature remains a consistent risk factor for human osteosarcoma. Whether evolutionarily conserved genes contribute to both human and canine osteosarcoma predisposition merits evaluation.

A noncoding regulatory variant in IKZF1 increases acute lymphoblastic leukemia risk in Hispanic/Latino children.

Hispanic/Latino children have the highest risk of acute lymphoblastic leukemia (ALL) in the US compared to other racial/ethnic groups, yet the basis of this remains incompletely understood. Through genetic fine-mapping analyses, we identified a new independent childhood ALL risk signal near IKZF1 in self-reported Hispanic/Latino individuals, but not in non-Hispanic White individuals, with an effect size of ∼1.44 (95% confidence interval = 1.

In Utero Origins of Acute Leukemia in Children.

Acute leukemias, mainly consisting of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML), comprise a major diagnostic group among hematologic cancers. Due to the early age at onset of ALL, particularly, it has long been suspected that acute leukemias of childhood may have an in utero origin. This supposition has motivated many investigations seeking direct proof of prenatal leukemogenesis, in particular, twin and "backtracking studies".

The genetic risk of acute lymphoblastic leukemia and its implications for children of Latin American origin.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children, and disproportionately affects children of Hispanic/Latino ethnicity in the United States, who have the highest incidence of disease compared with other racial/ethnic groups. Incidence of childhood ALL is similarly high in several Latin American countries, notably in Mexico, and of concern is the rising incidence of childhood ALL in some Hispanic/Latino populations that may further widen this disparity. Prior studies have implicated common germline genetic variants in the increased risk of ALL among Hispanic/Latino children.

Evaluation of the genetic basis of familial-associated early-onset hematologic cancers in an ancestral/ethnically diverse population.

Genetic predisposition to hematologic malignancies has historically been addressed utilizing patients recruited from clinical trials and pedigrees constructed at major treatment centers. Such efforts leave unexplored the genetic basis of variations in risk by race/ethnic group shown in population-based surveillance data where cancer registration, compulsory by law, delivers universal enrollment. To address this, we performed exome sequencing on DNA isolated from newborn bloodspots derived from sibling pairs with early-onset cancers across California in which at least one of the siblings developed a hematologic cancer, using unbiased recruitment from the full state population.

Epigenomic signature of major congenital heart defects in newborns with Down syndrome.

Background: Congenital heart defects (CHDs) affect approximately half of individuals with Down syndrome (DS), but the molecular reasons for incomplete penetrance are unknown. Previous studies have largely focused on identifying genetic risk factors associated with CHDs in individuals with DS, but comprehensive studies of the contribution of epigenetic marks are lacking. We aimed to identify and characterize DNA methylation differences from newborn dried blood spots (NDBS) of DS individuals with major CHDs compared to DS individuals without CHDs.

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

Background: 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.

Evaluating genomic polygenic risk scores for childhood acute lymphoblastic leukemia in Latinos.

The utility of polygenic risk score (PRS) models has not been comprehensively evaluated for childhood acute lymphoblastic leukemia (ALL), the most common type of cancer in children. Previous PRS models for ALL were based on significant loci observed in genome-wide association studies (GWASs), even though genomic PRS models have been shown to improve prediction performance for a number of complex diseases. In the United States, Latino (LAT) children have the highest risk of ALL, but the transferability of PRS models to LAT children has not been studied.

Evaluating Genomic Polygenic Risk Scores for Childhood Acute Lymphoblastic Leukemia in Latinos.

The utility of polygenic risk score (PRS) models has not been comprehensively evaluated for childhood acute lymphoblastic leukemia (ALL), the most common type of cancer in children. Previous PRS models for ALL were based on significant loci observed in genome-wide association studies (GWAS), even though genomic PRS models have been shown to improve prediction performance for a number of complex diseases. In the United States, Latino (LAT) children have the highest risk of ALL, but the transferability of PRS models to LAT children has not been studied.

Epigenomic signature of major congenital heart defects in newborns with Down syndrome.

Background: Congenital heart defects affect approximately half of individuals with Down syndrome but the molecular reasons for incomplete penetrance are unknown. Previous studies have largely focused on identifying genetic risk factors associated with CHDs in individuals with DS, but comprehensive studies of the contribution of epigenetic marks are lacking. We aimed to identify and characterize DNA methylation differences from newborn dried blood spots of DS individuals with major CHDs compared to DS individuals without CHDs.

