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Article ; Online: Does Cytomegalovirus Play a Role in Pediatric Lymphoblastic Leukemogenesis?

Wiemels, Joseph L

JAMA network open

2023 Volume 6, Issue 1, Page(s) e2250226

MeSH term(s)	Child ; Humans ; Cytomegalovirus ; Precursor Cell Lymphoblastic Leukemia-Lymphoma
Language	English
Publishing date	2023-01-03
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Comment
ISSN	2574-3805
ISSN (online)	2574-3805
DOI	10.1001/jamanetworkopen.2022.50226
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Article ; Online: Infections and Acute Lymphoblastic Leukemia: Is the Sum Worth More than the Parts? Evidence from Birth Characteristics.

Wiemels, Joseph L / Gallant, Rachel E

Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology

2023 Volume 32, Issue 3, Page(s) 292–294

Abstract: The etiology of childhood acute lymphoblastic leukemia (ALL) has long been studied piecemeal with investigations leading to a lengthy list of putative risk factors including several with immune modulatory effects. The ubiquity of many of these factors (e. ...

Abstract	The etiology of childhood acute lymphoblastic leukemia (ALL) has long been studied piecemeal with investigations leading to a lengthy list of putative risk factors including several with immune modulatory effects. The ubiquity of many of these factors (e.g., daycare attendance, low parity, breastfeeding, normal vaccinations) belies the rarity of ALL as an outcome. In this commentary, Pombo-de-Oliveira and colleagues show that a key feature may be the combination of particular risk factors, as the birth characteristics "cesarean section" and "birth order" when combined interact to impart higher risk of ALL than would be suggested by the additive risk of both factors. This statistical interaction would be predicted by the "delayed infection hypothesis" wherein infant immune isolation promotes developmental vulnerability to ALL upon infection exposure later in childhood. Pombo-de-Oliveira and colleagues show further that lack of breastfeeding, a postnatal factor leading to further immune isolation, induces additional risk. In sum, the data reveal a combination of factors that together could impart a healthy "trained" immune system allowing for moderated responses to later exposures with microbial and viral antigens. Such priming of the immune system avoids maladaptive immunologic consequences of delayed antigenic stimulation leading to ALL and other diseases. Further research utilizing biomarkers of specific exposures (in addition to the proxy measures used here) will be helpful to realize the full potential for immune modification for ALL prevention. See related article by Pombo-de-Oliveira et al., p. 371.
MeSH term(s)	Female ; Pregnancy ; Infant ; Humans ; Birth Order ; Cesarean Section ; Risk Factors ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; Antigens, Viral
Chemical Substances	Antigens, Viral
Language	English
Publishing date	2023-03-16
Publishing country	United States
Document type	Editorial ; Research Support, N.I.H., Extramural ; Comment
ZDB-ID	1153420-5
ISSN	1538-7755 ; 1055-9965
ISSN (online)	1538-7755
ISSN	1055-9965
DOI	10.1158/1055-9965.EPI-22-1257
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Zs.A 3693: Show issues

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Article ; Online: Mendelian randomization study of birthweight, gestational age, and risk of childhood acute lymphoblastic leukemia.

Rogne, Tormod / DeWan, Andrew Thomas / Metayer, Catherine / Wiemels, Joseph L / Ma, Xiaomei

American journal of obstetrics & gynecology MFM

2023 Volume 5, Issue 9, Page(s) 101058

MeSH term(s)	Humans ; Birth Weight ; Gestational Age ; Mendelian Randomization Analysis ; Risk Factors ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/diagnosis ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/epidemiology ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/etiology
Language	English
Publishing date	2023-06-16
Publishing country	United States
Document type	Letter
ISSN	2589-9333
ISSN (online)	2589-9333
DOI	10.1016/j.ajogmf.2023.101058
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Article ; Online: Impact of pinworm infection on the development of murine B-cell leukemia/lymphoma in the presence and absence of

Fitch, Briana A / Situ, Jamilla / Wiemels, Joseph L / Kogan, Scott C / Zhou, Mi

Haematologica

2023 Volume 108, Issue 12, Page(s) 3480–3484

MeSH term(s)	Humans ; Mice ; Animals ; Core Binding Factor Alpha 2 Subunit/genetics ; Enterobiasis ; Precursor Cell Lymphoblastic Leukemia-Lymphoma ; Precursor B-Cell Lymphoblastic Leukemia-Lymphoma/genetics ; Leukemia, Lymphocytic, Chronic, B-Cell ; Lymphoma ; Oncogene Proteins, Fusion/genetics
Chemical Substances	Core Binding Factor Alpha 2 Subunit ; Oncogene Proteins, Fusion ; RUNX1 protein, human
Language	English
Publishing date	2023-12-01
Publishing country	Italy
Document type	Journal Article
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2022.282591
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Article ; Online: Evaluation of the genetic basis of familial-associated early-onset hematologic cancers in an ancestral/ethnically diverse population.