Multi-ancestry genome-wide association study of 4069 children with glioma identifies 9p21.3 risk locus.

Background: Although recent sequencing studies have revealed that 10% of childhood gliomas are caused by rare germline mutations, the role of common variants is undetermined and no genome-wide significant risk loci for pediatric central nervous system tumors have been identified to date.

Methods: Meta-analysis of 3 population-based genome-wide association studies comprising 4069 children with glioma and 8778 controls of multiple genetic ancestries. Replication was performed in a separate case-control cohort.

Incorporation of DNA methylation quantitative trait loci (mQTLs) in epigenome-wide association analysis: application to birthweight effects in neonatal whole blood.

Background: Epigenome-wide association studies (EWAS) have helped to define the associations between DNA methylation and many clinicopathologic and developmental traits. Since DNA methylation is affected by genetic variation at certain loci, EWAS associations may be potentially influenced by genetic effects. However, a formal assessment of the value of incorporating genetic variation in EWAS evaluations is lacking especially for multiethnic populations.

Meta-Analysis of DNA Methylation Datasets Shows Aberrant DNA Methylation of Thyroid Development or Function Genes in Down Syndrome.

In Down syndrome (DS), there is high occurrence of congenital hypothyroidism (CH) and subclinical hypothyroidism (SH) early in life. The etiology of CH and early SH in DS remains unclear. Previous research has shown genome-wide transcriptional and epigenetic alterations in DS.

DNA methylation at birth in monozygotic twins discordant for pediatric acute lymphoblastic leukemia.

Aberrant DNA methylation constitutes a key feature of pediatric acute lymphoblastic leukemia at diagnosis, however its role as a predisposing or early contributor to leukemia development remains unknown. Here, we evaluate DNA methylation at birth in 41 leukemia-discordant monozygotic twin pairs using the Illumina EPIC array on archived neonatal blood spots to identify epigenetic variation associated with development of pediatric acute lymphoblastic leukemia, independent of genetic influence. Through conditional logistic regression we identify 240 significant probes and 10 regions associated with the discordant onset of leukemia.

Periconceptional folate intake influences DNA methylation at birth based on dietary source in an analysis of pediatric acute lymphoblastic leukemia cases and controls.

Background: Periconceptional folate intake is associated with the establishment of DNA methylation in offspring; however, variations in this relation by food sources compared with folic acid supplements are not described. Also, maternal folate intake is associated with decreased risk of pediatric acute lymphoblastic leukemia (ALL), but the mechanism is not known.

Objectives: We evaluated the relation between periconceptional folate intake by source and DNA methylation at birth in a cohort of pediatric ALL cases and controls in an epigenome-wide association study.

Associations between early-life and in utero infections and cytomegalovirus-positive acute lymphoblastic leukemia in children.

Childhood infections and cytomegalovirus (CMV) are associated with pediatric acute lymphoblastic leukemia (ALL). CMV dysregulates the host immune system and alters the immune response to subsequent antigenic exposures. We suspect that this immune dysregulation contributes to increased numbers of symptomatic infections in childhood allowing for expansion of pre-leukemic clones.

Localized variation in ancestral admixture identifies pilocytic astrocytoma risk loci among Latino children.

Background: Pilocytic astrocytoma (PA) is the most common pediatric brain tumor. PA has at least a 50% higher incidence in populations of European ancestry compared to other ancestral groups, which may be due in part to genetic differences.

Methods: We first compared the global proportions of European, African, and Amerindian ancestries in 301 PA cases and 1185 controls of self-identified Latino ethnicity from the California Biobank.

Clonal hematopoiesis and risk of prostate cancer in large samples of European ancestry men.

Little is known regarding the potential relationship between clonal hematopoiesis (CH) of indeterminate potential (CHIP), which is the expansion of hematopoietic stem cells with somatic mutations, and risk of prostate cancer, the fifth leading cause of cancer death of men worldwide. We evaluated the association of age-related CHIP with overall and aggressive prostate cancer risk in two large whole-exome sequencing studies of 75 047 European ancestry men, including 7663 prostate cancer cases, 2770 of which had aggressive disease, and 3266 men carrying CHIP variants. We found that CHIP, defined by over 50 CHIP genes individually and in aggregate, was not significantly associated with overall (aggregate HR = 0.