Feng, Qianxi / Xu, Keren / Shah, Mancy / Li, Shaobo / Leavitt, Andrew D / Godley, Lucy A / De Smith, Adam J / Wiemels, Joseph L

Haematologica

2024

Abstract: 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 ... ...

Abstract	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. We identified pathogenic/likely pathogenic (P/LP) variants among 1172 selected cancer genes that were private or present at low allele frequencies in reference populations. Within 64 subjects from 32 families, we found 9 LP variants shared between siblings, and an additional 7 such variants in singleton children (not shared with their sibling). In eight of the shared cases, the ancestral origin of the local haplotype that carries P/LP variants matched the dominant global ancestry of study participant families. This was the case for Latino sibling pairs on FLG and CBLB, non-Latino White sibling pairs in TP53 and NOD2, and a shared GATA2 variant for a non-Latino Black sibling pair. A new inherited mutation in HABP2 was identified in a sibling pair, one with diffuse large B-cell lymphoma and the other with neuroblastoma. Overall, the profile of P/LP germline variants across ancestral/ethnic groups suggests that rare alleles contributing to hematologic diseases originate within their race/ethnic origin parental populations, demonstrating the value of this discovery process in diverse, population-based registries.
Language	English
Publishing date	2024-01-11
Publishing country	Italy
Document type	Journal Article
ZDB-ID	2333-4
ISSN	1592-8721 ; 0017-6567 ; 0390-6078
ISSN (online)	1592-8721
ISSN	0017-6567 ; 0390-6078
DOI	10.3324/haematol.2023.284224
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Article ; Online: Backtracking to the future: unraveling the origins of childhood leukemia.

de Smith, Adam J / Wiemels, Joseph L / Mead, Adam J / Roberts, Irene / Roy, Anindita / Spector, Logan G

Leukemia

2023 Volume 38, Issue 2, Page(s) 416–419

MeSH term(s)	Humans ; Leukemia/genetics ; Child
Language	English
Publishing date	2023-12-20
Publishing country	England
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	807030-1
ISSN	1476-5551 ; 0887-6924
ISSN (online)	1476-5551
ISSN	0887-6924
DOI	10.1038/s41375-023-02111-8
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Zs.A 2295: Show issues

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Article ; Online: Perspectives on the causes of childhood leukemia.

Wiemels, Joseph

Chemico-biological interactions

2012 Volume 196, Issue 3, Page(s) 59–67

Abstract: Acute leukemia is the most common cancer in children but the causes of the disease in the majority of cases are not known. About 80% are precursor-B cell in origin (CD19+, CD10+), and this immunophenotype has increased in incidence over the past several ... ...

Abstract	Acute leukemia is the most common cancer in children but the causes of the disease in the majority of cases are not known. About 80% are precursor-B cell in origin (CD19+, CD10+), and this immunophenotype has increased in incidence over the past several decades in the Western world. Part of this increase may be due to the introduction of new chemical exposures into the child's environment including parental smoking, pesticides, traffic fumes, paint and household chemicals. However, much of the increase in leukemia rates is likely linked to altered patterns of infection during early childhood development, mirroring causal pathways responsible for a similarly increased incidence of other childhood-diagnosed immune-related illnesses including allergy, asthma, and type 1 diabetes. Factors linked to childhood leukemia that are likely surrogates for immune stimulation include exposure to childcare settings, parity status and birth order, vaccination history, and population mixing. In case-control studies, acute lymphoblastic leukemia (ALL) is consistently inversely associated with greater exposure to infections, via daycare and later birth order. New evidence suggests also that children who contract leukemia may harbor a congenital defect in immune responder status, as indicated by lower levels of the immunosuppressive cytokine IL-10 at birth in children who grow up to contract leukemia, as well as higher need for clinical care for infections within the first year of life despite having lower levels of exposure to infections. One manifestation of this phenomenon may be leukemia clusters which tend to appear as a leukemia "outbreak" among populations with low herd immunity to a new infection. Critical answers to the etiology of childhood leukemia will require incorporating new tools into traditional epidemiologic approaches - including the classification of leukemia at a molecular scale, better exposure assessments at all points in a child's life, a comprehensive understanding of genetic risk factors, and an appraisal of the interplay between infectious exposures and the status of immune response in individuals.
MeSH term(s)	Adolescent ; Age Factors ; Child ; Child, Preschool ; Genetic Predisposition to Disease ; Humans ; Leukemia/chemically induced ; Leukemia/etiology ; Leukemia/genetics ; Leukemia/microbiology ; Phenotype
Language	English
Publishing date	2012-02-02
Publishing country	Ireland
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't ; Research Support, U.S. Gov't, Non-P.H.S. ; Review
ZDB-ID	218799-1
ISSN	1872-7786 ; 0009-2797
ISSN (online)	1872-7786
ISSN	0009-2797
DOI	10.1016/j.cbi.2012.01.007
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Zs.A 686: Show issues

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

Li, Shaobo / Mancuso, Nicholas / Metayer, Catherine / Ma, Xiaomei / de Smith, Adam J / Wiemels, Joseph L

Clinical epigenetics

2022 Volume 14, Issue 1, Page(s) 158

Abstract: 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 ... ...

Abstract	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. Methods: Using single nucleotide polymorphism (SNP) from Illumina Omni Express or Affymetrix PMDA arrays and DNA methylation data from the Illumina 450 K or EPIC array from 1638 newborns of diverse genetic ancestries, we generated DNA methylation quantitative trait loci (mQTL) databases for both array types. We then investigated associations between neonatal DNA methylation and birthweight (incorporating gestational age) using EWAS modeling, and reported how EWAS results were influenced by controlling for mQTLs. Results: For CpGs on the 450 K array, an average of 15.4% CpGs were assigned as mQTLs, while on the EPIC array, 23.0% CpGs were matched to mQTLs (adjusted P value < 0.05). The CpGs associated with SNPs were enriched in the CpG island shore regions. Correcting for mQTLs in the EWAS model for birthweight helped to increase significance levels for top hits. For CpGs overlapping genes associated with birthweight-related pathways (nutrition metabolism, biosynthesis, for example), accounting for mQTLs changed their regression coefficients more dramatically (> 20%) than for other random CpGs. Conclusion: DNA methylation levels at circa 20% CpGs in the genome were affected by common SNP genotypes. EWAS model fit significantly improved when taking these genetic effects into consideration. Genetic effects were stronger on CpGs overlapping genetic elements associated with control of gene expression.
MeSH term(s)	Infant, Newborn ; Humans ; Epigenome ; Quantitative Trait Loci ; DNA Methylation ; Birth Weight/genetics ; CpG Islands
Language	English
Publishing date	2022-12-01
Publishing country	Germany
Document type	Journal Article ; Research Support, N.I.H., Extramural
ZDB-ID	2553921-8
ISSN	1868-7083 ; 1868-7075
ISSN (online)	1868-7083
ISSN	1868-7075
DOI	10.1186/s13148-022-01385-6
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Article ; Online: Evaluating genomic polygenic risk scores for childhood acute lymphoblastic leukemia in Latinos.

Jeon, Soyoung / Lo, Ying Chu / Morimoto, Libby M / Metayer, Catherine / Ma, Xiaomei / Wiemels, Joseph L / de Smith, Adam J / Chiang, Charleston W K

HGG advances

2023 Volume 4, Issue 4, Page(s) 100239

Abstract: 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 ... ...

Abstract	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. In this study, we constructed and evaluated genomic PRS models based on either non-Latino White (NLW) GWAS or a multi-ancestry GWAS. We found that the best PRS models performed similarly between held-out NLW and LAT samples (PseudoR
MeSH term(s)	Child ; Humans ; United States/epidemiology ; Genetic Risk Score ; Genetic Predisposition to Disease/genetics ; Genome-Wide Association Study ; Genomics ; Hispanic or Latino/genetics ; Precursor Cell Lymphoblastic Leukemia-Lymphoma/genetics
Language	English
Publishing date	2023-09-14
Publishing country	United States
Document type	Journal Article
ISSN	2666-2477
ISSN (online)	2666-2477
DOI	10.1016/j.xhgg.2023.100239
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Article: Evaluating Genomic Polygenic Risk Scores for Childhood Acute Lymphoblastic Leukemia in Latinos.

Jeon, Soyoung / Lo, Ying Chu / Morimoto, Libby M / Metayer, Catherine / Ma, Xiaomei / Wiemels, Joseph L / de Smith, Adam J / Chiang, Charleston W K

medRxiv : the preprint server for health sciences

2023

Abstract	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. In this study we constructed and evaluated genomic PRS models based on either non-Latino white (NLW) GWAS or a multi-ancestry GWAS. We found that the best PRS models performed similarly between held-out NLW and LAT samples (PseudoR
Language	English
Publishing date	2023-06-12
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.06.08.23291167
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